JP2524803B2 - Novel camptothecin derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an ester derivative of a higher fatty acid at the 20-hydroxyl group of camptothecin, which is useful as a medicine or an intermediate thereof, and a method for producing the same.

[Background technology]

Camptothecin is used in the camptotheca acum
Alkaloids extracted and isolated from inata) etc. have a strong nucleic acid synthesis inhibitory action, and are characterized by rapid and reversible action, and do not show cross-resistance with existing anti-cancer agents. It is an antitumor substance with a unique mechanism of action, and has been shown to have a strong anti-tumor effect on experimental transplant cancers such as mouse L1210 leukemia and rat Walker 256 sarcoma, but it has a toxic effect. At present, the usefulness of the drug is naturally limited.

Therefore, attempts have been made to reduce toxicity while maintaining anticancer activity by changing this camptothecin to its derivative. However, due to reasons such as poor solubility of camptothecin in various organic solvents and resistance to electrophilic substitution reaction due to the hetero function in its structure, there are various obstacles in converting to derivatives, and it is planned on the desk. In reality, it is not easy to obtain such a novel derivative.

Regarding the chemical modification of the 20th hydroxyl group of camptothecin, simple acylation (eg, acetylation, hexanoylation, etc.) is known [eg, J. Amer.
m.Soc., 88,3888 (1966), Phytochemistry, 18,1085 (19
79)]. The modified product thus obtained has no anticancer activity. Further, it is difficult to introduce an acyl group having various steric hindrances or an acyl group having a functional group by a normal reaction operation, and conventionally, physiological activity and physical properties due to the chemical modification of the 20-position hydroxyl group have been conventionally known. There was a situation in which no attempt at improvement could be made.

[Disclosure of Invention]

The present inventor, as a result of various studies on synthesizing a higher fatty acid ester at the 20-position of camptothecin,
It was found that the target ester at the 20-position can be obtained in high yield by treating camptothecin and higher fatty acid with a carbodiimide type condensing agent in the presence of a suitable base substance.

That is, the present invention provides a novel compound represented by the general formula (I) (Wherein R ¹ is an acyl group of a saturated or unsaturated higher fatty acid having 16 to 20 carbon atoms, and the acyl group may have a hydroxyl group as a substituent). In addition, as a method for producing the same, it is generally characterized by treating camptothecin and a saturated or unsaturated higher fatty acid in the presence of a basic substance with a carbodiimide compound as a condensing agent to effect esterification. Formula (II) (Wherein R ² represents an acyl group of a saturated or unsaturated higher fatty acid), and a method for producing the camptothecin derivative.

As the basic substance used in the above production method,
Although not specified, it is particularly preferable to use 4-N, N-dimethylaminopyridine. Various types of carbodiimide-type compound condensing agents known to be suitable for esterification are known, but dicyclohexylcarbodiimide is preferably used in the above-mentioned production method of the present invention, although not particularly specified.

Further, the present inventors treat the ester of unsaturated higher fatty acid obtained by the above-mentioned production method with osmium tetroxide, introduce a hydroxyl group to the unsaturated bond in the acyl group, and have a hydroxyl group. It has been found that it can be used as an acyl group of saturated fatty acid. That is, the present invention further provides a compound represented by the general formula (III) (Wherein R ³ represents an acyl group of an unsaturated fatty acid), the camptothecin derivative is treated with osmium tetroxide and represented by the general formula (IV) (Wherein, R ⁴ represents an acyl group of a saturated fatty acid having a hydroxyl group as a substituent), and provides a method for producing a camptothecin derivative.

Usually, to introduce an acyl group of a fatty acid having a hydroxyl group,
Introducing a protective group for the hydroxyl group, and further, a complicated step of removing the protective group is required. However, according to the above-mentioned production method of the present invention, a simple operation is performed and a high yield is obtained. An ester having an acyl group having a hydroxyl group can be obtained.

According to the above method of the present invention, for an ester derivative with a fatty acid having 1 to 3 double bonds in the acyl group, the molar number of osmium tetroxide corresponding to the number of the double bonds. By reacting with
A hydroxyl group can be introduced at each position of the corresponding double bond.

The camptothecin derivative represented by the formula (I) according to the present invention has anticancer activity, and the method of the present invention has established a method for efficiently chemically modifying the 20-position hydroxyl group of camptothecin. Is also applicable to many promising existing derivatives.

Hereinafter, the present invention will be described in more detail with reference to Examples.
The invention is not limited to such an embodiment.

Example 1 20-O-oleylcamptothecin Camptothecin (1 mmol) and oleic acid (1 mmol), dicyclohexylcarbodiimide (1 mmol) and 4-N, N-
Dimethylaminopyridine (catalytic amount) is dissolved in methylene chloride and the mixture is stirred at room temperature for 24 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to flash column chromatography (n-hexane, ethyl acetate, methanol, 4:
5.5: 0.5) to give the title compound as a solid in 76
Obtained in% yield. mp78 ° C. ¹ NMR (200 Mz, CDCl ₃ ): δ0.85 (3H, t, J = 0.25), 0.95
(3H, t, J = 0.5Hz), 1.25 (20H, broad singlet), 1.6
(2H, m), 1.9 (4H, m), 2.35 (2H, m), 2.45 (2H, t, J
= 0.25Hz), 5.25 (4H, m), 5.4 & 5.7 (2H, d, J = 1H
z), 7.22 (1H, s), 7.68 (1H, t, J = 0.5Hz), 7.85 (1
H, t, J = 0.5Hz), 7.95 (1H, d, J = 0.5Hz), 8.2 (1H, d, J
= 0.5Hz), 8.4 (1H, d, J = 0.5Hz).

IR (CHCl ₃ , cm ⁻¹ ); 1760,1680,1620 Example 2 20-O- (9 ′, 10′-dihydroxy) stearoylcamptothecin 20-O-oleoylcamptothecin obtained in Example 1 (0.4 mmol) ) Was dissolved in pyridine (3 ml), osmium tetroxide (0.4 mmol) was added, and sodium bisulfite (1
57.5mg), water (2.62ml), pyridine (1.75ml),
Stir at room temperature for 4 hours. After the reaction mixture turns orange, it is extracted with methylene chloride. The extract is purified by flash column chromatography (n-hexane, ethyl acetate, methanol, 2: 7.5: 0.5) to give the title compound as a white powder. Yield 45% mp 106 ° C ¹ NMR (200
Mz, CDCl ₃ ): δ0.85 (3H, t, J = 0.25Hz), 0.95 (3H, t, J
= 0.5Hz), 1.3 (24H, broad singlet), 1.6 (2H, m),
1.8 (2H, unresolved signal), 2.2 (2H, m), 2.45 (2
H, t, J = 0.25Hz), 3.5 (2.H, m), 5.25 (2H, s), 5.4 &
5.7 (2H, d, two doublets, J = 1Hz), 7.18 (1H, s), 7.6
(1H, t, J = 0.5Hz), 7.7 (1H, t, J = 0.5Hz), 7.9 (1H, t
d, J = 0.5Hz), 8.15 (1H, d, J = 0.5Hz), 8.35 (1H,
s).

^{_{IR (CHCl 3, cm -1)}} : 3600,1780,1700,1650.

MS: 647 (M + 1, C 38 H 51 O 7 N 2).

Example 3 20-O-Linoleoylcaptothecin Using linoleic acid in place of oleic acid in Example 1, the reaction was carried out in the same manner as in Example 1, and flash column chromatography (n-hexane, acetic acid). 59% of the title compound by purification with ethyl, 1: 3)
It was obtained in a yield of. mp81 ° C ¹ NMR (200Mz, CDCl ₃ ); δ0.85 (3H, t, J = 0.25Hz), 0.9
5 (3H, t, J = 0.5Hz), 1.25 (14H, broad singlet), 1.6
5 (2H, m), 1.95 (4H, m), 2.2 (2H, m), 2.45 (2H, t, J
= 0.25Hz), 2.7 (2H, t, J = 0.25Hz), 5.25 (6H, m),
5.4 & 5.65 (2H, two doublets, J = 1Hz), 7.2 (1H, s),
7.65 (1H, t, J = 0.5Hz), 7.8 (1H, t, J = 0.5Hz), 7.95
(1H, d, J = 0.5Hz), 8.2 (1H, d, J = 0.5Hz), 8.38 (1H,
s).

^{_{IR (CHCl 3, cm -1)}} : 1745,1670,1620 MS: 610 (M +, C 38 H 46 O 5 N 2).

Example 4 20-O- (9 ', 10', 12 ', 13'-Tetrahydroxy) stearoylcamptothecin The 20-O-oleoylcamptothecin in Example 2 was replaced with the linoleoyl obtained in Example 3. The reaction was performed according to the method described in Example 2 using camptothecin and purified by flash column chromatography (ethyl acetate, methanol, 1: 0.1) to give the title compound
Obtained in a yield of 7%. mp108 ℃ ¹ NMR (200Mz, CDCl ₃ ): δ0.78 (3H, unresolved triple
t), 0.9 (3H, t, J = 0.5Hz), 1.25 (14H, broad single
t), 1.6 (6H, m), 1.88 (2H, m), 2.2 (2H, m), 2.42
(2H, m), 3.5 (4H, m), 3.75 (2H, m), 4.1 (2H, s),
5.2 (2H, s), 5.35 & 5.62 (2H, two doublets, J = 1H
z), 7.15 (1H, s), 7.6 (1H, t, J = 0.5Hz), 7.75 (1H, s)
t, J = 0.5Hz), 7.9 (1H, d, J = 0.5Hz), 8.15 (1H, d, J =
0.5Hz), 8.32 (1H, s).

^{_{IR (CHCl 3, cm -1)}} : 3460,1745,1670,1620.

Example 5 20-O-Linolenoylcamptothecin Using linolenic acid in place of oleic acid in Example 1, the reaction was carried out in the same manner as in Example 1, and the flash column chromotagraphie (n-hexane, acetic acid was used. 60% of the title compound by purification with ethyl, 1: 3)
It was obtained in a yield of. mp77 ° C ¹ NMR (200Mz, CDCl ₃ ): δ0.9 (6H, m), 1.25 (10H, broa
d singlet), 1.6 (2H, m), 2.1 (6H, m), 2.45 (2H, m
m), 2.75 (2H, m), 5.25 (8H, m), 5.35 & 5.68 (2H, tw
o doublets, J = 1Hz), 7.2 (1H, s), 7.65 (1H, t, J = 0.
5Hz), 7.8 (1H, t, J = 0.5Hz), 7.92 (1H, d, J = 0.5H)
z), 8.2 (1H, d, J = 0.5Hz), 8.38 (1H, s).

^{_{IR (CHCl 3, cm -1:}} 1750,1670,1610 MS: 608 (M +, C 38 H 44 O 5 N 2).

Claims (5)

(57) [Claims] 1. A general formula (I) (In the formula, R ¹ is an acyl group of a saturated or unsaturated higher fatty acid having 16 to 20 carbon atoms, and the acyl group may have a hydroxyl group as a substituent). 2. A general formula (II) characterized in that camptothecin and a saturated or unsaturated higher fatty acid are treated with a carbodiimide compound as a condensing agent in the presence of a basic substance for esterification. (Wherein R ² represents an acyl group of a saturated or unsaturated higher fatty acid), and a method for producing a camptothecin derivative. 3. The method for producing a camptothecin derivative according to claim 2, wherein the carbodiimide compound is dicyclohexylcarbodiimide. 4. The method for producing a camptothecin derivative according to claim 2, wherein the basic substance is 4-N, N-dimethylaminopyridine. 5. General formula (III), (Wherein R ³ represents an acyl group of an unsaturated fatty acid), the camptothecin derivative is treated with osmium tetroxide and represented by the general formula (IV) (In the formula, R ⁴ represents an acyl group of a saturated fatty acid having a hydroxyl group as a substituent), and a method for producing a camptothecin derivative.