JPH01246287A - Novel camptothecin derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula (R<1> is 16-20C acyl of a fatty acid which may have hydroxyl group as a substituent group). EXAMPLE:20-O-Oleylcamptothecin. USE:An anticancer agent or an intermediate therefor. PREPARATION:For example, camptothecin and a saturated or unsaturated higher fatty acid, a basic substance of 4-N,N-dimethylaminopyridine and a condensing agent of dicyclohexylcarbodiimide are dissolved in methylene chloride, reacted while being stirred at ambient temperature for 24hr and evaporated to dryness under reduced pressure to purify the residual substance by flash column chromatography and afford the aimed compound. Furthermore, an ester of an unsaturated fatty acid having an acyl group is treated with osmium tetrachloride to afford the ester having the acyl group with hydroxyl group.

Description

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

[Background technology]

Camptothecin is derived from camptothecin.
An alkaloid extracted and isolated from plants such as cααcuminatα, it has a strong nucleic acid synthesis inhibitory effect, and its action is rapid and reversible.It is unique in that it does not show cross-resistance with existing anticancer drugs. It is an antitumor substance with a unique mechanism of action, and is recognized to have strong anticancer effects against experimentally transplanted cancers such as L1210 leukemia in mice and Walker 256 sarcoma in rats. Currently, their usefulness as pharmaceuticals is naturally limited.

Therefore, attempts have been made to reduce toxicity while retaining anticancer activity by changing camptothecin to its derivatives. However, due to the poor solubility of camptothecin in various organic solvents and the resistance to electrophilic substitution reactions derived from the heterocycle in its structure, there are various obstacles to converting it into derivatives, and it has not been possible to plan it on paper. The reality is that it is not easy to obtain novel derivatives.

Regarding the chemical modification of the 20-hydroxyl group of camptothecin, simple acyl (1 (e.g., acetylation,
hexanoylation, etc.) [for example, J, A
yner, Chem, Soc,, 88.3888 (
1966), Phytochemistry, 18.
1085 (1979)].

The modified product thus obtained does not exhibit anticancer activity. In addition, it is difficult to introduce acyl groups with various steric hindrances or functional groups through normal reaction operations, and conventionally, chemical modification of the 20-position hydroxyl group has been used to improve physiological activity and physical properties. Attempts to improve the situation were not possible.

[Disclosure of the invention]

As a result of various studies on the synthesis of higher fatty acid esters at position 20 of camptothecin, the present inventor found that
It has been found that the desired ester at position 20 can be obtained in high yield by treating camptothecin and a higher fatty acid with a carbodiimide type condensing agent in the presence of an appropriate base substance.

That is, the present invention provides a novel compound having the formula (I) (wherein R1 is an acyl group of a saturated or unsaturated higher fatty acid having 16 to 20 carbon atoms, and this acyl group has a hydroxyl group as a substituent. The present invention provides a derivative of camptothecin represented by A method for producing a camptothecin derivative represented by general formula (II) (wherein R2 represents an acyl group of a saturated or unsaturated 1000-grade fatty acid), which is characterized by esterification by treatment using a condensing agent. This is what we provide.

The basic substance used in the above production method is not specified, but it is particularly preferable to use 4-N,N-dimethylaminopyridine. Although various suitable types are known, dicyclohexylcarbodiimide is preferably used in the above production method of the present invention, although it is not particularly specified.

In addition, the present inventors treated the unsaturated flat fatty acid ester obtained by the above production method with tetradispersed ichiosmium, introduced a hydroxyl group into the unsaturated bond in the acyl group, and removed the hydroxyl group. It has been found that the acyl group of a saturated fatty acid can be used as the acyl group of a saturated fatty acid.

That is, the present invention further provides - formula (I[0 (in the formula,
A camptothecin derivative represented by the general formula (In the formula, R4 represents an acyl group of a saturated fatty acid having a hydroxyl group as a substituent) is treated with osmium tetroxide. The present invention provides a method for producing a camptothecin derivative represented by the following formula.

Normally, the introduction of an acyl group into a fatty acid having a hydroxyl group requires a complicated process of introducing a protective group to the hydroxyl group and removing the protective group. For example, the desired ester having an acyl group having a hydroxyl group can be obtained in high yield with a simple operation.

In the above-described method according to the present invention, tetroxidation of an ester derivative with a fatty acid having 1 to 3 double bonds in the acyl group is carried out in the number of moles corresponding to the number of double bonds. By reacting with osmium, a hydroxyl group can be introduced into 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 present invention has established a method for efficiently chemically modifying the hydroxyl group at position 20 of camptothecin. The method is also applicable to many promising existing derivatives.

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 20-0-oleoylcamptothecin 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 purified by flash column chromatography (n-hexane, ethyl acetate, methanol, 4:5.5:[15]) to give the title compound as a solid in 76% yield. . m, p, 78℃
lNMR (200Mg, CDCls): δ185
(3H,t, J=125), o,'? 5 (3H,
t, J=15Hz), 1.25(20H, broad
si-nglet), 1.6 (2H,m),
1.9 (4H, m), 2.35 (2H, m), 2.4
5 (2H, t, J=α25Hz), 5.25 (4
H, m), 5.4 & 5.7 (2H, d, J= I
Hz), 7.22 (IH, &), 7.68 (I H, t
, J = 0.5Hz), 7.85 (IH,t, J
= 15Hz), 7.95 (I H, d, J = 15H
z), δ2 (I H, d, J=0.5Hz), δ4
(IH, d, J=CJ, 5Hz).

IR (CHCIs, cm-'): 1760.1
680.1620 Example 2 20-0-(9', 10
'-dihydroxy)stearoylcamptothecin 20-0-oleoylcamptothecin (cL47'ILrrwl) obtained in Example 1 was dissolved in pyridine (3 m/).
Add osmium tetroxide (0,4 mm trl), sodium bisulfite (157,5 m9), water (2,62 m/).

Add pyridine (1.75 mQ) and stir at room temperature for 4 hours.

After the reaction mixture turned orange, it was extracted with methylene chloride.

The extract was subjected to flash column chromatography (n-
Hexane, ethyl acetate, methanol, 2: 7.5
: Purification according to 0.5) gives the title compound as a white powder. Yield 45%m,p,j06℃”
NMR (200Mz, CDC13): δ0.85
(3H, t, J=l125Hz), Q, 95 (3H,
t, J=Q, 5H2), 1.3 (24H, broa
tl 5iqlet), 1.6 (2H, ff1), 1.
8 (2H, unresolved 51gm1), 2
．． 2 (2H.

m), 2.45 (2H, t, J=f125Hz),
3.5 (2, H, m), 5.25 (2 H, s), 5.4
& 5.7 (2Ht d, two double
ts, J= , 11. Hz), 7.18 (1H9S)
, Z6 (IH, t, J=15H2), 7.7 (IH,
LJ=CL5H2), 7.9 (IH, d, J=0.
5 Hz), C15'(IH, d, J= 0.5 Hz)
), C35 (IH, 8).

IR (CHC13, crn, -'): 3600.17
80.1700.1650°MS: 647 (M+
1, C3sHs10rNz).

Example 3 20-0-Liluoylcamptothecin Using linoleic acid in place of oleic acid in Example 1, a reaction was carried out in the same manner as in Example 1, and flash column chromatography (n-hexane, ethyl acetate, 1:
3), the title compound was obtained in a yield of 59%. m, p, 81°C' NMR (200MZ, CDC13): δ0.
85 (3H, t, J= 0.25Hz), 0.95
(3H, t, J= Q, 5H2), 1.25 (1
4H, broaclsingiet), 1.65 (
2H, m), 1.95 (4H, m), 2.2 (2H
.

m), 2.45 (2H, t, J=0.25Hz), 2
．． 7 (2H,L J=0.25Hz), 5.25 (
6H, m ), 5.4 & 5.65 (2H, two
doublets.

J = IH2), 7.2 (IH,s), 7.65
(IH, t, J=0.5H2), 7.8 (IH, t
, J=0.5H2), 7.95 (I H,d, J
= 0.5H2), 8.2 (IH, d, J=0.5
Hz), C38 (IH, 8).

IR (CHC13, cm-”): 1745.167
0.1000MS:610(M, C38H4gC
58H4゜Example 4 2o-o-(4', 1o', 1-, 13'-tetrahydroxy)stearoylcamptothecin Instead of 20-0-oleoylcamptothecin in Example 2, the 20-0-oleoylcamptothecin obtained in Example 3 was used. The reaction was carried out according to the method described in Example 2 using lyluoylcamptothecin, followed by flash column chromatography (ethyl acetate,
Purification with methanol, 1:(Ll) afforded the title compound in a yield of 57. m, p, 108℃' NMR (200Mz, CDCls): δ(
178 (3H+ unresolved triplet
), (19 (3H, t, J=0.5Hz), 1.2
5 (14H, broadsinglet), 1.6
(6H, m), 1.88 (2H, m), 2.2 (2
H,fi), 2.42 (2H,m), 3.5 (4
H, m), 3.75 (2H, m), 4.1 (2H, s
), 5.2 (2H,s), 5.35 & 5.62
(2H, two do-ublets, J=I
Hz), 7.15 (IH, s), 7.6 (1H, t,
J=0.5H2), 7.75(IH,t, J=0.
5Hz), 7.9 (IH, d, J=0.5Hz)
, C15 (IH, d, J=l15Hz), C32 (I
H,s).

IR (CHCi3.c-i-'): 3460.1
745.1670.1620.

Example 5 20-0-! ) Lunoylcamptothecin The reaction was carried out in the same manner as in Example 1 except that oleic acid in Example 1 was replaced with lylunic acid, and flash column chromatography (n-hexane, ethyl acetate, 1:
3) The title compound was obtained in 60% yield by purification. m, p, 77°C" NMR (200Mz, CDC13): δQ,
9 (6H, m), 1.25 (10H, broad s
inglet), 1.6 (2H,m,), 2.1
(6H, m), 2.45 (2H, m), 2.75
C2H, m), 5.25 (8H, m), 5.65&
5.68 (2H, two doublets, J=
I H2), 7.2 (IH, 8), 7.65 (IH
, t, J=CJ, 5H2), 7.8 (IH, t,
J=0.5Hz), 7.92 (IH, d, J=C
1.5Hz), C2 (IH, d, J=0.5Hz),
C38 (IH, s).

IR(,CHC13,C,77L-”): 1750
．． 1670.1610M5: 608 (M+,
C38H4405N2).

Patent applicant: Yakult Honsha Co., Ltd.

Claims (1)

[Claims] 1) General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (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 this acyl group may have a hydroxyl group as a substituent). 2) General formula (II) characterized by esterifying camptothecin and a saturated or unsaturated higher fatty acid in the presence of a basic substance using a carbodiimide compound as a condensing agent ▲Mathematical formula, chemical formula, table ▼(II) A method for producing a camptothecin derivative represented by the formula (wherein R^2 represents an acyl group of a saturated or unsaturated higher fatty acid). 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 or 3, wherein the basic substance is 4-N,N-dimethylaminopyridine. 5) Treating a camptothecin derivative represented by general formula (III), ▲mathematical formula, chemical formula, table, etc.▼(III) (in the formula, R^3 represents an acyl group of an unsaturated fatty acid) with osmium tetroxide. Camptothecin represented by the general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (wherein R^4 represents an acyl group of a saturated fatty acid having a hydroxyl group as a substituent) Method for producing derivatives.