JP3009716B2 - New camptothecin derivatives - Google Patents

Description

The present invention relates to a camptothecin derivative having potent antitumor activity and being water-soluble and suitable for formulation, specifically, 7-ethyl-10- [4- (Chlorophenyl) piperazino] carbonyloxycamptothecin.

(Background technology)

The 10-position hydroxycamptothecin, which is known as a natural camptothecin derivative, is an interesting compound that has stronger antitumor activity than camptothecin itself and that its toxicity is reduced. Since it is very poorly soluble in such solvents, its formulation is difficult, and it has not been put to practical use as a pharmaceutical.

The present inventors have carried out various studies on chemical modification of 10-hydroxycamptothecin. First, they have found that a compound having enhanced antitumor activity can be obtained by introducing an alkyl group at the 7-position ( JP-A-58-39683
Also, the hydroxyl group at the 10-position was modified to make it water-soluble (see JP-A-60-19790). All of these water-soluble derivatives have a strong antitumor activity superior to camptothecin and 10-hydroxycamptothecin (Japanese Patent Application Laid-Open No. 61-85389), and particularly, the side chain of the carbamate bond at the 10-position is piperidinopiperidine. 7-Ethyl-10- [1- (4-piperidino) piperidino] carbonyloxycamptothecin (hereinafter referred to as CPT-11) is water-soluble and has a strong antitumor activity in vitro. Which indicates that the compound is useful as an antitumor agent.

The present inventors have searched for a more powerful and highly effective derivative, and as a result of research, have found that a compound in which the carbamate side chain is replaced with a chlorophenylpiperazinocarbonyl group is
It has been found that it has stronger antitumor activity than the above CPT-11. The present invention is based on this finding.

[Disclosure of the Invention]

The present invention relates to a compound of the formula (I) And a novel camptothecin derivative and an acid addition salt thereof.

The compound according to the present invention is a novel compound created by the present inventors, and this compound is described in the above-mentioned JP-A-60-19790 using 7-ethyl-10-hydroxycamptothecin as a raw material. It can be manufactured by performing operations in accordance with the method described above. To explain this in detail, 10-chlorocarbonyloxycamptothecin obtained by reacting 7-ethyl-10-hydroxycamptothecin with phosgene in the presence of triethylamine is reacted with the corresponding chlorophenylpiperazine to obtain a high yield. Obtained at a rate. As another synthesis method, it can also be obtained by directly reacting 7-ethyl-10-hydroxycamptothecin with a chloroformate derivative of chlorophenylpiperazine.

The compound according to the present invention is a water-soluble compound similarly to the above-mentioned CPT-11, and its antitumor activity is 1/10 to 1/2 of CPT-11 as apparent from the experiment described later. CPT-1
It shows antitumor activity equivalent to that of 1, indicating that it is a very useful compound.

The acid addition salt of the derivative of the general formula (I) according to the present invention is usually a salt with a suitable pharmaceutically acceptable acid by a method used for producing the salt from a basic compound. it can. The most commonly used acid addition salts are non-toxic and pharmaceutically useful addition salts with inorganic or organic acids. Salts of inorganic acids include hydrochloride, sulfate or phosphate. And as salts of organic acids,
Examples include acetate, propionate, lactate, citrate or methanesulfonate.

When the compound according to the present invention is used as a medicine, a composition comprising an effective amount of the compound and a pharmaceutically acceptable inert carrier or diluent is parenterally or orally administered by a usual formulation technique. It is prepared into various suitable dosage forms.

Hereinafter, the present invention will be described in detail with reference to examples of the present invention and experimental examples.

Example 1 Synthesis of 7-ethyl-10- [4- (3-chlorophenyl) piperazino] carbonyloxycamptothecin 7-ethyl-10-hydroxycamptothecin (10 g, 2
5.6 mmol) of a pyridine solution (100 ml) was added with a chloroformate derivative (1.1 eq.) Prepared from 3-chlorophenylpiperazine and phosgene, and reacted at room temperature for 15 hours with stirring. After completion of the reaction, the reaction solution is dried under reduced pressure, and the residue is dissolved in methylene chloride (500 ml). The organic layer is washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered to remove insolubles, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-chloroform) to give the title compound.

Yield 31% Pale yellow powdery crystals Melting point 179-180.5 ° C (n-hexane-CHCl ₃ ) ▲ IRν ^KBr _max ▼ cm ^-1 : 3410,2970,2920,2870,2800,1740,1
715,1660,1595,1490,1360,1225,1180,1155,1035. ¹ H-NMR (in CDCl ₃ ) δ ppm: 1.04 (3H, t, J = 7 Hz), 1.41
(3H, t, J = 7Hz), 1.80-2.00 (2H, m), 3.17 (2H, q, J
= 7Hz), 3.20-3.30 (4H, m), 3.70-4.00 (4H, m),
5.26 (1H, s), 5.31 (1H, d, J = 16Hz), 5.75 (1H, d, J =
16Hz), 6.90 (2H, d, J = 9Hz), 7.26 (2H, d, J = 9Hz),
7.61 (1H, dd, J = 2Hz, 8Hz), 7.87 (1H, d, J = 2Hz), 8.2
4 (1H, d, J = 8Hz).

Example 2 Synthesis of 7-ethyl-10- [4- (2-chlorophenyl) piperazino] carbonyloxycamptothecin In Example 1, 2-chlorophenylpiperazine was used instead of 3-chlorophenylpiperazine.
The title compound was obtained by performing the operation according to Example 1.

Yield 36% pale yellow powdery crystals Melting point 241 to 242 ° C (n-hexane-CHCl ₃ ) ▲ IRν ^KBr _max ▼ cm ^-1 : 3400,2960,2910,2870,2800,1743,1
715,1655,1600,1510,1450,1410,1225,1180,1160,1030,7
60. ¹ H-NMR (in CDCl ₃ ) δ ppm: 1.04 (3H, t, J = 7 Hz), 1.42
(3H, t, J = 7Hz), 1.80-2.00 (2H, m), 3.10-3.30 (4
H, m), 3.16 (2H, q, J = 7Hz), 3.80-4.00 (4H, m), 5.
27 (2H, s), 5.31 (1H, d, J = 16Hz), 5.75 (1H, d, J = 16
Hz), 7.04-7.42 (4H, m), 7.62 (1H, dd, J = 2Hz, J = 8H
z), 7.65 (1H, s), 7.88 (1H, d, J = 2Hz), 8.24 (1H,
d, J = 8 Hz).

Example 3 Synthesis of 7-ethyl-10- [4- (4-chlorophenyl) piperazino] carbonyloxycamptothecin 4-chlorophenylperazine was used in place of 3-chlorophenylpiperazine in Example 1, and the others were the same as in Example 1. The title compound was obtained by performing the operation in accordance with the above.

Yield 33% pale yellow powdery crystals Melting point 159-163 ° C (n-hexane-CHCl ₃ ) ▲ IRν ^KBr _max ▼ cm ^-1 : 3400,2960,2920,2870,2800,1750,1
720,1655,1590,1455,1350,1220,1180,1155,1100,1050,9
30. ¹ H-NMR (in CHCl ₃ ) δ ppm: 1.03 (3H, t, J = 7 Hz), 1.41
(3H, t, J = 7Hz), 1.80-2.00 (2H, m), 3.16 (2H, q, J
= 7Hz), 3.30 (4H, m), 3.70-3.90 (4H, m), 5.24 (2
H, s), 5.29 (1H, d, J = 16Hz), 5.72 (1H, d, J = 16H)
z), 6.83-7.20 (4H, m), 7.59 (1H, dd, J = 2Hz, 8H
z), 7.62 (1H, s), 7.87 (1H, d, J = 2 Hz), 8.22 (1H,
d, J = 8 Hz).

Next, experimental examples of the antitumor effect of the compound according to the present invention will be described.

Antitumor activity It has already been clarified that examining the antitumor effect in rodents can provide reliable conclusions on the antitumor effect in other warm-blooded animals. The tumor effect was examined.

Experimental method 5 × 10 ⁵ mouse leukemia cells L ₁₂₁₀ were _aged 7 weeks (weight 17
Implanted intraperitoneally into female CDF ₁ mice (1 group 6 mice) of ～19G), a test substance is administered intraperitoneally in 1.5 and 9 days after transplantation, for observation of survival benefit.

When the test substance was administered as an acid addition salt, the test substance was used after being dissolved in a physiological saline solution. 25mg total dose intraperitoneally
Performed at / 100 mg / kg. The antitumor effect was expressed as a value (T / C%) obtained by multiplying the ratio of the average survival days (T) of the drug-administered group to the average survival days (C) of the non-drug-administered group by 100 times (T / C%) under the above experimental conditions. If the life is extended by more than
The minimum effective dose and the maximum tolerated dose were examined, and then the therapeutic index was calculated.

Experimental Results Table 1 shows the results obtained by conducting an antitumor effect test on the substances obtained in the above examples by the above-mentioned experimental method.

As is clear from Table 1 below, the compound according to the present invention exhibited the same antitumor activity as CPT-11 at a smaller dose than CPT-11, and was confirmed to be extremely excellent. .

Continued on the front page (72) Inventor Tomio Furuta 1-1-1 Higashi-Shimbashi, Minato-ku, Tokyo, Japan Yakult Honsha (72) Inventor Teruo Yokokura 1-1-19, Higashi-Shimbashi, Minato-ku, Tokyo (56) References JP-A-60-19790 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 491/22 A61K 31/495 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The compound of the general formula (I) A novel camptothecin derivative represented by the formula: and an acid addition salt thereof.