JPH0310630B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel camptothecin derivatives. To explain in more detail, the present invention is based on the general formula The present invention relates to a novel camptothecin derivative represented by the formula (wherein X is a nitro group, an amino group, an alkylamino group, an alkanoylamino group, or a halogen atom).

Camptothecin is an alkaloid extracted and isolated from plants such as Camptothecaacuminata Nyssaceae, and has a strong effect of inhibiting nucleic acid synthesis.Its action is rapid and reversible, and has cross-resistance with existing anticancer drugs. It is an antitumor substance with a unique mechanism of action that does not show
Although it has been recognized to have a strong anticancer effect on experimentally transplanted cancers such as 256 sarcoma, its usefulness as a drug is naturally limited due to its toxic effects.

Therefore, attempts have been made to chemically convert camptothecin into other substances, that is, to convert it into camptothecin derivatives, thereby reducing 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 tehero ring 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 had previously succeeded in introducing various substituents into the 10-position of camptothecin;
As a result of repeated research, it was discovered that when 1,2,6,7-tetrahydrocamptothecin obtained by catalytic reduction of camptothecin is directly treated with sulfuric acid, its 11th position is selectively nitrated. By using this 11-nitro-1,2,6,7-tetrahydrocamptothecin as a starting material and converting its nitro group, various new 11-substituted camptothecin derivatives represented by the above general formula can be obtained. I found out.

The present invention has been made based on this knowledge.

The present invention will be explained in detail below. First, 11-nitro-1,2,6, which was created by the present inventor,
7-Tetrahydrocamptothecin can be produced by the following method.

First, catalytic reduction of camptothecin is carried out, and in this case, the B ring of camptothecin is reduced by converting camptothecin into acetic acid or dioxane-
Hydrogenation can be carried out efficiently by hydrogenation in acetic acid in the presence of a platinum catalyst at normal pressure and room temperature. Next, the obtained 1,2,6,7-tetrahydrocamptothecin is treated with nitric acid in concentrated sulfuric acid to nitrate, and the 11-position is selectively nitrated, resulting in 11-nitro-1,2, 6,7-tetrahydrocamptothecin is obtained.

Using this 11-nitro-1,2,6,7-tetrahydrocamptothecin as a starting material, various novel 11-substituted camptothecins or 11-substituted tetrahydrocamptothecin derivatives can be produced by the following methods.

11-Nitrocamptothecin is obtained by oxidizing (aromatic nucleation) 11-nitro-1,2,6,7-tetrahydrocamptothecin. This oxidation (aromatic nucleation) can be efficiently achieved by conventional oxidation methods, such as DDQ oxidation, air oxidation, or nitric acid oxidation. By this method, 11-nitrocamptothecin, which cannot be obtained by nitration of camptothecin itself with sulfur/nitric acid, can be obtained from 1,2,6,7-tetrahydrocamptothecin in a yield of approximately 30%. . 11-Nitrocamptothecin or 11-nitro-1,2,6,7 thus obtained
-Tetrahydrocamptothecin contains iron in hydrochloric acid,
Alternatively, the nitro group at position 11 can be quantitatively converted to the corresponding amino group by reduction or catalytic reduction using a metal such as tin. The obtained 11-amino compound can be converted into a 11-alkanoylamino compound or an alkylamino compound by alkanoylating and alkylating the amino group. The 11-amino compound thus obtained can also be converted into a diazonium salt by converting its amino group into a diazonium salt, and the diazonium group can be further converted into various functional groups. For example, the 11-hydroxy substituted product can be obtained by diazotizing the 11-amino compound in an aqueous sulfuric acid solution and then heating, and the 11-methoxy substituted product can be obtained by treating the diazonium salt with methanol. Can be done. 11-chlorocamptothecin or 11-bromocamptothecin can be obtained by diazotizing the above-mentioned 11-amino compound using hydrochloric acid or hydrobromic acid and treating it with cuprous chloride or cuprous bromide. .

According to the present invention, starting material is camptothecin, which can be obtained relatively abundantly from plants such as Kiju, and pharmacological agents including 11-hydroxycamptothecin, which originally exists only as a trace component in nature. Various interesting 11-position substituents can be efficiently obtained via reduction of the B ring of camptothecin. Examples are listed below,
The present invention will be explained in more detail, but the present invention is not limited to such examples.

Example 1 (a) Production of 1,2,6,7-tetrahydrocamptothecin Camptothecin (500 mg, 1.43 mmol) was suspended in acetic acid (100 ml), platinum oxide (100 mg) was added,
Atmospheric catalytic reduction at room temperature (1.5 hours, absorbing approximately 140 ml of hydrogen). After removing the catalyst, the reaction mixture was dried under reduced pressure and the residue was dissolved in chloroform (200ml).
The chloroform layer was dried over magnesium sulfate, filtered, dried under reduced pressure, and subjected to silica gel (20 g) column chromatography. When purified with (chloroform), 285 mg (conversion rate) of the title compound was obtained as yellowish-white crystals (conversion rate:
56.3%, yield 76.7%). 113 mg (crude) of unreacted starting material was recovered.

mp (decomposition) 240-242℃ [from MeOH] IRν ^KBr _nax cm ^-1 : 3470, 1745, 1645, 1565, 1495,
1165, 1030.

(b) Production of 11-nitro-1,2,6,7-tetrahydrocamptothecin 1,2,6,7-tetrahydrocamptothecin (100 mg, 0.254 mmol) obtained in (a) above was dissolved in concentrated sulfuric acid (5 ml). Melt this in an ice-salt bath to 61%
Nitric acid (d=1.38) (25.5 μ, 0.305 mmol) was slowly added dropwise while stirring. After the addition is complete, stirring is continued for 1 hour. Dilute the reaction solution with ice water (100ml),
Extract with chloroform (100ml x 3 times). This chloroform layer was dried over magnesium sulfate, dried under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl ₃ ) to yield the title compound (58 mg, 51.4%) along with camptothecin (16 mg, 16.2%). can get.

mp 178℃ (decomposition) (from CHCl ₃ -hexane) MS: m/e 397 [M ⁺ ] (as C ₂₀ H ₁₉ N ₃ O ₆ = 397) IRν ^KBr _nax cm ^-1 : 3450, 3120, 1740, 1650 ,1570,
1525, 1342, 1324, 1295, 1250, 1150 NMR (in DMSO- _d6 ) δ: 0.75 (3H, t, J = 7
Hz, −CH ₂ C H ₃ ), 1.72 (2H, q, J=7Hz, −
CH2CH3 ) _, 2.36 (1H, br.m, C-6 _- H),
2.70-2.87 (2H, m, C-7-H), 3.99-4.11
(2H, m, C-5-H), 4.99 (1H, br.m, C
-2-H), 5.22 (2H,s,C-17-H), 6.29
(1H, br.s, NH), 6.52 (1H, s, C-20-
OH), 7.13-7.46 (4H, m, C-9-H, C-
10-H, C-12-H and C-14-H) (c) Production of 11-nitrocamptothecin 1,2,6,7-tetrahydrocamptothecin (352 mg, 1.00 mmol) obtained in (a) above was Dissolve in concentrated sulfuric acid (15ml), and slowly add 61% nitric acid (90μ, 1.2mmol) dropwise to this under an ice-salt bath while stirring. Thereafter, stirring was continued for 1 hour, the reaction solution was diluted with ice water (200 ml), and extracted with chloroform (200 ml x 3 times). This chloroform layer is dried with magnesium sulfate and then dried under reduced pressure. Dissolve the residue in dioxane (30 ml) and add
Add DDQ (416 mg, 0.83 mmol) and boil at reflux for 160 minutes. After that, it was dried under reduced pressure, and the residue was dissolved in chloroform (300 ml) and water (100 ml x 3 times).
wash with After drying this chloroform layer with magnesium sulfate, the solvent is distilled off and the residue is purified by silica gel column chromatography (CHCl ₃ ) to obtain the title compound (121 mg, 30.8%) along with camptothecin (23 mg). .

mp 246℃ (decomposition) (from CHCl ₃ ) Elemental analysis value (as C ₂₀ H ₁₅ N ₃ O ₆ ) Calculated value: C 61.10 H 3.75 N 10.43 Actual value: C 61.07 H 3.84 N 10.68 MS: m/e 393 [ M ⁺ ] IRν ^KBr _nax cm ^-1 : 1745, 1660, 1600, 1535, 1345,
1230, 1155 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J=7
Hz, −CH ₂ C H ₃ ), 1.88 (2H, q, J=7Hz, −
CH ₂ CH ₃ ), 5.34 (2H, s, C-5-H), 5.44
(2H, s, C-17-H), 6.55 (1H, s, C-
20-OH), 7.42 (1H, s, C-14-H), 8.40
~8.42 (2H, m, C-9-H and C-10-
H), 8.87 (1H, s, C-7-H), 8.95 (1H,
s, C-12-H) Example 2 Production of 11-aminocamptothecin 11-nitrocamptothecin (100 mg, 0.254 mmol) obtained in Example 1(c) was mixed with ethanol (30 ml),
Dissolve in a mixed solvent of dioxane (20 ml), add platinum oxide (15 mg), and catalytically reduce the solution at room temperature and pressure for 1 hour. After removing the catalyst and drying the solvent under reduced pressure, the title compound was obtained quantitatively.

MS: m/e 363 [M ⁺ ] (as C ₂₀ H ₁₇ N ₃ O ₄ = 363) IRν ^KBr _nax cm ^-1 : 3390, 3330, 3220, 1735, 1645,
1590, 1505, 1250, 1155, 1045, NMR (in DMSO-d ₆ ) δppm: 0.92 (3H, t, J
= 7.5Hz), 1.86 (2H, q, J = 7.5Hz), 5.11
(2H, s), 5.36 (2H, d, J=3Hz), 5.00~
5.40 (2H, br.), 7.04 (1H, s), 7.35 (1H,
s), 6.90-7.80 (2H, m), 8.32 (1H, s) Example 3 Production of 11-dimethylaminocamptothecin 11-Aminocamptothecin (5 mg, 0.014 mmol) obtained in Example 2 was dissolved in acetone (10 ml). To this were added anhydrous potassium carbonate (15 mg) and methyl iodide (1 ml), and the mixture was stirred at room temperature for 30 minutes.
Thereafter, insoluble matters were removed by filtration, and the liquid was dried to give the title compound (5 mg, 91.3%).

MS: m/e 391 [M ⁺ ] (as C ₂₂ H ₂₁ N ₃ O ₄ = 391) Example 4 Production of 11-acetaminocamptothecin 11-Aminocamptothecin obtained in Example 2 (5 mg, 0.014 mmol) was suspended in chloroform (5 ml), pyridine (0.5 ml) and acetic anhydride (0.1 ml) were added thereto, and the mixture was stirred at room temperature for 1 hour. Thereafter, the solvent was dried under reduced pressure to obtain the title compound (5 mg, 88.2%).

MS: m/e 405 [M ⁺ ] (as C ₂₂ H ₁₉ N ₃ O ₅ = 405) NMR (in DMSO-d ₆ ) δppm: 0.90 (3H, t, J
= 7.5Hz), 1.86 (2H, q, J = 7.5Hz), 2.15
(3H, s), 5.23 (2H, s), 5.39 (2H, s),
6.41 (1H, s), 7.35 (1H, s), 7.66 (1H, s),
7.81-8.05 (2H, m), 8.54 (1H, s), 10.39
(1H, s) Example 5 Production of 11-chloroformcamptothecin 11-nitrocamptothecin (200 mg, 0.509 mmol) obtained in Example 1(c) was added to ethanol (60 ml).
and dioxane (40 ml), add platinum oxide (30 mg), and perform catalytic reduction at room temperature and pressure for 1 hour. After removing the catalyst and distilling off the solvent under reduced pressure, 11-aminocamptothecin is obtained. Dissolve this in 18% hydrochloric acid (20 ml), add sodium nitrite (35 mg,
Gradually add an aqueous solution of 0.560 mmol). After stirring for 10 minutes after the dropwise addition, this diazonium salt aqueous solution was heated to 60 to 70°C and added with cuprous chloride (252
mg, 2.545 mmol) in 18% hydrochloric acid solution (10 ml).
It drips gradually. After the addition is complete, continue stirring for 100 minutes. The reaction solution was diluted with ice water (200 ml) and extracted with chloroform (200 ml x 3). After drying this chloroform layer with magnesium sulfate,
Evaporation under reduced pressure yields 11-chlorocamptothecin (107 mg, 56.0% yield). Recrystallization from chloroform-hexane gives pale yellow needles.

mp 257℃ (decomposition) (from CHCl ₃ -hexane) Elemental analysis value (C ₂₀ H ₁₅ N ₂ O ₄ Cl) Calculated value: C 62.52 H 3.89 N 7.02 Cl 8.98 Actual value: C 62.75 H 3.95 N 7.32 Cl 9.26 MS : m/e 382 [M ⁺ ], 384 [M + 2] IRν ^KBr _nax cm ^-1 : 1745, 1655, 1605, 1590, 1225,
1155 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J=7
Hz, −CH ₂ C H ₃ ), 1.87 (2H, q, J=7Hz, −
CH ₂ CH ₃ ), 5.27 (2H, s, C-5-H), 5.42
(2H, s, C-17-H), 6.50 (1H, s, C-
20-OH), 7.35 (1H, s, C-14-H), 7.71
(1H, dd, J=9Hz, 2Hz, C-10-H),
8.12-8.29 (2H, m, C-9-H and C-12
-H), 8.71 (1H,s,C-7-H) Example 6 Production of 11-bromocamptothecin 11-nitrocamptothecin (300 mg, 0.763 mmol) obtained in Example 1(c) was added to Example 5 Catalytic reduction was carried out as follows to obtain 11-aminocamptothecin, which was dissolved in 18% hydrogen bromide (24 ml) and added with sodium nitrite (58 mg,
0.843 mmol) was gradually added dropwise. After the dropwise addition was completed and stirred for 10 minutes, this diazonium salt aqueous solution was heated to 60-70°C and mixed with cuprous bromide (1094 mg, 7.63 mmol) in 24% hydrogen bromide water (10 ml).
Gradually drop it into the solution. After finishing the dripping, 1
Continue stirring for an hour. The reaction solution was diluted with ice water (200 ml) and extracted with chloroform (200 ml x 3).
This chloroform layer is dried over magnesium sulfate and then distilled off under reduced pressure to obtain 11-bromocamptothecin (133 mg, 40.8% yield). Recrystallization from chloroform gives pale yellow needles.

mp 260-261℃ (decomposition) (from CHCl ₃ ) MS: m/e 426 [M ⁺ ], 428 [M + 2]
(as C ₂₀ H ₁₅ N ₂ O ₄ Br = 426) IRν ^KBr _nax cm ^-1 : 1745, 1655, 1600, 1225, 1155 NMR (in DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7
Hz, -CH ₂ C H ₃ ), 1.87 (2H, q, J = 7Hz, -
CH ₂ CH ₃ ), 5.25 (2H, s, C-5-H), 5.41
(2H, s, C-17-H), 6.48 (1H, s, C-
20-OH), 7.34 (1H, s, C-14-H), 7.79
(1H, dd, J=9Hz, 2Hz, C-10-H),
8.08 (1H, d, J=9Hz, C-9-H), 8.35
(1H, d, J=2Hz, C-12H), 8.69 (1H,
s, C-7-H) Reference Example 1 Production of 11-hydroxycamptothecin 11-nitrocamptothecin (100 mg, 0.254 mmol) obtained in Example 1(c) was catalytically reduced as in Example 5, 11-Aminocamptothecin was obtained, suspended in 17% sulfuric acid (6 ml), and an aqueous solution of sodium nitrite (19 mg, 0.275 mmol) was slowly added dropwise in an ice-salt bath. Thereafter, the mixture was stirred for 10 minutes, then concentrated sulfuric acid (1 ml) was added thereto, and the mixture was boiled and refluxed for 1.5 hours. The reaction solution was diluted with ice water (100 ml), chloroform (100 ml) was added, and after shaking, the precipitated insoluble matter was removed and purified by silica gel column chromatography to yield the title compound (25 mg, 27.0%). can get.

mp＞300℃ (from Py-MeOH) MS: m/e 364 [M ⁺ ] (as C ₂₀ H ₁₆ N ₂ O ₅ = 364) IRν ^KBr _nax cm ^-1 : 3470, 1740, 1645, 1610, 1590,
1565, 1480, 1460, 1375, 1235, 1155 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J = 7
Hz, −CH ₂ C H ₃ ), 1.87 (2H, q, J=7Hz, −
CH ₂ CH ₃ ), 5.20 (2H, s, C-5-H), 5.41
(2H, s, C-17-H), 6.47 (1H, s, C-
20-OH), 7.22-7.35 (3H, m, C-14-H,
C-10-H and C-12-H), 7.94 (1H, d,
J = 9Hz, C-9-H), 8.52 (1H, g, C-
7-H) Reference Example 2 Production of 11-methoxycamptothecin 11-hydroxycamptothecin (20 mg, 0.055 mmol) obtained in Reference Example 1 was suspended in methanol, and an ether solution (10 ml) of 0.6% diazomethane was added to this. Add and stir at room temperature for 3 hours. After that, the solvent was removed to dryness under reduced pressure to obtain the title compound (18 mg, 86.6
%) is obtained.

mp 277-279℃ (decomposition) (from CHCl ₃ ) MS: m/e 378 [M ⁺ ] (as C ₂₁ H ₁₈ N ₂ O ₅ = 378) IRν ^KBr _nax cm ^-1 : 3450, 2920, 1740, 1655 ,1615,
1505, 1450, 1375, 1235, 1150 NMR (in DMSO- _d6 ) δ: 0.89 (3H, t, J=8
Hz, -CH ₂ C H ₃ ), 1.87 (2H, q, J = 8Hz, -
CH2CH3 ₎ , 3.97(3H,s, _C -11- OCH3 ₎ ,
5.24 (2H, s, C-5-H), 5.42 (2H, s, C
-17-H), 6.48 (1H,s,C-20-OH),
7.29-7.40 (2H, m, C-10-H and C-14
-H), 7.55 (1H, d, J=2Hz, C-12-
H), 8.02 (1H, d, J=9Hz, C-9-H),
8.59 (1H, s, C-7-H).

Claims (1)

[Claims] 1. General formula A novel camptothecin derivative represented by the formula (wherein X is a nitro group, an amino group, an alkylamino group, an alkanoylamino group, or a halogen atom).