JPH07118271A - New camptothecin derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an antitumor agent, an antiviral agent and further as an intermediate for production of various kinds of medical substances. CONSTITUTION:A compound is shown by the formula (R<1> is H or a lower alkyl; R<2> and R<3> are each H or a lower acyl), e.g. 2-amino-4- ethylpyrido-[3',4':6,7]indolizino[1,2-b]quinoline-3,14(2H,12H)dione. Among the exemplified compounds of the formula, a compound satisfying R<1>=R<2>=R<3>=H in the formula is obtained, e.g. by suspending camptothecin in hydrazine hydrate and boiling refluxing in an atmosphere of nitrogen. Another compound satisfying R<1> = ethyl and R<2>=R<3>=H in the formula can be synthesized by using 7- ethylcamptothecin in the place of camptothecin.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel camptothecin derivative of N-aminopyridone type or N-aminolactam type which is useful as a medicine or as a precursor for manufacturing a medicine, and a method for producing the same.

[0002]

BACKGROUND ART Camptothecin, a natural alkaloid having a strong antitumor activity, has been abandoned for clinical application because of its toxicity. However, its more effective and less toxic derivative is tolerated. Studies to search are ongoing, and many naturally-occurring derivatives and semisynthetic or total synthetic derivatives have been reported. These derivatives are roughly classified into (1) those in which various functional groups are introduced into the A and B rings (quinoline ring), (2)
It is classified into those modified with the C ring (pyrrole ring) and those modified with the (3) E ring lactone ring.

Among these, the compound in which the lactone ring which is the E ring is modified is provided by the present inventors. This compound is obtained by reacting camptothecin with diamines to open the amide type, and then acylating and protecting the hydroxy group at the 17-position to give a solubilized derivative (formula 5) (JP-A-1- 131179).

[0004]

[Chemical 7]

As the above-mentioned amide-type ring-opened compound, a methylamide compound and an isopropylamide derivative (formula 6) have been reported (The Alkaloid, ed. By A. Br.
Ossi, Academic Press, N.M. Y. ，
1983 and J.M. Med. Chem. , 22, 31
0,1979), but these have extremely weak antitumor activity or no activity.

Hertzberg et al. Also produced lactam-type derivatives (the following formulas) via azide derivatives and the like, but reported that the antitumor activity disappeared (J. Med. Chem., 32,715-720,1
989).

[0007]

[Chemical 8]

Ring E is N-aminopyridone type structure or N
Derivatives having an -aminolactam type structure have not been reported so far, and, of course, their activity, toxicity and physicochemical properties are not known at all.

The object of the present invention is to provide a novel camptothecin derivative in which the E ring has an N-aminopyridone type structure or an N-aminopyridone type structure.
-To provide a novel derivative having an aminolactam type structure.

The above novel camptothecin derivatives are a group of compounds that are extremely useful as intermediates for introducing substituents that can be modified to impart various properties useful as pharmaceuticals to these camptothecin compounds.

[0011]

DISCLOSURE OF THE INVENTION The present inventors have camptothecin, or 7
-Reaction of lower alkyl camptothecin or each derivative of 17-O-acyl camptothecin with hydrazine gives a high yield of the reaction product, and the structure of the obtained reaction product shows that the E ring is N It was found that they have an -aminopyridone type structure or an N-aminolactam type structure.

That is, the present invention provides the following general formula (1) or (2)

[Chemical 9]

[Chemical 10] The present invention provides a novel camptothecin derivative represented by and a method for producing the same.

The camptothecin derivative in which the E ring has an N-aminopyridone type structure or an N-aminolactam type structure according to the present invention is a completely novel compound that has not been reported so far. This novel compound according to the present invention has an N-amino group on the E ring, and can be covalently modified with this amino group as a basic group, and is compatible with water or various other solvents. It is possible to modify the substituent for solubilization and to bond with various amino acids, carboxylic acids and the like. Further, it is also possible to prepare a preparation having selective properties by covalent bonding with various carriers. INDUSTRIAL APPLICABILITY The novel compound according to the present invention can be used in medicine as an antitumor agent, an antiviral agent, and as an intermediate for the production of various medicinal substances.

The method for producing the novel compound according to the present invention and the structure determination will be described below. E according to the present invention
A camptothecin derivative whose ring has an N-aminopyridone type structure or an N-aminolactam type structure can be prepared by using camptothecin or a 7-position lower alkyl camptothecin, or their 17-position O-acylated derivative in a hydrazine hydrate. It is obtained as yellow-orange needle crystals by boiling under reflux. As a result of examination of various spectral data and X-ray crystallographic analysis, the reaction product with camptothecin or 7-position lower alkyl camptothecin shows that the E ring is N-
It is a derivative having an aminopyridone type structure, and is in the 17-position O.
-The reaction product with the acylated derivative was found to be a derivative in which the E ring had an N-aminolactam type structure.

This N-aminopyridone type structure or N
-Various types of camptothecin derivatives, which are raw materials for camptothecin derivatives having an aminolactam type structure, are disclosed in JP-A-56-1588786 and JP-A-1-1311.
It can be produced by the method disclosed in Japanese Patent Publication No. 79-79. That is, the 7-lower alkylcamptothecin derivative can be obtained in high yield by the radical alkylation reaction of camptothecin and lower alkylaldehyde. The 17-position O-acylated derivative can be produced by reacting camptothecin or 7-lower alkylcamptothecin with a diamine such as N, N-dilower alkylethylenediamine and an acylating agent.

Further, the derivative having an N-aminopyridone type structure is converted to an N, N-diacyl derivative by acylation under a suitable acylation condition, and the diacyl derivative is treated under mild alkaline conditions. As a result, an N-monoacyl derivative can be obtained.

The present invention will be described in more detail below with reference to examples.

【Example】

Example 1 2-Amino-4-ethylpyrido [3 ', 4': 6,7]
Indolizino [1,2-b] quinoline-3,14 (2
H, 12H) dione (in the general formula (1), R ¹ =
Compound of H, R ² = R ³ = H) Camptothecin (1.0 g, 2.87 mmol) was suspended in hydrazine hydrate (30 ml), and the mixture was boiled under reflux for 2 hours under a nitrogen atmosphere. The yellow needle crystals precipitated from the reaction solution were cooled with ice, collected by filtration, washed with water and dried to give the title compound (54
0 mg, 55%) was obtained. Recrystallization from DMSO gave yellow-orange needle crystals.

Mp 325-330 ° C. (dec.). IR
(KBr): 1665, 1645, 1615 cm ^-1 .
¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3H,
t, J = 7 Hz), 2.86 (2H, q, J = 7H
z), 5.27 (2H, s), 6.80 (2H, s),
7.24 (1H, s), 7.67-7.91 (2H,
m), 8.08-8.25 (2H, m), 8.65 (1
H, s), 8.73 (1H, s). ¹³ C-NMR (DMSO-d ₆ ) δ: 13.44,1
9.43, 48.94, 93.72, 106.61, 1
21.33, 127.51, 128.10, 128.
37, 128.89, 129.94, 130.23, 1
31.36, 135.45, 138.83, 143.5
1, 147.97, 152.69, 158.12, 1
59.13. MS (EI-DI) m / z: 344 (M)
⁺ . UV λ (McOH) nm (ε): 210 (2320
0), 258 (31700), 292 (21000),
340 (10600), 360 (12000), 402
(9300). Anal. Calcd for C ₂₀ H ₁₆ N ₄ O _{2
· 1 / 4H 2 O: C} , 68.86; H, 4.77; N,
16.06. Found: C, 69.19; H, 4.70; N, 1
6.23.

The results of X-ray crystal structure analysis of the obtained compound are shown below. Crystal is monoclinic, space group C2 / C
And its lattice constant is a = 22.421 (2),
b = 9.883 (1), C = 16.665 (1) Å, β
= 105.359 (5) Å, V = 3563.1 (6) Å
³ , Z = 8, Dx = 1.506Mgm ⁻³ , λ (Cu
K _a1 ) = 1.54050Å, μ = 2.791 mm
^-1 , F (000) = 1672, T = 296K, fin
al R = 0.063, Rw = 0.066 (219
It was 2).

Example 2 2-amino-4,11-diethylpyrido [3 ', 4':
6,7) indolizino [1,2-b] quinoline-3,
14 (2H, 12H) dione (a compound of the general formula (1) in which R ¹ = Et, R ² = R ³ = H) In Example 1, 7-ethylcamptothecin (1.0 g, 2. 66 mmol) was used to carry out a similar reaction and post-treatment to give the title compound (63
9 mg, 64%) was obtained. Recrystallization from DMSO gave pale yellow-orange needle crystals.

Mp322-324 ° C. (dec.). IR
(KBr): 1665, 1640, 1620 cm ^-1 .
¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3H,
t, J = 7 Hz), 1.31 (3H, t, J = 8H
z), 2.84 (2H, q, J = 7Hz), 3.18.
(2H, q, J = 8Hz), 5.28 (2H, s),
6.78 (2H, s), 7.19 (1H, s), 7.6
7-7.90 (2H, m), 8.15-8.31 (2
H, m), 8.72 (1H, s). MS (EI-DI)
m / z: 372 (M) ⁺ . Anal. Calcd for C ₂₂ H ₂₀ N
₄ O ₂ : C, 70.95; H, 5.41; N, 15.0
4. Found: C, 71.21; H, 5.51; N, 1
5.37.

Example 3 2- (N, N-Diacetylamino) -4-ethylpyrido [3 ', 4': 6,7] indolidino [1,2-b]
Quinoline-3,14 (2H, 12H) dione (a compound of the general formula (1) in which R ¹ = H and R ² = R ³ = Ac) The aminopyridone derivative obtained in Example 1 (600 mg,
1.74 mmol) was suspended in a mixture of pyridine (120 ml) and acetic anhydride (60 ml), and the mixture was heated and stirred at 50 ° C. for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was reprecipitated from n-hexane-chloroform to obtain the title compound (720 mg, 97%) as yellow crystals. A part thereof was recrystallized from n-hexane-chloroform to obtain yellow needle crystals.

Mp 241-243 ° C. (dec.). IR
(KBr): 1740, 1675, 1635, 1215
cm ^-1 . ¹ H-NMR (DMSO-d ₆ ) δ: 1.1
5 (3H, t, J = 7Hz), 2.30 (6H, s),
2.84 (2H, q, J = 7Hz), 5.26 (2H,
s), 7.20 (1H, s), 7.68-7.92 (2
H, m), 8.09-8.25 (2H, m), 8.66
(1H, s), 8.98 (1H, s). MS (EI-
DI) m / z: 428 (M) ⁺ . UV λ (MeOH) nm (ε): 210 (3470)
0), 258 (36700), 264 (37800),
294 (29300), 320 (16300), 338
(14300), 354 (12200), 396 (10
500), 416 (15100), 440 (1170)
0). Anal. Calcd for C ₂₄ H ₂₀ N ₄ O _{4
· 1 / 4H 2 O: C} , 66.58; H, 4.77; N,
12.94. Found: C, 66.62; H, 4.68; N, 1
3.15.

Example 4 2-N-acetylamino-4-ethylpyrido [3 ',
4 ′: 6,7] Indolizino [1,2-b] quinoline-3,14 (2H, 12H) dione (Compound of R ¹ ═R ² ═H, R ³ ═Ac in General Formula (1)) Implementation Diacetyl derivative obtained in Example 3 (120 mg, 0.2
8 mmol) was suspended in methanol (2 ml), 1N sodium hydroxide (1.0 ml) was added, and the mixture was stirred at room temperature for 10 minutes. 1N hydrochloric acid (2.0 ml) was added to the reaction solution,
After drying under reduced pressure, the residue was washed with water and dried to obtain the title compound (106 mg, 98%) as yellow crystals. A part thereof was recrystallized from methanol-chloroform to obtain yellow needle crystals.

Mp 333-335 ° C. (dec.). IR
(KBr): 3200, 1710, 1675, 1620
cm ^-1 . ¹ H-NMR (DMSO-d ₆ ) δ: 1.1
5 (3H, t, J = 7Hz), 2.11 (3H, s),
2.80 (2H, q, J = 7Hz), 5.20 (2H,
s), 7.12 (1H, s), 7.64-7.90 (2
H, m), 8.02-8.21 (2H, m), 8.47.
(1H, s), 8.60 (1H, s), 11.48 (1
H, s). MS (EI-DI) m / z: 386
(M) ⁺ . UV λ (MeOH) nm (ε): 210 (3390)
0), 257 (40200), 262 (39500),
294 (30700), 320 (16600), 338
(15000), 354 (13600), 394 (10
500), 412 (14300), 436 (1140)
0). Anal. Calcd for C ₂₂ H ₁₃ N ₄ O _{3
· 1 / 2H 2 O: C} , 66.83; H, 4.84; N,
14.17. Found: C, 67.07; H, 4.69; N, 1
4.56.

Example 5 2-Amino-4,11-diethyl-4-hydroxy-1
H-pyrido [3 ', 4': 6,7] indolizino [1,
2-b] quinoline-3,14 (2H, 4H, 12H) dione (a compound of R ¹ = Et in the general formula (2)) 7-ethyl-17-parachlorobenzoyloxycamptothecin-21- (2- Dimethylamino) ethylamide (in the general formula (5), R ¹ = Et, R ² = -COC ₆
Compound of H ₄ Cl, R ³ = Me) (80 mg, 0.1
3 mmol) was dissolved in methanol (8 ml), hydrazine hydrate (0.5 ml) was added, and the mixture was boiled under reflux for 2.5 hours. The pale yellow needle crystals precipitated from the reaction solution were collected by filtration,
After drying, the title compound (18 mg, 35%) was obtained (recrystallized from methanol-chloroform).

Mp 228-290 ° C. (dec.). IR
(KBr): 3360, 1660, 1650, 1610
cm ^-1 . ¹ H-NMR (DMSO-d ₆ ) δ: 0.7
1 (3H, t, J = 7Hz), 1.33 (3H, t, J
= 8 Hz), 1.78 (1H, dq, J = 14,7H
z), 1.96 (1H, dq, J = 14,7Hz),
3.23 (2H, q, J = 8Hz), 4.45 (1H,
d, J = 18 Hz), 4.56 (1H, d, J = 18H)
z), 5.27 (2H, s), 5.33 (2H, s),
6.01 (1H, s), 7.29 (1H, s), 7.7
0-7.90 (2H, m), 8.17 (1H, d, J =
8 Hz), 8.29 (1H, d, J = 8 Hz). ¹³ C-NMR (DMSO-d ₆ ) δ: 7.93,1
3.99, 22.26, 34.19, 48.93, 4
9.38, 72.72, 97.50, 119.41, 1
24.08, 126.56, 127.48, 127.8
6,129.89,129.98,144.98,14
5.59 148.54, 149.20, 152.1
9,157.55,167.28. MS (EI-DI) m / z: 390 (M) ⁺ , 361.
(M-29) ⁺ , 332 (M-58) ⁺ . Anal, Calcd for C ₂₂ H ₂₂ N
₄ O ₃ : C, 67.68; H, 5.68; N, 14.3
5. Found: C, 67.67; H, 5.61; N, 1
4.41.

Example 6 Separately Synthesis of the Title Compound of Example 5 Compounds 15, 16, 17 and 18 listed in Table 1 below were used as starting 17-O-acyl compounds, and each compound and hydrazine were used. To react with. That is, each compound of 15 to 18 (0.1 mmol) was dissolved in methanol (6 ml), hydrazine hydrate (100 μl, 2 mmol) was added, and the mixture was boiled under reflux for 2.5 hours. The reaction solution is dried under reduced pressure and the residue is DMS.
The title compound of the above (5) was dissolved in O (10 ml), and each reaction product was quantified by HPLC using an internal standard method. The results are shown in Table 1.

The operating conditions of HPLC are as follows. Detector: ultraviolet absorptiometer (measurement wavelength: 254 nm) Column: Inertsil ODS2 (5 mm x 25 c
m) Column temperature: constant temperature around 40 ° C. Mobile phase: 0.01N potassium dihydrogen phosphate liquid / methanol / acetonitrile mixed liquid (3: 1: 1) Flow rate: 1.2 ml / min.

[0030]

[Table 1]

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Tomio Furuta 1-1-19 Higashi-Shimbashi, Minato-ku, Tokyo Yakult Honsha Co., Ltd. (72) Inventor Teruo Yokokura 1-1-19 Higashi-Shimbashi, Minato-ku, Tokyo Issue Yakult Honsha Co., Ltd. (72) Inventor Kentaro Yamaguchi 1-9-22-406 Nakamagome, Ota-ku, Tokyo (72) Inventor Sada Miyasaka 1-27-11 Aobadai, Midori-ku, Yokohama-shi, Kanagawa

Claims (4)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² and R ³ are a hydrogen atom or a lower acyl group), and a camptothecin derivative. 2. A general formula (2): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group)
A camptothecin derivative represented by. 3. A compound represented by the general formula (3): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group)
Represented by the following general formula (4): ## STR00004 ## characterized by reacting a camptothecin derivative represented by (In the formula, R ¹ is a hydrogen atom or a lower alkyl group)
A method for producing a camptothecin derivative represented by: 4. A compound represented by the general formula (5): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² is a lower acyl group, pivaloyl group, a benzoyl group having a substituent or an unsubstituted benzoyl group, and R ³ is a lower alkyl group. A 17-O-acylcamptothecin derivative represented by hydrazine is reacted with hydrazine. Which is characterized by the general formula (2): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group)
A method for producing a camptothecin derivative represented by: