JPH0149268B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel fredericamycin A derivatives,
More specifically, the following general formula () (In the formula, R represents a hydrogen atom, an alkanoyl group, a lower alkyl group, a lower alkoxy group, or a benzoyl group that may be substituted with a halogen atom)
The present invention relates to a fredericamycin A derivative represented by: Conventionally, from a culture of Streptomyces griseus FCRC-48, the following formula () It is known that Fredericamycin A (NSC-305263), an antitumor antibiotic expressed by
Volume, pp. 1389-1401 (1981) and Vol. 34, pp. 1402-
1407 pages (1981)]. However, this fredericamycin A has weak antibacterial activity and is unstable. Therefore, in order to overcome these drawbacks of fredericamycin A, the present inventor synthesized various derivatives and examined their pharmacological action and stability, and found that tetrahydrofredericamycin A and The present invention was completed by discovering that the diacyl derivative has excellent antibacterial and antitumor effects and is extremely stable compared to fredericamycin A. Accordingly, the present invention provides tetrahydrofredericamycin A and its diacyl derivatives (2) useful as antibacterial and anticancer agents. Tetrahydrofredericamycin A of the present invention
is produced by reducing fredericamycin A() with a suitable reducing agent and then partially oxidizing it. Reduction is carried out using a conventional reducing agent, and catalytic reduction is preferably carried out by passing hydrogen gas in the presence of a catalyst such as palladium-attached activated carbon or platinum oxide. Partial oxidation is carried out by subjecting the reduced product to air oxidation in an appropriate solvent after reduction. The diacyltetrahydrofredericamycin A of the present invention is obtained by adding R ₁ OH (wherein R ₁ is an alkanoyl group, a lower alkyl group, a lower Indicates a benzoyl group that may be substituted with an alkoxy group or a halogen atom)
It is produced by reacting a carboxylic acid represented by or a reactive derivative thereof. Examples of the carboxylic acid represented by R ₁ OH include aliphatic carboxylic acids, benzoic acids, and benzoic acids having substituents such as lower alkyl groups, lower alkoxy groups, and halogen atoms. In addition, as reactive derivatives of carboxylic acids, acid halides, acid anhydrides, mixed acid anhydrides, active esters, etc. are used, and in this case, 3 to 10
It is preferable to carry out the reaction using twice the molar equivalent of the carboxylic acid derivative in a solvent such as pyridine at a temperature of 0 to 4°C for 2 to 48 hours. Alternatively, tetrahydrofredericamycin A and the above carboxylic acid can be directly reacted using a condensing agent such as dicyclohexylcarbondiimide. The results of testing the antibacterial activity, antitumor activity, and stability of the representative compound of the present invention thus obtained are as follows. (1) Antibacterial action Table 1 shows the minimum inhibitory concentration (MIC) of diacyltetrahydrofredericamycin A against various microorganisms. The MIC of fredericamycin A is 100 μ against any microorganism.
g/ml or more. Test culture conditions: Inoculum size 10 ⁶ cells/ml. For bacteria, use Mueller Hinton Agar (manufactured by Difco) at 37°C for 18
The cells were cultured for ~20 hours, and in the case of yeast and mold, they were cultured for 120 hours at 28°C in a glucose-peptone medium.

【table】

[Table] (2) Antitumor effects Tetrahydrofredericamycin A and diacetyltetrahydrofredericamycin A for Ehrlich carcinoma (Ehrlich),
Meth-A (ascites type) and murine leukemia P-
The therapeutic effect on 388 was tested using the following method. The results are shown in Tables 2 and 3. In addition, the survival effect in the table is expressed as a percentage of the ratio of survival days (T) of the treated group to the survival days (C) of the untreated group. Experimental method: (i) Ehrlich 5 × ¹⁰⁶ tumor cells were injected into ICR mice (♀,
After 24 hours, tetrahydrofredericamycin A or diacetyltetrahydrofredericamycin A was intraperitoneally administered once a day for a total of 10 times. (ii) Meth-A (ascites type) 1 × 10 ⁶ tumor cells were transferred to CDF ₁ mice (〓,
After 24 hours, tetrahydrofredericamycin A or diacetyltetrahydrofredericamycin A was intraperitoneally administered once a day for a total of 10 times per day. (iii) Mouse leukemia P-388 1×10 ⁶ P-388 cells were intraperitoneally transplanted into CDF ₁ mice (Charles River, Japan), and 24 hours later, they were injected with tetrahydrofredericamycin A or diacetyltetrahydrochloride. Fredericamycin A was administered intraperitoneally once a day for a total of 10 times.

【table】

[Table] (3) Stability Compound 5 of the present invention and Fredericamycin A
The stability of the compound in an aqueous solution was tested by the following method. The results are shown in Table 4. Experimental method: Dissolve the test compound in dimethyl sulfoxide,
The final concentration of the test compound was adjusted to 10 μg/ml by diluting with physiological saline. For this test liquid,
The residual rate of the test compound after a predetermined time was measured by high performance liquid chromatography (HPLC method).

[Table] Next, examples will be given and explained. Example 1 0.50 g of fredericamycin A was dissolved in 30 ml of tetrahydrofuran, and 0.07 g of 10% palladium on carbon was added.
In addition, catalytic reduction was carried out under stirring at room temperature. After 10 hours of reaction, the precipitated yellow reduced product was dissolved in a chloroform-methanol mixture to remove palladium on carbon.
A small amount of dimethyl sulfoxide was added to the liquid, and the mixture was stirred at room temperature for 3 hours. Take the precipitated red crystals,
Recrystallization was performed from a chloroform-methanol mixture to give 0.29 g of red crystals of tetrahydrofredericamycin A [Compound 1; R=H in the formula ()] (yield
60%). Melting point 300℃ or higher Ultraviolet absorption spectrum λ dioxane maxnm (ε) 243 (69000), 285 (18500), 298 (18900), 322
(9500), 337 (11400), 353 (10600), 507 (10600) (Fig. 1) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1750, 1720, 1650, 1610 (Fig. 2) ¹ H-NMR spectrum ( δppm) Deuterochloroform + deuterium trifluoroacetic acid 10:1
Measurement was performed in the mixed solution at 90MHz using TMS as an internal standard. 0.88 (t, 3H), 1.25-1.64 (6H), 3.32 (t,
2H), 3.96 (s, 3H), 6.32 (s, 1H), 6.44 (s,
1H), 6.96 (s, 1H) (Figure 3) Mass spectrum (EI, 70eV) m/z 543 (M ⁺ ) Elemental analysis value (%) C ₃₀ H ₂₅ NO ₉ (Molecular weight 543.53)
As C H N Experimental value 66.11 4.65 2.57 Theoretical value 66.29 4.63 2.58 Example 2 Dissolve 0.25 g of tetrahydrofredericamycin A in 6 ml of pyridine, add 0.5 ml of acetic anhydride,
Stirred at 0-4°C for 1 hour. The reaction solution was ice-cooled.
- It was added to hexane with stirring, and the resulting precipitate was collected and dried. This precipitate was dissolved in ethyl acetate.
Recrystallized from an acetic acid mixture to obtain diacetyltetrahydrofredericamycin A [Compound 2;

0.26 g (yield: 90%) of pale orange-yellow crystals of [Formula]] was obtained. Melting point 265℃ (decomposition) Ultraviolet absorption spectrum λ dioxane maxnm (ε) 238 (67700), 323 (sh), 338 (15700), 352
(17600) (Figure 4) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1785, 1760, 1725, 1690, 1660, 1620 (Figure 5) ¹ H-NMR spectrum (δppm) In deuterium chloroform with TMS as internal standard ,
Measured at 90MHz. 12.06 (s, 1H), 10.27 (s, 1H), 6.75 (s,
1H), 6.14, (s, 1H)), 6.10 (s, 1H), 3.85
(s, 3H), 3.25 (t, 2H) 0.76 (t, 3H) (Figure 6) Mass spectrum (EI, 70eV) m/z 627 (M ⁺ ) Elemental analysis value (%) C ₃₀ H ₂₉ NO ₁₁ As C H N Experimental value 65.11 4.65 2.18 Theoretical value 65.07 4.66 2.23 Examples 3 to 5 The following compounds were obtained in the same manner as in Example 2. The compound is represented by R in the formula (). Compound 3 Melting point 278-279℃, pale orange-yellow crystal Ultraviolet absorption spectrum λ dioxane maxnm (ε) 237 (59500), 338 (13800), 352 (15100) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1780, 1760, 1725, 1690, 1660, 1625 ¹ H-NMR spectrum (δppm) In deuterated chloroform, with TMS as internal standard,
Measured at 90MHz. 12.08 (s, 1H), 10.20 (b, s, 1H), 6.81
(s, 1H), 6.20 (s, 1H), 6.15 (s, 1H),
3.90 (s, 3H), 3.28 (t, 2H), 2.83 (q, 4H),
2.45 (m, 4H), 1.7-1.1 (m, 6H), 1.35 (t,
6H), 0.77 (t, 3H) Mass spectrum (EI, 70eV) m/z 655 (M ⁺ ) Compound 4 Melting point 254-255℃, pale orange-yellow crystal Ultraviolet absorption spectrum λ dioxane maxnm (ε) 237 (66800), 339 (14600), 353 (16200) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1780, 1760, 1725, 1690, 1660, 1625 ¹ H-NMR spectrum (δppm) In deuterated chloroform, with TMS as internal standard,
Measured at 90MHz. 12.07 (s, 1H), 10.74 (s, 1H), 6.73 (s,
1H), 6.14 (s, 2H), 3.88 (s, 3H), 3.24 (t,
3H), 2.79 (t, 4H), 2.44 (m, 4H), 2.0~1.0
(m, 18H), 0.91 (t, 6H), 0.73 (t, 3H) Mass spectrum (EI, 70eV) m/z 739 (M ⁺ ) Compound 5 Melting point 216-217℃, pale orange-yellow crystal Ultraviolet absorption spectrum λ dioxane maxnm (ε) 237 (63000), 339 (13700), 353 (15100) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1780, 1760, 1725, 1690, 1655, 1625 ¹ H-NMR spectrum (δppm) In deuterated chloroform with TMS as internal standard,
Measured at 90MHz. 12.13 (s, 1H), 10.08 (b, 1H), 6.79 (s,
1H), 6.19 (s, 1H), 6.13 (s, 1H), 3.88 (s,
3H), 3.27 (t, 2H), 2.78 (t, 4H), 2.45 (m,
4H), 2.0-0.9 (m, 42H), 0.87 (t, 6H),
0.78 (t, 3H) Examples 6-7 The following compounds were obtained in the same manner as in Example 2. The compound is represented by R in the formula (). Compound 6 Melting point 290-292℃, pale orange-yellow crystal Ultraviolet absorption spectrum λ dioxane maxnm (ε) 239 (79700), 338 (14200), 352 (15200) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1755, 1725, 1690, 1655, 1625 ¹ H-NMR spectrum (δppm) in deuterated chloroform with TMS as internal standard.
Measured at 90MHz. 12.10 (b, s, 1H), 8.70 (b, 1H), 8.22
(d, 4H), 7.56 (m, 6H), 6.74 (s, 1H),
6.14 (s, 1H), 6.10 (s, 1H), 3.84 (s, 3H),
3.22 (t, 2H), 2.45 (m, 4H), 1.7~1.0 (m,
6H), 0.83 (t, 3H) Mass spectrum (EI, 70eV) m/z 751 (M ⁺ ) Compound 7 Melting point 289-290℃, pale orange-yellow crystal Ultraviolet absorption spectrum λ dioxane maxnm (ε) 245 (93900), 338 (15000), 352 (16400) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1755, 1725, 1690, 1655, 1625 ¹ H-NMR spectrum (δppm) in deuterated chloroform with TMS as internal standard.
Measured at 90MHz. 12.16 (b, 1H), 10.20 (b, 1H), 8.18 (d,
4H), 7.47 (d, 4H), 6.73 (s, 1H), 6.14 (s,
2H), 3.84 (s, 3H), 3.22 (t, 2H), 2.45 (m,
4H) 1.7-1.1 (m, 6H), 0.77 (t, 3H) Mass spectrum (EI, 70eV) m/z 819, 821, 823 (M ⁺ ) Examples 8-9 In the same manner as Example 2, the following The compound was obtained. The compound is represented by R in the formula (). Compound 8 Melting point 285-287℃, pale orange crystal UV absorption spectrum λ dioxane maxnm (ε) 242 (81000), 336 (14500), 350 (15500) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1755, 1725, 1690, 1655, 1625 ¹ H-NMR spectrum (δppm) in deuterated chloroform with TMS as internal standard.
Measured at 90MHz. 12.20 (b, 1H), 9.86 (b, s, 1H), 8.18
(d, 4H), 7.32 (d, 4H), 6.76 (s, 1H),
6.16 (s, 1H), 6.14 (s, 1H), 3.84 (s, 3H),
3.21 (t, 2H), 2.45 (m, 4H), 2.41 (s, 6H),
1.8-1.0 (m, 6H), 0.79 (t, 3H) Mass spectrum (EI, 70eV) m/z 751 (M ⁺ ) Compound 9 Melting point 283-284℃, pale orange-yellow crystal Ultraviolet absorption spectrum λ dioxane maxnm (ε) 260 (85, 100), 336 (14400), 351 (15200) Infrared absorption spectrum ν ^KBr _nax cm ^-1 1755, 1725, 1690, 1655, 1625 ¹ H-NMR spectrum (δppm) In deuterated chloroform, with TMS as internal standard,
Measured at 90MHz. 12.20 (b, 1H), 10.07 (b, s, 1H), 8.25
(d, 4H), 9.99 (d, 4H), 6.75 (s, 1H),
6.16 (s, 1H), 6.14 (s, 1H), 3.86 (s, 6H),
3.84 (s, 3H), 3.21 (t, 2H), 2.46 (m, 4H),
1.8-1.0 (m, 6H), 0.78 (t, 3H) Mass spectrum (EI, 70eV) m/z 751 (M ⁺ )

[Brief explanation of drawings]

Figure 1 shows tetrahydrofredericamycin A.
Figure 2 is the infrared absorption spectrum of the same substance, Figure 3 is ^{the 1} H− of the same substance.
It is a drawing showing an NMR spectrum. Figure 4 is the ultraviolet absorption spectrum of diacetyltetrahydrofredericamycin A, Figure 5 is the infrared absorption spectrum of the same substance, and Figure 6 is ¹ H-NMR of the same substance.
It is a drawing showing a spectrum.

Claims (1)

[Claims] First-order general formula () (In the formula, R represents a hydrogen atom, an alkanoyl group, a lower alkyl group, a lower alkoxy group, or a benzoyl group which may be substituted with a halogen atom.) A fredericamycin A derivative represented by: