JPS6144867A - Novel fredericamycin a derivative - Google Patents

Abstract

NEW MATERIAL:A fredericamycin A derivative shown by the formula I (m is 0-4; n is 1-4). EXAMPLE:A dimethyl derivative of leucotetraacethylhydrofredericamycin A compound. USE:A carcinostatic. Having antitumor activity, and higher safety than fredericamycin A. PREPARATION:Fredericamycin A, an antitumor antibiotic shown by the formula IIisolated from a culture material of Streptomyces griseus FCRC-48, is reduced with a proper reducing agent, acetylated to give leucotetraacetyltetrahydrofredericamycin A shown by the formula III, which is alkylated to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of sedentary use] The present invention provides novel flebrimycin A derivative 1, more specifically, the following general formula (I) (wherein m represents the number of O to 4, n represents a number from 1 to 4).

[Conventional technology]

Conventionally, Streptomyces griseus F
Fredericamycin A, an antitumor antibiotic expressed by the following formula from the CRC-480 layer:
(Fredericarnycin A (NSC-3
05263): ] is known to be isolated (
J. Antibiotics 34, 1389-1.
401 pages (I981) and volume 34.

1402-1407 (I981)).

[Problem that the invention seeks to solve]

However, this frebrimycin A has a weak antibacterial effect and is unstable.

[Means for solving problems]

Therefore, in order to overcome these drawbacks of frebricamycin A, the present inventor synthesized various derivatives and examined their pharmacological action and stability, and found that frebricamycin represented by the above formula (I) The inventors completed the present invention by discovering that A derivative has excellent anti-urinary effect and is extremely stable compared to flebrimycin A.

Therefore, the present invention provides a flebrimycin A receptor (I) useful as an anticancer agent.

Among the 7-rederimycin human derivatives of the present invention, leucotetraacetyl expressed by the following formula 1) is produced by reducing flebrimycin A ([1) with a suitable reducing agent and then acetylating it] It is produced by subjecting nato2hydrofleterimycin A to an alkylation reaction. This alkylation reaction is alkyl iodide-
Using the silver oxide method, 0.0% was measured in a solvent such as 1-acetone, nooxane, or 1,2-dimethoxyethane at a temperature of 55 to 80°C.
It is preferable to carry out the treatment for 5 to 5.0 hours.

[For production]

The results of testing the antitumor activity and stability of the representative compound of the present invention thus obtained are as follows.

CL) Antitumor activity The therapeutic effect of fredericamycin A derivatives on Ehrlich carcinoma (Ehrlich) K was tested using the following method. The results are shown in Table 1. 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: 5 x 10' tumor cells were injected into ICR mice (♀).

After 24 hours, Compound 1 obtained in Example 1 was intraperitoneally administered once a day for a total of lθ times, and observation was continued for 45 days after the start of administration.

Table 1 (2) Stability The stability of Flegellymicin A derivative (I) and Flegellymicycin A (n) in an aqueous solution was tested by the following method. Kinuta is shown in Table 2.

Experimental method: Compound 1 and Fredericamycin A prepared in Example 1 were each dissolved in dimethyl sulfoxide, diluted with physiological saline, and the final concentration of the test compound was 10 μt/ml.
-Adjusted to -.

The obtained test solution was subjected to high performance liquid chromatography (HP
The residual rate of the test compound after a predetermined time was measured by LC method).

Table 2 [Effects of the Invention] As is clear from the results of the above stability test, the compound of the present invention has antitumor activity and also has higher stability than Fredericamycin A.

〔Example〕

Next, the present invention will be described with reference to Reference Examples and Examples.

Reference Example Production of leucotetraacetyltetranohydrofredericamycin A@): Dissolve 0.5Of of phlebrylic mineral A in tetrano1ide μfuran 30-, add 10% of 9radium carbon o, os
After adding r, catalytic reduction was performed at room temperature with stirring. After reacting for 10 hours, pyridine 10- and acetic anhydride 1- were added to the reaction solution in a nitrogen stream, and the mixture was further stirred at room temperature for 1 hour. This reaction solution was filtered, and solution F was added to ice-cooled n-hexane with stirring, and the resulting precipitate was collected. This precipitate was recrystallized from a chloroform-ethyl acetate mixture to obtain leucotetraacetyldetrahydrofledericamycin A (button yellow crystals at 0.539 (80%)).

Melting point: 273℃ (min%) W　λ6″)′ynm(#) ax 241 (51,300), 287 (68,400).

338 (I7,100), 352 (20,000) KB
r +1 ”” m1LX Tan 1780.1740, 1715, 1660, 1650゜1H-N1m electric δ ppnl (DMSOd -6) 1
2.96 (8, IH), 1L52° (s r L H)
e7.87 (s, IH), 6.90 (s, i
H), 6.35 (s, IH), 3.96 (s, 3
H), 3.16(t, 2H).

2.5 (m, 4H), 2.44 (8, 12H), 1.
8-i, 1 (m, 6H), 0.80 (t, 3H) + Mass M m/z 713 elemental analysis value (%) 03g H2S NOf! (Molecular weight 713.
69) as CHN Experimental value 63.93 4.95 1.93 Theoretical value 63
．． 95 4.94 1.96 Example 1 Leukotetraacetyltetrahalide fredericamycin A(I) 2.14 t (3 mmoj) K silver oxide 3
．． 48 t (I5 mmol) and 200 mm of acetone were added, and 15 m of methyl iodide was heated under stirring under reflux.
After the dropwise addition was completed, the mixture was heated for 1 hour under the same conditions, inorganic substances were removed by filtration, and the F solution was dried under reduced pressure.

The residual liquid was purified by silica dull column chromatography, and the yellow crystals obtained from the elution fraction with a 5% (v/v) acetone-toluene mixture were recrystallized from an inozolobyl ether-acetone mixture to obtain leucotetraacetyltetra. Pale yellow crystals 1.25f (yield: 56.3cm) of the dimethyl form of hydrofredericamycin A [formula (I), m==1 + n-=1 (compound 1)] were obtained.

Melting point: 147-149℃ tOH Takumi λ nrrl (ε) ax 241 (52,400), 285 (68,600).

323 (7,900), 337 (9,800).

360 (I0,000) 1785.1745, 1715.1620 Figure 1"H
-NMRδ pI)m (CPDlp@)7.26(
s, IH), 7-21 (s, IH), 6.88 (s, I
H), 3.97 (s, 3H), 3.91 (s-3H).

3.38 (s, 3H), 3.31 (t, 2H), 2.6
(m, 4H), 2.47 (s t3H) t2.46 (s
+3H)*2.41(s, 6H), 1.9~1.2(m
, 61), 0.89 (t, 3H) Figure 2 Mass M+m/z 741 Example 2 Same as Example 1 except that ethyl iodide was used instead of methyl iodide (I) In the formula, m=
2, a compound with n=2 (compound 2) was obtained.

Melting point: 131-132℃, pale yellow crystals tOH ■　λ　　　nm(ε) ax 241 (52,200), 285 (67,400).

323 (7,800), 337 (9,800).

360 (9,900) ■R, KBr ,,,,1 ax 1780.1740.1710.1620IH-NMR
δppm (CDCl5)7.28(s, It()
, 7.24 (s, IH) e6.89 (8, IH), 4.
48 ((I, 2H), 3.94 (!1, 3H).

3.62 (q 12H) #3.33 (t-28)-2,
6 (m, 4H), 2.48 (s, 3H) I2.46 (s
, 3) 1).

2.41 (s, 6H), 1.9~L2 (m,
9H), 0.88(t, 3H), 0.71(t
, 3H) Mass M+m/z 769 Example 3.4 0 Icotetraacetyltetrahydrofrederi Force Mycin AQi) 0.71 ? Add 1.169 (5 mmol) of silver oxide and 50 mmol of anhydrous dioxane to (ImmoA'), and add about 1 mol of butyl iodide while stirring at 70-75°C.
It was added dropwise over a period of minutes.

After the dropwise addition was completed, the mixture was heated under the same conditions for 30 minutes, the cold inorganic substances were removed using FjMt, and the solution E was dried under reduced pressure. The residue was separated and purified by silica gel column chromatography, and the yellow crystals obtained from the frozen 2% (V/V) acetone-toluene mixture elution fraction were reconsolidated from an isozolopylether-acetone mixture to obtain leucotetraacetyl. Sibutyl form of tetrahydroflebrimycin A ((I) in the formula, m
=4, n=4 (compound 3)] pale yellow crystals o, u
xp (yield 13.3%) was obtained.

Melting point 104-105℃ tOH Takumi λ nm (g) ax 241 (53,900), 286 (69,200), 3
23 (8,400), 337 (I0,300), 360
(I0,300) KBr -1 ■R'max α 1780.1735.1710.1615IH-NMR
221m (CDCJs)7.28(s, 1]H)*
7.24(s-IH)-6,89(s,IH), 4.4
2(t, 2H), 3.96 (as 3H).

3.56 (t, 2H), 3.33 (t, 2H), 2.6
(m, 41), 2.50 (s, 6H), 2.43 (s,
6H).

1,9-1.2 (m, 14)1), 0.9
1 (m, 6H).

0.58 (t, 3H) + M&ss M m/z 825 then 2
The yellow crystals obtained from the fraction eluted with ~5% (V/V) acetone-toluene mixture were recrystallized from an isozolobyl ether-acetone mixture to obtain the motuptil form of leucotetraacetyltetrano-idorofredericamycin A [(I ) in the formula,
m=0, n=4 (compound 4)] pale yellow Shaoxo o, 3o
y (yield 39.0%) was obtained.

", a 2" 8~220 C4゜ tOH W　λ　　nm(ε) ax 237 (57,700), 284 (67,900).

324 (9,800), 338 (I2,200).

358 (I0,900) Br IRν wound-1 ax 1780.1740, 1710.1615 Figure 3'
H-NMRa ppm (CDCIB) 8.94 (
s, IH), 7.23 (s, IH), 7.05 (s,
IH), 6.88 (8, IH), 4.47 (t, 2H
).

3.95 (8, 3H), 3.31 (t, 2H), 2.6
(rn, 4H) -2,50(s -6H) e 2.
43 (s -6H).

1.9-1.2 (m, 10H), 1.9 (m, 6H) Figure 4 + Mass M m/z 769

[Brief explanation of drawings]

Figures 1 and 2 show the IR and "H-N" of compound 1, respectively.
It is a drawing showing an MR spectrum. Figures 3 and 4 show the IR and IH-N of compound 4, respectively.
It is a drawing showing an MR spectrum.

Claims (1)

[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, m represents a number from 0 to 4, and n represents a number from 1 to 4.) A fredericamycin A derivative represented by