JPS6178796A - 14-formyloxy-4-demethoxydaunorubicin - Google Patents

Abstract

NEW MATERIAL:14-Formyloxy-4-demethoxydaunorubicin shown by the formula I. USE:The compound itself is useful as a carcinostatic agent, and is can be converted to 4-demethoxyadriamycin by subjecting the compound under hydrolyzing condition. PREPARATION:14-Bromo-4-demethoxydaunorubicin(salt) shown by the formula II is reacted with a formylating agent (e.g., sodium formate, etc.) preferably in a solvent (e.g., acetone, etc.) at 0 deg.C- room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 14-formyloxy-4-demethoxydaunorubicin represented by:

The 14-formyloxy-4-demethoxydaunorubicinin represented by the formula (1) of the present invention itself has anticancer activity comparable to adriamycin, which is an excellent anticancer drug, and has use as an anticancer drug. . Furthermore, 14-formyloxy- represented by the above formula <I) of the present invention
4-; Methoxydaunorubicin can be easily converted to 4-demethoxyadriamycin by subjecting it to hydrolysis conditions (see Reference Example 2 below).

In general, adriamycin derivatives are very unstable under alkaline conditions (for example, HoUmezawa et al.
et al., J., Ant 1biot,.
33. 15g 1 (1980); Special Publication Showa 47-465
97), when the 14-bromo form of formula (II) shown below is directly treated under alkaline conditions, only a low yield of 4-demethoxyadriamycin with low purity is obtained (see Comparative Example 1 below). . On the other hand, it is well known that formyloxy groups can be hydrolyzed and converted into hydroxyl groups under very weak alkaline conditions (for example, C6B, Rees
eet al, Tetrahedron Lett,,
4273 (1968)).

The present inventors focused on this point and found that 14-formyloxy-4-demethoxydaunorubicin would be a useful intermediate when trying to efficiently convert 4-demethoxydaunorubicin to 4-demethoxyadriamycin. Heading Completing the Invention.

14-formyloxy-4-demethoxydaunorubicin represented by the above formula fl) of the present invention can be produced by reacting the 14-bromo form represented by the formula with a formylating agent. The 14-bromo compound, which is a raw material, is a compound that can be easily produced by a known method (see JP-A-56-156300).On the other hand, as a formylating agent, an alkali metal salt of formic acid such as sodium formate, potassium formate, etc. Quaternary ammonium salts such as tetrabutylammonium formate, benzyltrimethylammonium formate can be used.

When carrying out the reaction, it is desirable to carry out the reaction in a solvent.
Examples of solvents that can be used include tetrahydrofuran,
Examples include organic solvents such as acetone, dioxane, methanol, and ethanol, or mixed solvents of these and water.

The reaction proceeds smoothly at 0°Q to room temperature.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference example 1 (a)-4-demethoxydaunorubicin hydrochloride 20.0
→(0,037 mmol), anhydrous methanol 0.5
R1, methyl orthoformate 0.02d anhydrous dioxane 0.
After stirring the 8Rt mixture for 15 minutes, a solution of bromine in anhydrous dichloromethane (Br21.221!/10mCff
(2C12)0.08- was added and stirred for 1 hour. 20 ml of anhydrous ether was added to the reaction solution to precipitate a precipitate, and after removing the upper layer, the precipitate was washed twice with ether 5 and dried in vacuum. Anhydrous acetone 8R1 was added to the obtained 14-bromo conductor and stirred at room temperature for 1.5 hours.
An acetone solution of 4-demethoxydaunorubicin hydrochloride was obtained. This product was immediately used in the reaction of Example 1 without isolation.

Example 1 To the acetone solution of 14-bromo-4-demethoxydaunorubicin hydrochloride obtained in Reference Example 1, 0.5 d of water and sodium formate 40Q (0.59 mmol) were stirred for 15 hours. After the reaction, the solvent was distilled off under vacuum, methanol/chloroform = 1/2, 50 mL of 5% hydrogen carbonate solution was added to perform liquid separation extraction, and the extraction was repeated with chloroform. Ta.

The extracts were combined, washed twice with water, dried over anhydrous sulfuric acid, and then the solvent was distilled off. After dissolving the obtained residue in a small amount of methanol-chloroform solution (1:9),
．． When 0.1*J of 2sMHC+methanol solution and 15-J of anhydrous ether were added, an orange precipitate was deposited. The precipitate was collected by filtration to obtain (th)-14-formyloxy-4-demethoxydaunorubicin hydrochloride. Yield 9.69 (4
5 pieces mp186-189℃ (dec) [α), +185° (CO, 040, CH30H) Ma
ss (SiN2): rrVz 542 (MH) + factory X total): 3400, 1725.1620, 1590α
.

'HNMR (d, s-DMsO): J 1-1
8 (m, d, J = 6Hz, 6'-H5), 1
．． 69-z, oo<m, m, 2'-H2).

2-02-2-32 (2H, rn, 87H2)
, 2-92(11(,d, J=19Hz, 1O-aX
-H).

3.2o(lH, d, J=t9Hz, 10-6%-H,
).

3. 44-3.69 (2H,m,3'-H+4'
-H).

4.10-4.40 (IH, m, 5'-H), 5.
01 (IH.

brs, νl/2=8Hz, 7-H), 5.3
4 (3I(.

br s, 14-H2+1'-H), 5. ．． 46(lH
,d.

J = 6Hz, 4-Of (disappeared at D20), 5.
74 (IH, S, 9-OH, disappears with D20), 7.
8.8 (3H1brS, disappeared with NH-20), 7.
96-8.12 (2H, m, ArH), 8.24-8.
46 (2H.

m, ArH), 8.40 (IH,s, 0CHO
), 13.36 (IH, br s, ArOH, D2
disappeared at C1).

13.56 (disappeared with IH, br s, ArOH, D20).

Reference Example 2 (t)-14-formyloxy-4 obtained in Example 1
-demethoxydaunorubicin hydrochloride 9.619 (0,0
17 mmol) was dissolved in 25 sui of methanol, and
, 4M of 1M NaOHO were added thereto, and the mixture was stirred at 0-5°C for 10 minutes. In the reaction solution, 50M of chloroform and 50M of saturated saline were added.
m was added and liquid separation and extraction were performed. The extract was washed with water and then dried with anhydrous sulfuric acid and IJum. The residue after distilling off the solvent is
HcIV/MeOH=0.25M after dissolving in V12R1
HCI / Evening / -Le fljWIt O, 10m
An orange precipitate was deposited. Add 15ml of anhydrous ether, collect the precipitate by filtration, and vacuum dry over KOH...-4
-demethoxyadriamycin hydrochloride was obtained.

Yield 1t6.3q (671 mp225-228℃ (dec) [α), +187° (c O, 030cHsOH) Ma
s s (8HMS) :rriz514 (MH)+
, 384 (aglycone) 1 1R (lG3r): 3400 (OH, NH), 1725
(Co), 1620 (quinone), 1590 (fragrance *>儂-1゜'HkonIR (d6-1Ml0): J l -
16 (3H, d, J = 6) (Z, 6'-Hs)
, l-702-00 (2kl-rn-2'-H2)
.

2-00 2.30 (2)1. m, 8 H2),
3.02 (Aim, 8.10-H2), 3-40-3-6
8 (2) (, m.

3'-H+4'-H), 4.21(IH, (1, J=5
Hz, 5'-H), 4.60 (2H, brdd
, J=sHz, 14-H2, brd-os at D20
), 4.82 (IH, d, J = 5Hz
, 4'-OH.

D20te disappearance), 5.01 (IH, br s, yl/2
=8)(z,7-H),5.34(IH,br
s, yx/2=6Hz, l'-H), 5.47(I
H,s,9-OH.

Disappeared at D20), 7.90-8.10 (2H, m.

ArH), 8.22-8.42 (2H, m, ArH
).

Elemental analysis value: C26H28CIN01o, 1.75H2
Calculated value as 0: C153,70, H; 5.43,
N; 2.42 Analysis value: C; 53.63,) I; 4
．． 91, N; 2.09th Comparative Example 1 In the same manner as in Reference Example 1 (-1-1-4-demethoxydaunorubicin hydrochloride 10ml (0,019mmo+
) was converted to 14-bromo-4-demethoxydaunorubicin hydrochloride. The obtained 14-bromo compound was dissolved in 1N methanol, and 31 Ll of a 5% aqueous potassium carbonate solution was added.
After treatment at 0°C for 5 minutes and then at room temperature for 15 minutes,
Adjust the pH to 8 with M hydrochloric acid, extract with chloroform, wash with water,
It was dried (Na 2804 ) and the solvent was distilled off. The residue was dissolved in a small amount of methanol, 0.05-methanol of 0.25M HCl was added thereto, and then anhydrous ether 101 was added to precipitate an orange color. Filter the precipitate,
2. ．． This product obtained 1 cape is Q) 198-20
It showed 4°C (dec). T.L.C.

A chemical analysis revealed that it was thought to contain (t)-4-demethoxyadriamycin hydrochloride, but its purity was very poor.

Test Example 14-formyloxy-41, daunorubicin/-demetquine obtained in Example 1 was found to have the following properties as a result of a cell proliferation test using mouse lymphocytic leukemia cells (+) 388).
Compared to adriamycin, which is known to be an excellent anticancer agent, it showed almost the same activity in inhibiting growth of 50%. That is, mouse lymphocytic leukemia cells (9388X10
RPMI-t 640 culture medium containing % calf fat serum, and cultured cells were cultured at 5 x 10' cells/cells in an orderly manner. A solution of N-added methanol solution of saltwater oysters was sequentially diluted with culture medium and cultured at 37°C for 2 days. Measurements are made using a Coulter counter.
The number of floating cells was measured using er Counter )y9- and the results shown in FIG. 1 were obtained.

[Brief explanation of the drawing]

Figure 1 shows the results of a mouse lymphocytic leukosuppressive cell Cp3BB"XD cell proliferation test using 14-formyloxy-4-demethoxy≦Cn¥52=4gin and adriamycin. The vertical axis is p388. The growth suppression rate ((6) is
The horizontal axis is the concentration (mM).阜／Koichi---0---- 7 Zoria Mine--I4-Yonoruskin-4-Puttuto Shift Unorubishin Hand
Continuing amendment (spontaneous) July 3, 1985 4￥Revision Agency Director Gakudono Shiga1, Indication of the case 1982 Momme Patent Application No. 1987182, Name of the invention 14-Formyloki/-4-Demethoxydaunorubicin 36. Person who makes an amendment Column 5 of "Detailed Description of the Invention" of the specification, contents of the amendment 1) IX Specification, page 5, line 6, 2) Page 7, line 4 of the same: "Correction.

Claims (1)

[Claims] (1) 14-formyloxy-4-demethoxydaunorubicin represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼.