CS219079B1 - /7s/-4-methoxy-0-/2-hydroxyalkyl/7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphtacenchinones and method of preparation thereof - Google Patents

Description

(54) {7S) -4-Methoxy-O- (2-hydroxyalkyl) -7,8,9,10-tetrahydro-B, 9,11-trihydroxy-5,12-naphthacenchinones, and process for their preparation

The present invention relates to (7S) -4-methoxy-O- (2-hydroxyalkyl) -7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenchinones and a process for their preparation. These substances are biologically active, as evidenced by microorganism testing.

Known compounds of similar structure include, for example, 4-methoxy-7,8,9,10-tetrahydro-6,7,9,11-tetrahydroxy-5,12-naphthacenchinone (daunomycinone) of formula I [Wong C.M. al., Can. J. Chem. 51, 488 (1973)]

which form the starting materials for the semisynthetic preparation of anthracycline derivatives, some of which find use in clinical practice as cancerostatics (glycosides - adriamycin, daunomycin, carminomycin). 382 (1970)].

Accordingly, the present invention provides novel compounds of the formula (7S) -4-methoxy-O- (2-hydroxyalkyl) -7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenchinones of formula II

(II) where n = i2--4 in a S- (7) configuration.

The invention further provides a process for the preparation of these novel compounds. Its essence is that the starting compound 4-methoxy-7,8,9, l ^l 0-tetrahydro-6,7,9, ll-tetrahydroxy-5,12-naftacenchinon formula I is reacted in a dry environment in the presence of benzene * p-toluenesulfonic acid catalyst with s, η-alkanediol, where n = 2-4, at a temperature of from 1.20 to 140 ° C for 8 to 12 hours, wherein the molar ratio of the starting compound of formula I k1, n-alkanediol ranging from 0.2: 3.2 to 6.5 to give a mixture of the two stereoisomers 7- (S) and 7- (R) of formula III:

(III) where n = 2-4, approximately 8: 1 ratio. The mixture is separated chromatographically, and the isolated 7- (S) III stereoisomer is then hydrolyzed in a 1:50 mixture of 2% hydrochloric acid and methanol. at 65 ° C.

The starting material of formula I was prepared by fermentation of a strain of Streptomyces coeruleorubidus [Blumauerová M. at al .: Folia Microbiol. 22, 275 (1977)]. It has been found by testing on Bacil substilis that compounds of the invention having the absolute configuration of 7- (S) of formula II are biologically active. They inhibit the growth of said test microorganism in the plate tests as shown in the appended table.

Table

Biological activity of compounds of formula II with configuration 7- (S), tested for Baeillus subtilis

Test substance ____ Inhibition zone (mm); . · 50 megabytes 16 megabytes

II; n-2 II; n —3 II; n = 4 Daunomycin

17.8 14.0 11.0 0 12.3 0 25.0 31.8

Sample preparation: 1 mg of the substance was dissolved in 1 ml of methanol and supplemented with 1 ml of phosphate buffer pH 7.0. It is further diluted with methanol-buffer (1: 1).

The following are examples of methods for making the compounds of the invention.

EXAMPLE 1 4-Methoxy-7,8,9,1'-O-tetrahydro-6,7,9,11-tetrahydro-oxy-5,12-naphthacenchino (1 g) was dissolved in 250 ml of absolute benzene with addition of 10.1 g of 1,2-ethanediol and 0.25 g of p-toluenesulfonic acid. The reaction mixture was left at 130 ° C for 9 hours. Water was added to the mixture and shaken with chloroform. After evaporation of the extract, the residue was separated by silica gel column chromatography (Herrmann, Germany), eluting with benzene.

Column chromatography gave a mixture of stereoisomers which was separated by preparative thin layer chromatography (Silufol R ²⁰ , Kavalier) in hexane:

• chloroform: methanol, 4: 5: 1. The individual isolated stereoisomers were hydrolyzed with 2% hydrochloric acid in methanol at 65 ° C for 0.5 hour. The reaction mixture was shaken with chloroform after addition of water. Hydrolysis was performed quantitatively to give 160 mg of the compound of formula II having an absolute configuration of 7- (S) and 20 mg of the derivative having an absolute configuration of 7- (R).

Compound with absolute configuration 7- (S) has mp 115-116 ° C (methanol), 1 H-NMR spectrum (591.797 MHz, CDCl 3, 25 ° C, TMS):

1.93dd [J = 14.7 and 3.7Ήζ, He _n ),

2.41s (3H, -COCH 3),

2.47dd (J = 14.7 and 1.8 Hz, Hs _d ),

2.91 and 3.24 AB (2H, J _AB = T8.3 Hz, C ₍₁₀₎ H2),

3.84 brs (4H),

4.08s (3H, OCH 3),

5.12mt (H, H7),

7.21-8.17mt (3H, aromatic protons),

13.23s (1 H, OH),

14.25s (1 H, OH); mass spectrum m / / z [ ^{, o} / o relat. intensity, composition):

442 (6.3 Ο23Ή22Ο9, M),

362 (1C6, C21H14O6)

344 (69, C 21 H 12 O 5).

Example 2,

In the same manner as in Example 1, a compound of formula II was prepared wherein n = 3, mp 121-122 ° C (chloroform-petroleum ether), 1 H-NMR spectra (59.797 MHz, CDCl 3 25 ° C, TMS):

1.88mt (2H),

2.43s (3H, COCH 3),

2.96 and 3.26 AB (2Ή, J _AB = 18.9Hz, _C10 ) H2),

3.76mt (4H),

4.10s (3H, OCH 3),

5, O4mt (TH, Hz)

7.32-8, 11mt (3H, aromatic protons),

13.29s (TH, OH),

T4, Q9s (1H, OH), and mass spectrum m / z (% relative intensity, composition):

456 (10.6, C 24 H 24 O 9, M),

3612 (166 ', C 21 H 14 O 6),

344 (44, C21H12O5)

36L (25, C 19 H 9 O 4).

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Example 3

In the same manner as in Example 1, a compound of formula II was prepared in which n = 4, mp 11'3 ° C (chloroform-petroleum ether), ^x H-NiMR spectra (59.797 MHz, CDCl 3, 25 ° C, TMS):

1.69mt (4H),

1.92 dd (J = 14.7 and 3.7Hz, He _n ),

2.41s (3H, COCH3),

2,41dd (J = 14.7 and 2.5Hz, H3 _d)

2.95 and 3.23 AB (2H, J _AB = 19.5'Hz, C ₍₁₀₎ H2),

3-, 7-0mt (4 H),

4, O8s (3H, OCH 3),

7.37dd (J = 2.0 and 8.3Hz, 1H),

7.77t (J = 8.3Hz, 1H)

8, O5, dd (J = 2, O and 8.3Hz, 1H,

13.3'ls (1H, OH),

113, S '6s (1-H, OH):

mass spectrum m / z (% relative intensity, composition):

470 (0.5, C25H26O9, M),

3162 (.100, C21H14O6)

344 (5-9, C 21 H 12 O 5),

301 (30, C 19 H 9 O 4).

All of these substances are characterized by an antimicrobial spectrum and can be expected to be used in the research of new therapeutic agents. In view of the known anticancer effect of this class of substances, they can also be used in the study of cancerostatics.

Claims (2)

SUBJECT (7S) -4-Methoxy-O- (2-hydroxyalkyl) -7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naphthacenchinones of formula II wherein n = 2 —4, in the S- (7) configuration. 2. A method for producing compounds according to claim 1, characterized in that the starting compound 4-methoxy-7,8,9, l ^l-0 tetrahydrO'-6,7,9, ll-tetrahydroxy-5,12-naftacenchinon INVENTION It formula I is reacted in absolute benzene in the presence of p-toluenesulfonic acid catalyst with Ι, η-alkanediol, where n = 2-4, at 120 ° C to 140 ° C for 8 to 12 hours, the molar ratio of the starting compound of formula I k1, n-alkanediol is in the range of 0.2: 3.2 to 6.5, the resulting mixture of two stereoisomers 7- (S) and 7- (R) of formula III, wherein n = 2-4, approximately in 8: 1 ratio The J is separated by chromatography and the isolated stereoisomer 7- (S) of formula III is then hydrolyzed in a mixture of 2% hydrochloric acid and methanol (0.150) at 65 degrees Celsius.