HU225521B1 - Process for producing 7-nitro-9-(substituted amino) 6-demethyl-desoxytetracycline derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to the preparation of 7-nitro-9- (substituted amino) -6-desmethyl-6-deoxy-tetracycline compounds of formula (III), and salts thereof. These compounds can be used as intermediates for the preparation of antibiotic compounds. In the above formulas, the substituents are: Y is nitro, R is carbamoyl, or R4 (CH2) nCO where n = 1-4 and R4 is C1-6 alkylamino. EN 225 521 Β1 Scope of description 4 pages (including 2 sheets)

Description

The present invention relates to the preparation of 7-nitro-9- (substituted amino) -6-desmethyl-6-deoxytetracycline compounds of formula (III) and pharmaceutically acceptable organic or inorganic salts thereof.

The compounds of the present invention serve as intermediates for the preparation of compounds of formulas I and II. The compounds of formula (I) and (II) have significant antibiotic activity and are thus used in the form of pharmaceutical preparations against microorganisms.

U.S. Patent No. 3,338,963 and J. Med. Chem. Issue 4, 405-407. Spencer et al. (1963) describe compounds of similar structure to those of the present invention, but there is no indication of their use as intermediates in the preparation of other compounds having potent antibacterial properties.

The process of the present invention is carried out by reacting 9- (acyl- or sulfonylamino) -6-desmethyl-6-deoxytetracycline (14) in which R is as defined below with strong nitric acid or a metal nitrate. in an acidic medium.

In the formula (III), the substituents have the following meanings:

Y is nitro,

R is carbamoyl, or R ⁴ (CH ₂ ) _n CO-, where n = 1-4 and

R ⁴ is C 1-6 alkylamino.

For example, compounds of formula (I) are prepared from compounds of formula (III) by reacting a compound of formula (III) wherein Y and R are as defined above with an appropriate C 1-4 straight or branched aldehyde or ketone in the presence of an acid and hydrogen. (See Hungarian Patent Application Publication No. T 63 045 for details.)

The compounds of the present invention are prepared from the starting compounds of formula (14) which are unsubstituted in position 7. The 7-substituent compounds can be nitrated to give compounds of formula III.

There are two ways to nitrate:

(a) using nitric acid in a sulfuric acid solution, or

b) using a nitric salt such as potassium nitrite in a sulfuric acid solution.

Example 1 [4S- (4a, 12aa)] - 4- (Dimethylamino) -7-nitro-9 - [[(hexylamino) acetyl] amino] -1,4,4a, 5,5a , 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide disulfate

In the 7-position, the unsubstituted starting material in the other positions is dissolved in concentrated sulfuric acid and 1 molar equivalent of potassium nitrite is added at 8-10 ° C. The reaction mixture was stirred for 1 hour and then poured into ether. The final product is isolated as a yellow product.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 0.88 (t, 3H), 1.2-1.4 (m, 6H), 1.55 (m, 3H), 4.05 ( bs, 2H), 4.3 (s, 1H), 8.9 (s, 1H), 9.05 (s, 1H), 9, 55 (s, 1H), 10.0 (bs, 1H) and

10.45 (s, 1H).

MS (ES) 616.2 (M + H) @ +

2-4. examples

By following the procedure described in Example 1 and using the appropriate starting material, the following compounds can be prepared.

Example 2 [4S- (4a, 12aa)] - 4- (Dimethylamino) -7-nitro-9 - [[(butylamino) acetyl] amino] -1,4,4a, 5,5a , 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide disulfate ^1H-NMR (300 MHz, _DMSO-d6): δ 0.88 (t, 3H),

1.25-1.7 (m, 5H), 4.05 (bs, 2H), 4.25 (s, 1H), 8.9 (s,

1H), 9.05 (s, 1H), 9.55 (s, 1H), 9.95 (bs, 1H) and

10.45 (s, 1H).

MS (ES) 588.3 (M + H) @ +

Example 3 [4S- (4a, 12aa)] - 4- (Dimethylamino) -7-nitro-9 - [[(propylamino) acetyl] amino] -1,4,4a, 5,5a , 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide disulfate ^1H-NMR (300 MHz, _DMSO-d6): δ 0.9 (t, 3H), 1.5-1.8 (m, 3H), 4.05 (bs, 2H), 4.3 (s, 1H), 8.9 (s, 1H), 9.05 ( s, 1H), 9.55 (s, 1H), 9.95 (bs, 1H) and 10.4 (s, 1H). MS (ES) 574.1 (M + H) @ +

Example 4 [4S- (4a, 12aa)] - 4- (Dimethylamino) -7-nitro-9 - [[(1,1-dimethylethylamino) -acetyl] -amino] -1,4 , 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide disulfate ^1H-NMR (300 MHz, _DMSO-d6):? δ 1.3 (s, 9H), 1.5 (m,

1H), 4.15 (bs, 2H), 4.3 (s, 1H), 8.95 (s, 1H), 9.1 (s,

1H), 9.6 (s, 1H), 9.95 (bs, 1H) and 10.4 (s, 1H).

Claims (1)

Patent Claim Point A process for the preparation of compounds of formula III and organic or inorganic salts thereof, wherein Y is nitro, R is carbamoyl, or R ⁴ (CH ₂ ) _n CO-, where n = 1-4 and R ⁴ is a C 1 -C 6 -alkylamino group characterized in that a 9-acylamino-6-desmethyl-6-deoxytetracycline of formula (14) wherein R is as defined above with nitric acid or reacting with a metal nitrate in a strong acidic medium.