SE444172B - PROCEDURE FOR PREPARING PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS OF 1-N-ETHYLSISOMICINE - Google Patents

Description

The salts are prepared by known methods, such as by neutralizing the free base with the acid in question to about pH 5. Suitable acids for this purpose include those such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid / hydrobromic acid, acetic acid, propionic acid, maleic acid, ascorbic acid, citric acid, etc. Physically, the acid addition salts of the compounds of the invention are characterized as white solids, which are soluble in water, sparingly soluble in most polar solvents and insoluble in non-polar organic solvents.

The present compounds constitute broad-spectrum antibacterial agents which advantageously exhibit activity against many organisms, especially gram-negative organisms, which are resistant to their 1-N-unsubstituted precursors. Thus, they can be used separately or in combination with other antibiotics to prevent the growth or reduction of the number of bacteria in different environments. They can: for example, be used directly for disinfection of laboratory glass, dental and medical equipment contaminated with Staphylococcus aureus or other bacteria, can be inhibited by the compounds obtained according to the invention. The activity of the compounds against gram-negative bacteria makes these compounds extremely effective in controlling infections caused by gram-negative bacteria, such as species of Proteus and Pseudomonas. A They have veterinary use, especially in the treatment of mastitis in cattle and Salmonella-induced diarrhea in domestic animals, C such as in dogs and cats.

The starting material for the process according to the invention can be prepared according to known methods from sisomycin. 1-N-ethylation of sisomicin is preferably carried out by reaction with acetaldehyde in the presence of a reducing agent, as shown in Example 1.

Example 1. 1-N-ethylsisomicin A solution of 5 g of sisomicin in 250 ml of water is added with 1N sulfuric acid, until the pH of the solution is adjusted to about 5. The resulting solution of sisomicin sulfuric acid addition salt is added with 0.85 g of sodium cyanoborohydride. Continue stirring for 15 minutes at room temperature, concentrate the solution in vacuo to a volume of about 100 ml, treat the solution with a basic ion exchange resin [such as Amberlite JI IRA 4015 (OH-)] and lyophilize to a residue, comprising 1-N -style sisomycin. g 7805684-3 É 3 Purify by chromatography on 200 g of silica, eluting with the lower phase of the system chloroform / methanol / 7% ammonium hydroxide 2 (2: 1: 1). Combine equal eluate, as determined by thin layer chromatography, and concentrate the combined eluates of the major component in vacuo to a residue, comprising 1-N-ethyl-sisomicin (yield 1.25 g). Purify again by chromatography on 100 g of silica gel eluting with the system chloroform / methanol / 3.5% ammonium hydroxide (1: 2: 1). Pass the combined, similar eluates (as determined by thin layer chromatography) through a column of basic ion exchange resin and lyophilize the eluate to give 1N-ethylsisomicin 3 (yield o, s4 9), [a1š6 + 1s4 ° (0.3 s, a2o); PMR (ppm) (n20) = _; 1, os f (3H, t, J = 782, -CH2C§3); 1.19 (3H, δ, -C-C§3); 2.5 (3H, s, N-CQ3), 1.85 (1H, m, = C§-); 4.95 (1H, d, J = 4Hz, H1); 5.33 (lä, d, J = 2.5H¿ H1 '). + * Mass spectrum: (M + 1) m / e 476 also m / e 127, 154, 160, 173, 191, 201, 219, 256, 299, 317, 332, 345, 350, 360, 378, 390, 400 .

Example 2. Acid addition salts Sulfuric acid addition salts of 1-N-ethylsisomicin Dissolve 5.0 g of 1-N-ethylsisomicin in 25 ml of water and adjust the pH of the solution to 4.5 with 1N sulfuric acid. Pour the solution into about 300 ml of methanol while stirring vigorously, continue stirring for about 10-20 minutes and filter. Wash the precipitate with methanol and dry at about 600 in vacuo to give 1-N-ethylsisomicin sulfate.

NMR spectrum of 1-N-ethylsisomicin sulphate g 20% (w / v) solution in denteric oxide with sodium 2,2-dimethyl-2-sila-pentane-S-sulfonate so-:. ~ o as internal reference: 20 C Proton Chemical shift Intensity Multiplicity ötppm) 1-NHCHZCH3 1.33 3H triplet; J = 7Hz 4 "-CH3" 1.35 3H singlet 2.3 1.67 - 2.83 In 48 multiplets 3 "-xacaa 2.93 L sa singleæz 1-NHCH CR 3_18 _ ZH quartet; J - 7Hz 2 3 7805684-3 3. 5 ”-axial 2. 1" 4. 1.

HDO 3:45 3.47 1H 18 18 18 1H doublet: J doublet, J doublet of J = 4Hz, doubletï J J multiplet doubletz J 11HZ 12Rz doublets 10Bz 4Hz 1.5Hz lf _ \ v. Ha. A; f '.' »ÏÄ5; §i -». ÃÉÄ; '~:? HOW: «

Claims (1)

7805684-3 PATBNTKRAV A process for the preparation of pharmaceutically acceptable acid addition salts of 1. -N-Ethylsisomicin having the formula CH 2 NH 2 N 2 O 3 / Naczus 0 93 N32 QI Ho HC Nncn 3 is characterized in that a compound of formula I in the free base form is reacted with acid and thus the acid addition salt obtained is isolated.