DE1275536B - Process for the preparation of antibacterially active sulfonic acid amide salts of aminomethyltetracycline, -7-chloro- or -5-oxytetracycline - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY Int. CL:

C07c

German class: A 61k GERMAN 4VN ^ PATENT OFFICE 12-25 Number: 12 q-6/03 File number: 30 h-2/36 EDITORIAL Registration date: 1,275,536 Display day: P 12 75 536.1-42 (G 41143) 1275 536 July 22, 1964 22nd August 1968

The invention relates to the preparation of sulfonic acid amide salts of aminomethyltetracyclines, -7-chlorotetracyclines or -5-oxytetracyclines the general formula

CH ₃ HO

N (CH ₃ ) ₂

HO O HO O
OH

CH, · H, N

SO ₂ -NH-R ₄

Method of making antibacterial
effective sulfonic acid amide salts of
Aminomethyltetracycline, -7-chloro- resp.
-5-oxytetracycline

Applicant:

Antonio Gallardo S. A., Barcelona (Spain)

Representative:

Dipl.-Ing. G. Schliebs, patent attorney,
6100 Darmstadt, Ludwig-Büchner-Str. 14th

'5 Named inventor:

Antonio Gallardo Carrera, Barcelona (Spain)

Claimed priority:
Spain of April 2, 1964 (298 251)

In this, R ₁ = H or OH, R ₂ = H or Cl; however, R _{1 must} not be OH when R ₂ = CI. R ₃ denotes the morpholyl, pyrrolidyl or piperidyl radical and R ₄ = H or the pyrimidine or 6-methoxypyridazine radical which is optionally substituted in the 2,6-position by two methoxy groups.

The formation of these salts, which are very sparingly soluble in water, can be carried out thanks to the acidic properties of the —SO ₂ —NH— group of the sulfonic acid amide and the basic properties of the tertiary amino groups of the tetracyclines.

These compounds are of great therapeutic interest because they are a broad antibacterial agent Own spectrum. It is possible to make stable suspensions of these compounds, namely for oral use as well as for injections with depot effect.

According to the invention, such compounds are synthesized by a reaction known per se a suitable aminomethyltetracycline, -7-chloro- or -5-oxytetracycline with 2-sulfanilamidopyrimidine ("Sulfadiazine"), 4- (4'-Benzolsulfamido) -2,6-dimethoxypyrimidine ("Sulfadimethoxin") or 3- (4'-AminobenzoIsulfonamido) -6-methoxypyridazine (»Sulfamethoxypyridazine«) in an organic solvent and cooling the reaction mixture or by usual double reaction of an alkaline aqueous solution of a sulfonic acid amide with the tetracycline.

Some examples are given below. example 1

The starting material is prepared as follows: 519 g of anhydrous tetracycline are suspended in 61 tertiary butyl alcohol and gives 120 g of shortly previously distilled morpholine and 84 g of a 37% strength Solution of formaldehyde added. The mixture must be stirred continuously and gradually within of 30 minutes to be brought to the boil.

With continued stirring and refluxing, 320 g of "sulfadimethoxine" (= 4 - (4 '- aminobenzenesulfonamido) - 2,6 - dimethoxypyrimidine) are added and the mixture is allowed to boil for a further 10 minutes. The resulting solution is filtered warm and rapidly cooled to 3O ⁰ C. The solid product obtained is filtered off, washed three times with tertiary butyl alcohol and dried in a stream of air at 30 ° C. for 24 hours. 989 g of the “sulfadimethoxine” salt of morpholinomethyltetracycline are obtained. The melting point is 140 to 144 ° C (decomposition).

Example 2

The pyrrolidinomethyltetracycline used as the starting material is prepared as follows: 519 g of tetracycline (anhydrous base) are suspended in 25 ml of tertiary butyl alcohol and, while stirring, adds 986 ml of pyrrolidine and 98 ml of 37% formaldehyde

809 597 474

3 4

solution added. The mixture formed is described under 2. They are fatal to Staphylococcus aureus

continued stirring gradually within 10Mi- dilutions between Viooooooo and Vioooooooo

utes brought to the boil. With continued rest and for the verified Escherichia coli-

Ren and refluxing one adds 327 g of strains in dilutions between Vioooooo

"Sulfamethoxypyridazine" (= 3- (4'-aminobenzene sul- 5 and Viooooooo ·

fonamido) -6-methoxypyridazine) added; Comparative experiments have shown the following advantageous ones

181 tertiary butyl alcohol and cools the mixture viamtchaftm ■

quickly to 30 ^° C. The solid product obtained ^ ¹⁸ ™ ^ "" ^ ¹

is filtered off, washed with tertiary butyl alcohol 1. With a single dose of 5 mg / kg orally and administered in a stream of air at 30 ° C. for 24 hours, bactericidal cones are dried in the serum. 990 g »sulfamethoxypyride concentrations for Staphylococcus aureus are obtained, azine "salt of pyrrolidinomethyl tetracycline. Enamel - which last for 18 hours after ingestion, point 149 to 152 ° C (decomposition). At this dose the following values are obtained:

The highest concentration is after 3 hours

Example 3 ₁₅ 39 minutes after ingestion at a value The starting material is prepared as follows: from 3.4 y / cm ³ ; after 8 hours it is 2.2 y / cm ³ ; 519 g of 5-oxytetracycline, 113 g of Mor- after 12 hours 1.6 y / cm ³ ; after 18 hours 1.1 y / cm ^{3 of} pholine and 110 ml of 37% formaldehyde solution in and after 24 hours 0.75 y / cm ³ . 25 1 tertiary butyl alcohol. The mixture is gradually brought to the boiling point of two capsules of 250 mg for persons of normal weight for 10 minutes with constant stirring. 3 hours concentrations that lie between 4 and 4.8 y / cm ³ with continued stirring and boiling, and the repetition of this dose flow cooler one adds 325 g of "sulfadimethoxine" every 8 hours produces fluctuating blood levels between and leaves that Boil the mixture for another 10 minutes. see 10 and 5 y / cm ³ , ie sufficient bacteria-One distills 18 l of tertiary butyl alcohol and 25 killing concentrations for most germs, which cools the mixture to 30 ^° C. The obtained are against this drug sensitive, solid product is filtered off, washed and 24 STUN from numerous clinical trials to be grounded dried in a 30 ⁰ C warm air stream. see that a clinical dose for moderately severe one receives 960 g of the "sulfadimethoxine" salt from cases two capsules of 250 mg every 8 hours of morpholinomethyl-5-oxytetracycline. Melting point includes 30 and that this antibiotic in many cases 168 to 171 ° C (decomposition). was successful and especially in cases where “. ■ \ λ previous treatments with tetracycline α e 1 s ρ 1 e 1 4 _{and anc} i _eren antibiotics not cured the sick The starting material is prepared as follows: had.

519 g of 7-chlorotetracycline are suspended in 201 35 2. The in nutrient broth with a pH of

tertiary butyl alcohol. While stirring, 120 ml of 7.4 comparative experiments carried out gave the following

Morpholine and 115 ml of 37% formaldehyde solution low average inhibitory concentrations:

added. The mixture is, with constant stirring, binding according to Example 1 of the invention 0.062 y / cm ³ ;

gradually heated to boiling for 5 minutes. Tetracycline 0.025 y / cm ³ ; Tetracycline and sulfonic acid

With constant stirring and boiling at the re-4 ° amide mixtures in equal parts (sulfamethoxy-

271 g of "sulfadiazine" (= 2-sulfanilpyridazine) 1 y / cm ³ compared to the staphylo-

amidopyrimidine) and leaves the mixture 5 Mi- coccus aureus, while for the Escherichia coli the

utes continue to boil. 19 1 of butyl alcohol are distilled to the corresponding inhibitory concentrations for the invented

and the mixture quickly cools to 30 ° C. duly manufactured product are 0.8 y / cm ³ , for

The solid product obtained is filtered off and the tetracycline is 6.4 y / cm ³ and for the mixture 12.8 y / cm ³ .

Solvent with a 40 ° C warm air stream 3. In »Die Antibiotika«, Verlag Hans Carl, Nuremberg

removed. 780 g of "sulfadiazine" salt are obtained from Berg, 1962, p. 506, it is stated:

Morpholinomethyl-7-chlorotetracycline. Melting point dl

137 to 141 ° C (decomposition). . ^ _{a) at the} ^ off

B is ρ ie 1 5 ⁵ ° intravenous 162 to 170 mg / kg

. ". ,. _,,. intraperitoneally 190 to 330 mg / kg

™? V Sf ^SOLUTION , ^vo ? _f ¹⁰ - ⁶ S anhydrous soda in _{al 2m to 3m m} ^ _k

200 ml of water dissolve 31 g of “sulfadimethoxine”. ^) _{Be the} i R _a tt _e

Regardless, one prepares a solution intravenously. 129 to 220 mg / kg

⁵⁴ U ^On , morpholinomethyl tetracycline hydrochloride 55 intraperitoneally 320 mg / kg

in 500 ml of water. The resulting solution adds 3000 mg / kg orally one of the previously prepared with vigorous stirring.

An insoluble precipitate is quickly secreted. ^The corresponding comparison results for the

of the "sulfadimethoxine" salt of morpholinomethyl- ^ 50 are:

tetracycline. The yield is 72.5 g, the 6 ° in rats

Melting point is 140 to 145 ° C (decomposition). intravenous

The compounds prepared according to the invention for "LAS 362" *) 197 mg / kg

exhibit the following properties, due to that for tetracycline 135 mg / kg

they differ from the group known as antibiotics orally

differentiate between tetracyclines: ⁶ 5 for »LAS 362« *) 13.5 g / kg

for tetracycline 4.3 g / kg

1. Their activity extends to gram-positive *} The "sulfadimethoxine" saiz of, prepared _{according to the example}

and gram negative germs. Morpholinomethyl tetracycline.

Claims (1)

Claim: Process for the production of antibacterially active sulfonic acid amide salts of aminomethyltetracyclines, -7-chloro- or -5-oxytetracyclines of the general formula HO N (CH ₃ ) ₂ OH 10 NH -1 R ₃ L-CH, • H ₂ N SO ₂ -NH-R ₄ in which R ₁ = H or OH and R ₂ = H or Cl, but R _{1 is} not OH when R ₂ = Cl, R _{3 is} the morpholyl, pyrrolidyl or piperidyl radical and R ₄ =. H or the pyrimidine or the 6-methoxypyridazine radical optionally substituted in the 2,6-position by two methoxy groups, characterized in that a suitable aminomethyltetracycline, -7-chloro- or -5-oxytetracycline is used in a manner known per se 2-sulfanilamidopyrimidine ("sulfadiazine"), 4- (4'-benzenesulfonamido) - 2,6 - dimethoxypyrimidine ("sulfadimethoxine") or 3- (4'-aminobenzenesulfonamido) -6-methoxypyridazine ("sulfamethoxypyridazine") in an organic Reacts solvent or its alkaline aqueous solution. Considered publications:
Austrian Patent No. 205 170;
French Patent No. 1194 208;
British Patent Nos. 799 044, 774 733, 573.