DE1767701C - Tetracycline n-alkyl sulfamates - Google Patents

Description

1 2

The invention relates to tetracycline-n-alkyl spraying of the alcoholic liquid in fine partial

sulfamates of the general formula chen with subsequent evaporation of the ventilation

TR _NH cfi H can be obtained by means of converting the particles into a

Bring ^{1 R} _{NHbU 3} H warm gaseous stream.

where T is tetracycline and R is n-hexyl, 5 Another method of preparation, starting from the represents n-dodecyl or n-hexadecyl group. These same n-alkyl sulfamic acids and tetracycline be compounds are excellent as anti-'stands in an "in situ" production of an aqueous biotic table Remedies with excellent local decomposition of alkali or ammonium n-alkyl sulfamate tolerability by all routes of administration. the corresponding carbon number in the alkyl

Tetracycline hydrochloride and tetracycline cyclo- io chain with direct re-crystallization of the acids with hexylsulfamate are for use as antibiotics telu of the desired base and in that one this known. However, these compounds have a solution with an aqueous solution of the tetracycline equally high acute toxicity. Furthermore, after a mineral acid is converted in the form of a salt, Its injection has a relatively quicker effect, which can also be done, if necessary, before the new case one. Finally, the known distribution reactions are suitable. Then you isolate The desired tetracycline-n-alkyl sulfamate does not bind particularly well for parenteral supply administration, as it is administered on this filtration, washes and dries it under diminution-ways Are poorly tolerated and complications are system pressure at moderate temperature in the presence can evoke. · Of phosphoric anhydride.

Surprisingly, it has been found that the temperature required for the reaction of the compounds according to the invention is determined essentially in all cases by the dissolution administration in all ways, in particular also the possibility of the n-alkyl sulfamates in water, renterally, with good Tolerance is particularly good because the longer the alkyl chain, the fewer salts, the toxicity of the compounds according to the invention being soluble and the higher the temperature required for the bonds about 3 to 4 times lower than the previous ones in order to bring about a solution, where the comparison substances mentioned are. Furthermore, in the case of thermal decomposition of the tetrahedra, the compounds according to the invention must avoid a cycline.
longer residence time in the Bluioahn so as you can the two reactants in ineffective waste into larger / i ^Ze: tintervallen domestic substantially stoichiometric amounts of use,
can be injected as the well-known tetracycline 30 The n-alkylsulfamic acids and their alkali or derivatives. Ammonium salts can be produced using known methods

Compounds of the invention, which are indicated as active ingredients in ren, which serve in detail in the following Beispieden pertaining medicaments, are indicated len,
by good solubility in organic solvents. The n-alkyl sulfates thus obtained from tetra-agents, especially in aliphatic alcohols and cyclin, generally have excellent glycols. Their solubility in water is of a higher degree of purity, but if necessary they can be subjected to additional purification, depending on the length of the alkyl chain, the greater the degree of solubility they are in a number of the carbon atoms of the alkyl radical. This alcoholic solvent or in acetone dissolves and fact, combined with a good stability of the 40 new substances from a weakly polar medium, such as ethyl ether, allows advantageous applications or anhydrous isopropyl alcohol, precipitates,
Depending on the task at hand, as pharmaceutical preparations that have an immediate and intense effect or that of the compound ^ 1 according to the invention are explained in the following examples.
Preparations with a long-term effect.

The tetracycline salts according to the invention can be used 45 Example 1
by producing the relevant n-alkyl

sulfamic acid in a moderately heated alcoholic solution. The starting material is prepared as follows: solution with the tetracycline base until complete To a solution of 121.5 g n-hexylamine solution of the two reaction components react (1.2 mol) in 500 cm ^{s of} chloroform, it is added dropwise, whereupon the desired product is isolated by a solution of 46.7 g of chlorosulfonic acid conventional means, for example by evaporation (0.4 mol) in 150 cm ^{3 of} chloroform with vigorous fening of the solvent under reduced pressure in a freezer provided with or by filling by adding a slightly polar solvent to the reaction medium, which is protected from ambient moisture, and ben. The mixture is stirred for 15 to 30 minutes, during which time the tetracycline-n-alkylsulf-55 formed and then the solution by means of 500 cm 2-n matronamate are insoluble. lye extracted. After releasing the aqueous

The alcohol used as the reaction medium is removed from the residual chloroform by mixing

is preferably 95% or anhydrous ethyl vapors under reduced pressure are SOvolu-

alcohol or isopropyl alcohol, and the moderate sulfuric acid is carried out until it is completely precipitated

Reaction added at a temperature in the range of 30-60. The crystals obtained are with

up to 60 ° C. Then the most common precipitation water washed (two to three times with each

liingsmcdium is Athytiither or anhydrous (such a volume fraction of 10 to 15 cm ^s ) and finally

propyl alcohol or petroleum ether and dried in a vacuum chamber at 60 ° C,

cases their mixtures were correct. There are 36.8 g (yield: 50.7 »/ 0) n-hexyl

Except for the above-mentioned procedures 6s sulfenic acid in the form of scale-like crystal

ztef Isolation of the new compounds from their oils, they are soft to the touch, in cold

alcoholic solution, these can be sparingly soluble in warm water and in ali-

ri'n working method naughty »fog formation«, i.e. soluble in volatile alcohols, as well as in chloroform

moderately soluble and very sparingly soluble in ethyl ether are received. Melting point: 140 to 143 ° C (Kofier). The infrared spectrum (KBr beads) shows the following characteristic bands: 3.22 μ, 3.4 μ, double bands at 9.25 and 9.3 μ, 12.95 μ and 13.9 μ and a high intensity band at 8 μ,

When titrating a sample dissolved in methanol with 0.1 η sodium hydroxide solution in the presence of phenolphthalein a content of 100.3% was found.

According to the invention, 18.13 g (O ₁ IMoI) n-hexylsulfamic acid, as obtained above, are then dissolved in 200 cm ^{3 of} absolute ethanol at 40 to 45 ° C. 44.44 g (0.1 mol) of anhydrous tetracycline base or the equivalent amount of the partially hydrated product were added to the resulting solution with vigorous stirring until it was completely dissolved. The stirring and the temperature are maintained for 15 to 20 minutes.

The reaction mixture is cooled to ambient temperature and poured into the six to * o seven times the volume of ethyl ether poured. The precipitate formed is filtered or decanted, it is washed by trituration with petroleum ether or hexane, filtered and under reduced pressure for several hours Print, preferably dried at 40 to 45 ° C.

There are 53.2 g of tetracycline n-hexyl sulfamate (Yield: 85%>) in the form of a light yellow powder, soluble in water, in aliphatic alcohols and in glycols and insoluble in ethyl ether, petroleum ether and hexane. Melting point 153 to 159 ° C with decomposition (Kofier; acetone: ether). The pH a 3% solution in distilled water is about 2.4. The infrared spectrum (KBr beads with the incorporation of alcohol to dryness) results in the following: main maxima: 3.05; 3.4; 6.4; 6.95; 8.2; 8.5 u; Double bands at 9.45 and 9.6 u.

Elemental analysis:

found N 6.63, S 4.95%>;

calcd for C ₂₈ H ₃₉ N ₃ O ₁ , S .. N 6.71, S5.12 ^o / o.

45

Bacteriological effect

(based on tetracycline hydrochloride):

Diffusion method 758; 765 · /. mg

Theoretical effect 768.5 y / mg

Example 2

To 250 cm "of absolute ethyl alcohol, 33.5 g of n-hexylsulfamic acid are added with stirring, and the mixture is heated to 40 to 45 ^ C until complete Dissolution heated. Then 82.1 g of anhydrous tetracycline base are added continuously Stir and add while maintaining the temperature until everything is dissolved. Man if the mixture is allowed to react for at least 30 minutes, the solution is freed from impurities by filtration and evaporated to dryness under reduced pressure. The product obtained is crushed and dried in a vacuum chamber at 50 to 60 ° C for several hours.

IUg (yield: 8.5 ^e / o) of tetracyeline-n-hexyl sulfan, which has the same characteristics as the product obtained according to Example 1, is obtained.

Example 3

5.30 g (0.02 mol) n-dodecylsulfamic acid are dissolved in 100 cm ^{3 of} 0.2 η sodium hydroxide solution at 50 to 60 ° C. The solution is obtained with intensive stirring, a solution of 9.62 g of tetracycline hydrochloride being added dropwise in 150 cm ^{: 1 of} water is added, it is stirred for 20 minutes at 50 to 60 ° C., after which the liquid of the precipitate formed is decanted, washed by ^{suspending it in 200 cm 3 of} water, filtered and the cake is repeated twice at 50 cm ¹¹ Washes water and dries in a vacuum chamber at 60 ° C in the presence of phosphoric anhydride.

There are 12.6 g (yield: 89%) of tetracycline n-dodecyl sulfamate in the form of a light yellow powder, which is practically tasteless, very little soluble in water, soluble in ethyl alcohol, isopropanol, propylene glycol, acetone, soluble in warm chloroform, almost is insoluble in ether and insoluble in petroleum ether or hexane. Melting point: 133 to 140 ° C (acetone: petroleum ether). The infrared spectrum (KBr beads with incorporation of alcohol) shows the following main maxima: 3.05; 3.42; 3.5; 6.22; 6, J5; 6.9; 8.2; 8.4 μ and double bands at ° .67 and 9.76 μ.

Elemental analysis:

found NT 5.82, S 4.45 "..:

calculated for C ₃₁ H ₅₁ N ₁ O _n S .. N 5.94, S 4.51 ¹ Vo.

Bacteriological effect

(based on tetracycline hydrochloride):

Diffusion method 670; 'mg

Theoretical effect 677; ·. mg

Example 4

32.15 g of n-hexadecylsulfamic acid (0.1 mol) are ^{suspended in 300 cm 3 of} absolute ethanol at 35 to 40 ° C. with stirring. 44.44 g of anhydrous tetracycline base (0.1 mol) or the equivalent of a partially hydrated product are added to the mixture until the two reaction components have dissolved. Stirring is continued, the temperature is maintained for 20 to 30 minutes and the solvent is evaporated to dryness under reduced pressure. The product is crushed and dried in a chamber at 50 to 60 ^° C. with a vacuum of less than 1 mm.

There are 74.3 g (yield: 97.0%) of tetra -yclin-n-hexadecyl sulfamate. a light yellow powder, tasteless, insoluble in water, soluble in aliphatic alcohols, acetone, chloroform, slightly soluble in ethyl ether and insoluble in petroleum ether.

Melting point: 132-136 ⁰ C (Kofler). The infrared spectrum (KBr beads, drying with alcohol) shows the same bands as the dodecylsulfamine homologue, but with relatively different intensities.

Elemental attack:

found N5.42, S4.01%;

calcd WrC ₁₁₈ H ₁₉ N ₅ O ₁₁ S .. N 5.49, S 4.18 "O.

Bacteriological effect

(relative to tetracycline hydrochloride):

Diffusion method 612 y / mg Theoretical effect 628 y / mg

Claims (1)

5 6 B ei β Di el 5 ^b ) Semi-acute toxicity: The ^p searches show a generally good tolerance for Using the tetracycline-n-dodecylsuifamate described in Example 4 as well as in The procedure is 321.5 g (1 mol) of n-hexadecyl tetracycline n-hexyl sulfate. It was at six sulfuminic acid dissolved in 1,000 cm ^{: 1} isopropanol and 5 male rabbits that within 30 days 444.4 g (1 mol) of anhydrous tetracycline base added equivalent of 50 mg / kg per day of the compounds ben to a solution of tetracycline-n-hexadecyi- administered, and they were well tolerated (a sulfamate in isopropanol. The dose received higher than the therapeutic dose, which is 10 to Solution is converted into mist form. 25 mg / kg / day). In this way, 705 g (yield: 92 ^β / ο) ίο. Get tetracycline-n-hexadecylsulfamate, which has the ² · acuity spectra same characteristics as that according to the previous- These were obtained by the dilution method using has the product obtained in the example, but determines a large number of different germs, with a lower bulk weight. and it was found that no significant Below are some toxicological, pharmaceutical differences within the activity spectra of Ecological and clinical trials listed the two of the two compounds mentioned at the outset in particular with two compounds, namely tetra according to the invention and other forms of cyclin-n-hexylsulfamate and tetracycline-n-dodecyl-tetracycline, sulfamate, the typical representatives of this compound "_, ... fertilize, were carried out. »O ³ · Tolerance and Absorpt.on , _. . Various attempts have been made with tetracycline i. loxicity n-hexyl-and-n-dodecylsulfamal executed, soft a) Acute toxicity (toxicity peak). The DL _S? - Good tolerance with intramuscular administration value, determined in mice by means of oral administration to rabbits, is below 2 g / kg for the two compounds fertilize. In the case of intraperitoneal administration, the claim is: the value about 659.8 mg / kg for the tetracycline-tetracycline-n-alkylsulfamate of the general n-Dodecyl sulfamate, approximately 567.3 mg / kg for the formula Tetracycline-n-Hexyl Sulphamate and approximately 856.5 mg / T- (R - NHSO ₃ H) kg for the tetracycline n-hexadecyl sulfamate. For the 30th Tetracycline hydrochloride is found when using wherein T is tetracycline; and R is a ri-hexyl, the same technique about 186.4 mg / kg. represents n-dodecyl or n-hexadecyl group. 1 sheet of drawings 183