DE1914194A1 - New alpha-6-deoxy-5-oxytetracyclines - Google Patents

Description

DR. JUR. DIPL-CHEM. WALTER BEIL

ALFREDHOEPPENER March 19, 1969

DR. JUR. DIPL-CHEM. H.-J. WOtFP DR. JUR. HANS CHR. AX

FRANKFÜRT AM MAIN-HOCHST ADaONSIRASSESa

Our no. 15 424

Chas. Pfizer & Co., Ine New York, N.Y., V, St.A.

New α -ö-Deoxy-S-oxytetracyclines.

The present invention relates to the preparation of new derivatives of the α -ö-Deoxy - ^ - oxytetracycline, the find therapeutic use under oral and parenteral administration. In particular concerns the Invention the preparation of the Mannich bases of the α-6-deoxy-5-oxytetracyclines and the corresponding pharmaceutically acceptable acid addition salts.

06-S-Deoxy-S-oxytetracycline is a valuable therapeutic agent (see. US Pat. No. 3,200,149), which is extremely effective against gram-positive and gram-negative microorganisms is effective.

The tetracyclines have a problem that intravenous and intramuscular and oral administration are very difficult. In general, aqueous solutions of the active ingredients are preferred for intravenous and intramuscular administration, but oc -6-deoxy-5-oxytetracycline and the other tetracycline bases are only very sparingly soluble in water, which is why aqueous dosage forms are unsuitable. By using

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water-soluble derivatives of tetracyclines, the Prob®ira has already been tackled. Preferred derivatives too for this purpose were the Mannich basers. made by condensation des tetracyclines with formaldehyde and a primary or secondary amine. Tetracycline mannich "bases were also made with amino acids. In addition to the improved water solubility there is another advantage (fer Mannich bases in that it is less toxic when administered parenterally are than the corresponding Staram connections.

The Mannich bases of the Qi / -6-Beoxy-5-oxytetraeycline are more water soluble than the parent compound, wad their acid salts exhibit in aqueous media when standing or when adjusting the pH from about 3 to 8 no rapid hydrolysis and precipitation. Furthermore, the novel compounds of the invention are rapidly and completely absorbed in the digestive tract. The compounds provide protection to animals against various infections, which are artificially or naturally caused. The compounds are also particularly suitable for parenteral administration since they give a longer lasting serum level than the corresponding parent compounds when administered intramuscularly. The improved water solubility over a wide pH range also makes them superior to parent antibiotics for intravenous administration. The acid addition salts of the present new compounds are more soluble than the free bases both in water and in organic solvents containing hydroxyl groups, such as lower alkanols, propylene glycol, glycerol and the like. This means that it can be used in various sterylized pharmaceutical preparations. The acid addition salts are particularly well absorbed by the digestive tract

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BATH ORIGINAL

a satisfactory level of antibiotic in the blood, both with oral and paronteral administration.

While all of the new compounds turn out to be oral and veterinary use, the compounds in particular are suitable for parenteral use in human medicine Amido-N- (pyrrolidinomethyl) -o ^ -ö-deoxy-S-oxytetracycline and amido-N- (morpholinomethyl) -c £ '-6-deoxy-5-oxytetracycline preferred as they do not induce any irritation at the site of the injection. object The present invention thus provides novel compounds represented by the following formula

CH ,, H OH. N (CH ₃ ) ₂

(D

CONHCH ₂ R

0 OH 0

in which R is an amino-, w-carboxy (lower) -alkylamino-, \ jr-amino-ui-carboxy (lower) alkylamino-, i ^ -carboxamido (lower) alkylamino-, or W-amino-ur-carboxami do (low) alley 1-amino group, or the group NR ^ Rp denotes in which R ^ is an alkyl group of 1-17 carbon atoms, a benzyl, phenethyl, cyclohexyl, hydroxyalkyl group with 2 to 4 carbon atoms, uf-amino (low) alkyl, ^ - (lower alkyl) amino (lower) alkyl or ur-di (lower alkyl) amino (lower) alkyl group and R _{2 represents} hydrogen or R ^, where R- | and R _? also together with the adjacent amino group a piperidino, pyrrolidino, morpholine, piperazino, N-methylpiperazino, 2,6-dimethylmorpholino, N- (β-II-hydroxyethyl) piperazino radical or a radical of the formula

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, NCH ₂ NHCO

can represent

as well as their acid addition salts and salts with bases.

The present invention also relates to a process for the preparation of compounds of the formula

CI-I-

HN (CH ₃ )

OH

CONHCH ₂ R

in which R is an amino-., Uü-carboxy (lower) alkylamino-, W-amino- (JU-carboxyClowerJalkylamino-, t / f-carboxamido- (lower) alkylamino-, or uj-amino- m / -carboxamide (lower ) alkylamino group, or the group NR ₁ R ₂ in which R _{1 is} an alkyl group. 1 - 17 carbon atoms, a benzyl, phenethyl, cyclohexyl, hydroxyalkyl group with 2 to 4 carbon atoms, W-amino (lower) oleo, alkyl -, W- (lower alkyl) amino (lower) alkyl, or Uw-di (lower alkyl) amino (lower) alkyl group and Hp

Represents hydrogen or R ₁ , where R. and R ₂ together with the adjacent amino group also form a piperidino, pyrrolidino, morpholino, piperazine, N-methylpiperazino, 2,6-dimethylmorpholino, N- (ß-hydroxyethyl) -

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piperazino radical or a radical of the formula

OH H CI-I-

" ¹ O

CH ₂ NHCO

O- 'OH O OH can represent,

and of their acid addition salts and salts with bases, which is characterized in that one 06-ö-Deoxy-S-oxytetracycline or its acid addition salts with a compound of the formula

ZR

(III)

or its acid addition salt reacts, where in formula III R has the above meaning and, in the presence of formaldehyde or its equivalents, Z is hydrogen, or <x -6- Deoxy-5-oxytetracycline or its acid addition salt in the absence of formaldehyde with a Reacts compound of formula III or its acid, addition salt, in which Z is the G grouping Y-CHp-, in which Y is chlorine, bromine, a hydroxyl, lower alkoxyl, SO ^ -, hydrosulfido, phthalimido, succinimido -, alkylmalonic ester group or acylmalonic ester group, and optionally auä. the product of the formula I with an inorganic or organic satire or base produces an S ^ .äureadditionssalz or base salt.

Under the term "Hiedrigälkyl" are used in the present Description of straight-chain or branched alleyl groups understood with up to 6 carbon atoms.

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The present invention also relates to dimeric products made from 2 moles of α-δ-deoxy-S-oxytetracycline, 2 moles of formaldehyde and 1 mole of piperazine are obtained. These derivatives can be suitably carried out by the following Play the formula

T-CH ₀ -N .N-OHo-T

in which T represents the α -ö-deoxy-üi-oxytetracycline residue, that via the 2-carboxamido group to the 1,4-bis-methylenepiperazine is bound. The new invention Compounds are amphoteric and therefore form salts with both acids and bases.

The compounds according to the invention are more soluble in water than the corresponding parent antibiotics, and in aqueous medium when standing or adjusting the When the pH is in the range of 3-8, they are not prone to hydrolysis and precipitation.

As already mentioned, the compounds according to the invention by reacting the Stamn antibiotic with formaldehyde or its equivalents, e.g. paraformaldehyde, and a compound having at least one primary or secondary amino group. The reaction is done by simply adding the α-6-deoxy -? - oxytetracycline with formaldehyde and the amine in aqueous or alcoholic medium, which can be improved by adding water-soluble organic solvents the solubility of the different reactants can be modified, brings into contact. For example becomes oc -ö-deoxy-ij-oxytetraoycline when used

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BATH

in the form of the anhydrous base, preferably dissolved in a water-miscible solvent, for example methanol, ethanol, bioxane, tetrahydrofuran, lower alkyl ethers of ethyl glycol and diethylene glycol such as lem diethyl ether, dimethylformamide and the like. Preferably enough solvent is used that the antibiotic remains in solution when added to the aqueous reaction medium. The reactants can be added simultaneously or one after the other in any order. In general, it is preferred to add the & -6-deoxy-5-oxytetracycline to a mixture of formaldehyde and the amino compound, since this has given the best results. However, the antibiotic can also be treated with formaldehyde first, after which the amino compound is added to the reaction mixture. In this latter process it may occasionally be possible to isolate the intermediate product atis antibiotic and formaldehyde before the reaction with the amino compound, although this procedure should not be associated with any particular advantages. Vigorous stirring of the reaction mixture is not absolutely necessary, but in most cases it is advisable, especially during the addition of the parent antibiotic. The reaction can be carried out between about -15 and about 8O ⁰ C within a wide temperature range, eg. Preferred reaction temperatures are between about 0 and about 30 C.

According to a further variant of the process, aminomethyl compounds are used for the transaminomethylation, for example those of the formula Y-CH ₂ -R, in which R has the above meaning and Y is chlorine, bromine, a hydroxyl, lower alkoxyl, SCU, hydrosulfide »-, Represents phthalimido, succinimido, alkylmalonic ester or acylmalonic ester group.

90984Ö / 17S

The reactants are preferably in im. essential equimolar proportions puts. Although one can work with excesses of formaldehyde and amino compound, this results in practice no significant advantages. The product forms almost immediately after the reactants are mixed. It is musty in the form of an oil, which can be crystallized using conventional methods. One such method exists in that, while stirring, the oil is turned into one.? Non-solvent introduces and then separates the solid in a known manner, for example by Filtration. Suitable non-solvents are acetone, ether, aromatic hydrocarbons, toluene, liquid e-aliphatic Hydrocarbons such as hexane, alkanols such as isopropanol and the like. Further procedures for Crystallization of oily products are available to those skilled in the art.

The compounds obtainable according to the invention form salts with organic and inorganic acids due to the presence of basic groups. Examples of suitable acids are: hydrochloric acid, sulfuric acid, Phosphoric acid, acetic acid, butyric acid, palmitic acid, oleic acid, citric acid, gluconic acid, lactic acid, Tartaric acid, ascorbic acid, pantothenic acid ", penicillins, succinic acid half-esters of D - (-) - threo-2-dichloroacetamino-1-p-nitronhenyl-1,3-propanediol> Maleic acid and the like. Certain compounds form polyacid addition salts. For example, the amido-N- (lysino- "-methyl) -ac -6-deoxy-5-oxytetracycline a mono-, di- or tri-hydrochloride due to the presence of 3 amino groups form. Due to the presence of free carboxyl groups, the compounds derived from amino acids can also use salts with inorganic or organic

somo / mt

form sen. Examples of such salts are the alkali metal salts such as potassium and sodium salts, ammonium salts and alkaline earth metal salts such as calcium salts, as well as the salts with organic amines. These salts are produced in a manner known per se.

In the preparation of the compounds according to the invention, di-JeOJ (y-5-Oxyteiracyoliii are used in various forms, for example as an acid addition salt or as a free base, in hydrated or anhydrous form. The amino compounds can also be used in the form of their acid addition salts or as free amino compounds If salts of the tetracycline and amino compounds are used, salts of mineral acids, for example hydrochlorides, are generally preferred, since these are easy to prepare and give good results. In addition to the hydrochlorides, the salts of phosphoric acid, sulfuric acid, nitric acid and hydrobromic acid are of course also suitable The product formed in the reaction corresponds to the ql> -6-deoxy-5-oxytetracycline used and the amino compound used the free base amido-N- (ßalaninome thyl) -cL -o-deoxy-S-oxytetracycline.

man. · 'In the process according to the invention, iysine can either be in use one of the optically active forms or as a racemate or as a mixture of the optically active forms. in the In general, the use of 1-lysine is preferred, since the 1-amino acid is the biologically active form. The product obtained with this amino acid can thus develop better properties in the body. Of course also show those with the other forms of

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Lysins manufactured products have the aforementioned pharmacological properties. The in vitro spectrum the new compounds according to the invention corresponds to this the parent antibiotic from which they were made.

For intramuscular or intravenous administration, the daily dose is generally between about 0.05 and 1.0 g. Pure preparations for intramuscular For administration, solutions with concentrations of 50-100 mg per ml are used. In preparations for intravenous Administration, the concentration is about 10. mg per ml.

The exact dose will be determined by the doctor in all cases. If desired, the new connections can also be administered orally, although, as already mentioned, parenteral administration is preferred.

Example 1

Amido-N- (lysinomethyl) -o £ / -6-de oxy— 5-oxytetracyclinker ο chlorine id

Dissolved 18.3 g (0.10 mol) of L-lysine rnonohydrochlorid in 100 ml of water, 10 ml of a 37 followed by aqueous formaldehyde solution were added. 44.4 g (0.10 mol) of anhydrous α-δ-deoxy-S-oxytetracycline, dissolved in 500 ml of tetrahydrofuran, are added to the resulting mixture. After careful mixing, the product forms in the course of about 15 minutes in the form of an oily layer which, after the aqueous phase has been separated off, is added dropwise to 3 liters of isopropyl alcohol with stirring. Since, s product is filtered, slurried ge AIIF with acetone, filtered again and 65 0 and dried in vacuo.

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BATH ORIGINAL

1914134

The procedure of Example 1 is repeated, wherein instead of the lysine, equivalent amounts of the following amino acids be used:

Glycine

^ -Aminobutyric acid

oj , Δ-diamino valeric acid arginine

Δ-aminocaproic acid

Similar results are obtained.

Example_3
Amido-N- (ß-alaninomethyl) -ci / -6-deoxy-5-oxytetracycline

The following reactants are introduced into a flask with stirring in the order given:

water

ß-alanine

Formaldehyde 37

Ethylene glycol dimethyl ether

V / ater. ".

<X, -ö-Deoxy ^ -oxytetracycline, dissolved in 250 ml of ethylene glycol dimethyl ether

A rubbery solid forms almost immediately. It is separated from the mixture in 500 ml of ethylene glycol dimethyl ether given, and stirred until .until a filterable product is obtained. This product is filtered off and washed with ether.

100 , '5 ml 4th G 10 ml .25 ml 10 , 2 ml 22nd G

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The process of Example 3 is repeated, 3.7 g of glycinate being used instead of the β-alanine. The title compound is formed in the process.

If the ^ lycinamide is replaced by the amides of ß-alanine, Lysine and serine, the corresponding reaction products are obtained .

.5 _ ■■.

Amido-N- ^ 4 '- (ß-hydroxyethyl) -piperazinomethyl_y ^r - et -S-

To a solution of 13 g of N- (ß-hydroxyethyl) -piperazine in 500 ml of isopropanol, 3 g of paraformaldehyde are added, then the mixture is 30 min. At 60 ⁰ C lnng heated occurred until complete dissolution. After the solution has cooled to 40 ° C., 22.2 g of anhydrous φ-6-deoxy-5-oxytetracycline are added and a stream of dry nitrogen is passed through the resulting reaction mixture for 3 hours while stirring. The reaction mixture is then filtered and the filter cake is washed twice with 200 ml of isopropanol. The filter cake is then suspended in 100 ml of anhydrous ether, filtered off, washed 3 times with 500 ml of anhydrous ether each time and dried in vacuo.

Example_iel_6_

Amido-N- (piperidinomethyl) -OL-6-deoxy-5-oxytetraeycline acetate

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To 22.2 g of c # -6-deoxy-5-oxytetracycline dissolved in 500 ml of tetrahydrofuran, 7.3 g of piperidine acetate and 7 ml of 37 % formaldehyde solution are added with stirring at a temperature of 20 ° C. The mixture is maintained for 2 hours stirred, the precipitate is da.nn filtered off, washed with tetrahydrofuran and dried in vacuo at about 40 ⁰ C.

For example £ iel_7

Amido ^ N- (pyrrolidinomethyl) -o £ -ö-deoxy-S-oxytetracycline-

3 »60 ml of 37% aqueous formaldehyde solution, 2.52 ml of pyrrolidine and 13.2 g of cCf -6-deoxy-5-oxytetracycline are added successively to 450 ml of ethanol.

The resulting mixture is at for a few minutes Stirred at room temperature, then the solid which separates out (1.32 g) is filtered off. The filtrate is with inoculated with a small amount of this solid and stirred at room temperature for about 2 1/2 hours.

The amido-N- (pyrrolidinomethyl) -c £ -6-deoxy-5-oxytetracycline which separates out of the solution is filtered off and washed successively with methanol and acetone. the Yield is 12.7 g

Analysis:

Ber. for: C ₂₇ H ₃₃ N ₃ 0 _g % 1/2 H ₂ O; C, 60.43; H 6.38; N 7.83.

Found: C, 60.49; H 6.21; N 7.82.

12 g of the above product are added to 260 ml of water. The pH of the * .. mixture is reduced with concentrated Hydrochloric acid adjusted to 1.9, then filtered. By lyophilizing the filtrate, 13 g are obtained

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a mixture of the mono- and di-hydrochloride of the amido-N- (pyrrolidinomethyl) - oi -ö-deoxy - ^ - oxytetracycline.

Analysis:

Ber. for: C ₂₇ Ii ^ N ₃ Og. 1.25 HCl.H ₃ O:

C 54.93; H 6.02; N 7.12; Cl 7.51; H ₃ O 3.03 Found: C 54.70; H 6.14; N 7.05; Cl 7.685 H ₂ O 2.49.

Example_8

Anido-IT- (morpholinomethyl) -ct -ö-deoxy-S-oxytetracycline h. Hydrochloride

To 512 a 0.01 η solution in methanol Clilorwasserstoff rni v / grounding 4.09 ml of a 37 -, "aqueous formaldehyde solution, 2.96 ml of morpholine IMD 15 g & -o-deoxy-5-oxytetracycline added. The pH of the resulting mixture is adjusted to about 4.7 with concentrated hydrochloric acid and the small amount (about 0.4 g) of crystalline material that locks out of solution is filtered off. The filtrate is inoculated with a few of these crystals . temperature _stirred: for about 3 hours at room. The crystalline amido-N- (morpholinomethyl) -ot> -6-deoxy-5-oxytetracycline which switches off from the solution after this time is filtered off and washed successively with methanol and acetone.

Analysis:

Ber. for: C ₀₁₇ H, -, N-, O _n . 1/2 H _o 0. HCl ^ ι oil i 9 2

C 55.06; H 5.98; N 7.13; Cl 6.02; H ₂ O 1.53. Found: C, 54.99; H 5.93; W 7.17; Cl 6.08; H ₂ O 1.32.

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.9
Ami do-Ιί- (4 '-rae thy lpip erazinorne thy 1) - g6 -6- de oxy- 5- oxy-

In 2 liters of L-ethanol are 22.2 g
06-peoxy-S-oxytetracycline, 16.9 g of 37% formaldehyde solution and 11.0 g of NT.ethylpiperazine diacetate dissolved I.Ian let the reaction mixture stand for 8 hours in the refrigerator, then it becomes hot pressure prevented
concentrated until the product shuts off. The precipitate is isolated, washed with IVIethanol and with
dried at 40 C to prevent jolting.

Amido-fT- (2, ö-dimethylmorpholinomethyl) - ^ -6-deoxy-5-

8.0 g of chlorine diethyl methyl ether are below at 15 C.
Stirring in a solution of 8.7 g of 2,6-dimethylmorpholine and 44.4 g of 06 -o-deoxy - ^ - oxytetracycline in 8OO ml of tetrahydrofuran added dropwise. After 2 hours, the precipitate formed is isolated, washed with cold tetrahydrofuran and ether and net getrock under reduced pressure.

] 3eisp_ien ___ lJL

y, 'J g frißchdeot-related dibensylamine and 6.0 ml 37> ig Forna] dehydlösun _; "; v / crderi to a Siispension of 11.1 g oO -G-Deoxy-fi-oxy-i.etracycline in 500 ml tert-butyl alcohol added; then G-o'nisch is first stirred at room temperature for λθ minutes, then simmer for 15 minutes

9 0 9 8 40/1758

heated. The hot solution is filtered to room temperature cooled down and the pestotoff that separates out is with tert-3utylalkob.o3. washed and at. Pre-reduced pressure dried.

Following the procedure of Example 11 v / ground below Using the appropriate starting materials, the following compounds are made:

Anicio-i? - (methylaminomethyl) -O6-6-deoxy-5-oxytetracycline

Amido-IT- / ~ di- (n-decyl) aminomethyl_7-06 -6-dcoxy-5-oxytetracycline Ami. do-I'T- (is opropylamin ome thy 1) - o6 - 6- de oxy- 5- oxy tet racy elin Amido-N- (2-iso-octylaminomethyl ) -cb -ß-deoxy-5-oxytetracj ^ clin Aniido-N-Cheptadecylaninomethji ·!) - ^ -ö-deoxy-S-oxytetracycline Ami do-N- (cyclohexylaminomethyl) - oO - G- de oxy-5-oxyte tracycline Ami do-N- (methyl-n-butylaminomethyl ) -οί -6-deoxy-5-o>: ytetracyclin Ami do-N- (methylfeenzylaminome thyl) - oo 6-de οxy-5-oxyte tracyclin Amido-N - ^ / ~ di- (n-hexyl) aminomethj '"l_T-o & -S-deoxy ^ -oxytetracycline Amido-N- (ß-phenethylaminomethyl) -oc -6-deoxy-5-oxytetracycline Ami do-N- (« -phenäthylaminomethyl) -ou-6-deoxy-5- oxytetracycline

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BADORfGfWAL

19T4194

Example_13

Amido-N- (ß-hydroxyethylaminomethyl) -ct -6-deoxy-5-oxy-

6.0 g of gaseous formaldehyde are introduced into a mixture of 12.2 g of monoethanolamine, 35 »2 g of ascorbic acid and 88.3 g of au -S-Deoxy-üJ-oxytetracycline in 1500 ml of methanol at 10 ° C. The mixture is left to stand for one hour and then concentrated at reduced pressure and room temperature. The concentrate is poured into 4000 ml of dry ether, then the product is separated off, washed with ether and dried. If this process is repeated with the corresponding hydroxyalkylamines, the following compounds are obtained in the form of their ascorbic acid salts:

is (ß-hydroxyethyl) arflinomethyl_J7-oC '-ö-deoxjr -? - oxytetracycline

Amido-iT- _< / ~ (u3-hydroxybutyl) aminomethyl__ / ^r -o6 -ö-deoxy-5-oxytetracycline

Amido-N- (2-hydroxypropylaminomethyl) - (X '-ö -deoxy-ij -oxytetracycline

Amido-N- / ~ "bis- (3-hydroxypropyl) aminomethyl_7-0 £ -6-deoxy-5-oxytetracycline.

1.7 ml of 18> iiger methanolic formaldehyde are in to a solution of 4.4 g of 6-6 deoxy-5-oxytetracycline (ammonium salt) in 100 ml of methanol. The mixture v.'ird left to stand for 3 hours, the precipitate is separated off, washed with ether and dried.

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BATH

EeisT) iel__l 5
Amido-IT- £ ~ (n-dietliylaminoethyl) -aminoneth.yl _- _7'-0t / -6-

In a mixture of 20 ml of methanol, 5.8 g of ß-diethylaninoethylamine, 6.0 ml of glacial acetic acid and 3.8 nl of 1S; Yigen! ^ Ethanolic formaldehyde ground 22.2 g of 6-Heoxy - 5-oxytetracycline "is added at 20 C in the course of 90 minutes. The resulting mixture is stirred for a further 30 limits and then concentrated at reduced pressure. The concentrate is poured into 1 liter of ether, the solid that forms is separated off, ' Washed with ether and dried. According to the above process, the following compounds are produced from the corresponding reaction participants in the form of their acetates:

A.raido-N- _j / ~ (> - aninopropyl) arniiaomethyl_ / ^r -o (/ - 6-deoxy-5- oz ^ y tetracycline

Ariiclo-N- ^ ~ di- (diethylaminoethyl) a: ninoueth; rl__T-ctr -6-deoxy-5-oxytetracycline

Ami do-IT- ^ ~ (\ ji-aminohexyl) aminome thyl_J7- oo - 6- de oxy- 5-oxytetracycline

Ainido-N- ^ imethylaniinoathylJaminomethyl ^ -nethylenod / -6-deoxy-5-oxy tetracycline

Amido-IT- ^ ~ "(: 3-isopropylaminoethyl) arninoT" ietliyl_7'-a £, -6-deoxy-5-oxytetracycline

Ani.ido-Ii- _i £ ~ (\ Hj-n-butylaminobutyl) aminomethyl_y ⁷ '- q, -6-deoxy-5-oxytetracycline

Amido-N- ^ ~ (ß-di-n-butylaminoätli3rl) aoinomethyl_7 ^r -qS -6-deoi ^ -S-oxytetracycline.

1,4-'ßis (c6 -6-deoxy-5-oxytetracycline-2-carbo: camidomethyl) -piperaain

SAD ORfOtNAL

'"<ι"' · Ζ Pipcrn ~ in and 14 "of 36.7% formaldehyde solution are dissolved in 10000 mil water at 15 ° C. 44.4 g (X / - 6 - Deoxy-5-oxytetracycline is added, and after the addition is complete, the mixture is stirred for a further 0.1 minutes. After standing for 3 hours under nitrogen, the product is "isolated" by iyophilization.

J3einpiel__17

The product of Example 1 is converted into the free base by treatment with an equivalent 1.1% sodium bicarbonate in aqueous solution. The free base is then converted into the dihydrochloride by solvent in Γ iethane oil containing 2 equivalents of hydrogen chloride. The resulting solution is isolated by concentration of the "^1" pressure at reduced pressure. The dihydrochloride is then isolated.

Those prepared according to Example 2 can also be used in an analogous manner Compounds into the corresponding hydrochloride be convicted. The salts of the following acids can also be prepared using the above process: '.roinhydric acid, phosphoric acid, sulfuric acid, Enoetic acid, Y / one acid, malic acid, citric acid, gluconic acid and the same.

üeirsniel 18

The product of Example 1 corresponding free base is dissolved Ln on a nc equivalent !! close sodium hydroxide Good] .Ό Tenden aqueous solution. The solution is then frozen and dried under reduced pressure, whereby powdery sodium salt is then obtained.

The potassium, calcium and magnesium salts are analogous of the products according to Examples 1 - Ί produced.

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BATH ORIGINAL

The Salse of the new compounds according to the invention with pharmaceutically acceptable acids and bases are suitable, especially for the production of various forms of preparation of these connections. Salts with pharmaceutically unacceptable acids and. Bases are suitable for cleaning of the compounds and for the preparation of the pharmaceutically acceptable salts.

ExampleJLel__19-

The products of Examples 6-10, 13 "and 15 are used by "treatment with an equivalent amount of I sodium bicarbonate converted into the free bases in aqueous solution. The free bases are then converted into other acid addition salts converted by dissolving them in methanol, which is an equivalent amount of any of the following Acids contains: hydrobromic acid, tartaric acid, g-luconic acid, Citric acid, palmitic acid, stearic acid, pantothenic acid, benzylpenicillin, butyric acid and succinic

of/
acidic ter'ti - (-) - threo- 2-Dichlorace t amino-1 -p-

nitrophenyl-1,3-propanediol.

In an analogous manner, according to Examples 5, 11, 12, 14 and 16 obtained free bases converted into the corresponding acid addition salts.

Following the procedure of Example 18, the free bases of the products of Examples 5-15 with sodium, Potassium, calcium or magnesium hydroxide treated, whereby the corresponding salts are formed.

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Claims (5)

Compound of formula CII CONHCH ₂ R ⁰ (D in which R is an amino-, U) -carboxy (lower) alky laraino-, U) -amino- u) -carboxy (lower) alkylamino- ,. uJ-Carboxamido (lower) alkylainino-, \ jq- Amino-u / -carboxamido (lower) alkylamino group, or a group HR, R ₂ means in which R ^ is an Alley! group with 1 to 17 carbon atoms, a benzyl, Phenethyl, cyclohexyl, hydroxyalkyl group with 2 to 4 carbon atoms, U) -amino (lower) alkyl, U / - (lower alkyl) amino (lower) alkyl or iA} -di (lower alkyl) amino (lower) alkyl group, Rp hydrogen or R., denotes, or R-] and R ^ ₁ together with the neighboring nitrogen a piperidino, pyrrolidino, morpholino, piperazino, H-methylpiperazino, 2,6-dimethylmorpliolino, IT- (G -ITydrox3'-ethyl) piperazino group or a group of the formula 909840/17 - 2Z- 19H194 Ν (σΐΐ ₃ > ₂ CII-. CI: mean, their acid addition salts and salts -nit bases. 2. Anido-H- (morpholinonethyl) -od / -6-deojty-S-oxytetracycline. . Araido-Ii- (pyrrolidinomethyl) -od / -o-deo ^ y ~ 5-orytetracycliii. 4. PharnasGutische preparation containing as component a connection according to claim 1. 5. Pharmaceutical preparation containing a compound according to claim 1 and a carrier. Pure: Chasy Pfizer 3; Co., Inc. Nev; York, Ii.Y. , Y.St.A .. 9090Λ0 / 176 « BAD ORiGtNAL