CH553211A - Rifamycin derivs antibacterial - Google Patents

Abstract

3-R-25-desacetylrifamycin S (I) and salts thereof 3-R-25-desacetylrifamycin SV (II) and salts thereof where R = opt. subst. NH2, -CH=NR1, or CH2R2 and R1 = H or a suitable substit. and R2 = opt. substd. NH2, opt. subst. NHNH2 or opt. subst. NHOH. a) Anti-tubercular (at 0.003 mu g/ml) and anti-Staphylococcal (at 0.015 mu g/ml.) b) Disinfectants and preservatives.

Description

  

  
 



   The invention relates to a process for the preparation of 25-deacetylrifamycin SV substituted in the 3-position by a free or substituted hydrazonomethyl group.



   The process of the present patent is characterized in that a Schiff base of a primary aliphatic amine is reacted with 3-formyl-25-deacetylrifamycin S with 2 molar equivalents of hydrazine or an N-substituted hydrazine.



   The Schiff's bases of 3-formyl-25-deacetyl-rifamycin S to be used as starting materials are obtained e.g.



  by reacting 25-deacetyl-rifamycin S, -SV, -O or B with 1 to 2 moles of formaldehyde and up to 4 moles of a primary aliphatic amine at room temperature or at elevated temperature in a suitable solvent in the presence of an oxidizing agent such as manganese dioxide or else molecular oxygen. When using one of the above-mentioned 25-deacetyl-rifamycin-S compounds with a quinone structure, e.g. Rifamycin-S or 0, the oxidation is already brought about by this starting material. However, a further oxidizing agent, e.g. one of the above, admit or



  to act on it. The reaction time varies between 3 and 72 hours depending on the temperature chosen.



   The process according to the implementation of the Schiff's base with the hydrazine or hydrazine substituted on an N atom can be carried out in an inert organic solvent, e.g.



  Ethyl acetate, preferably by standing at room temperature. One can e.g. use the raw Schiff base prepared as described above as starting material. You pour e.g. the above-obtained condensation product of 25-deacetyl-rifamycin S with formaldehyde and a primary amine in water, extracted with a water-insoluble solvent, dries the organic phase and treats it directly with about 2 mol equivalents of the desired hydrazine or substituted hydrazine . But you can also isolate and purify the condensation product before the reaction.



   The new compounds which can be prepared by process are mostly orange-yellow colored compounds which are considerably more soluble in water than the corresponding derivatives acetylated in the 25-position. But they are also readily soluble in most organic solvents such as alcohols, halogenated hydrocarbons, esters, dioxane, etc. They form alkali salts, the aqueous solutions of which react almost neutrally. As acids, they form acid addition salts and optionally also quaternary ammonium salts, in particular with esters of lower alkanols with hydrohalic acids, sulfuric acid or sulfonic acids, provided they have a basic substituent in the remainder of the hydrazo group.



  Acids which are suitable for the formation of therapeutically useful salts are mainly used to prepare the acid addition salts. Examples of these are: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, lemon, ascorbic, maleic, hydroxymaleic or pyruvic acid , Phenyl acetic, benzoic, p-aminobenzoic, anthranil, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, emboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid, halobenzenesulphonic, toluenesulphonic, , Methionine, tryptophan, lysine or arginine.



   These or other salts of the new compounds, e.g. the picrates can also be used to purify the bases obtained by converting the bases into salts, separating them off and in turn liberating the bases from the salts.



  As a result of the close relationship between the bases in free form and in the form of their salts, in the preceding and in the following the free bases are to be understood, appropriately and appropriately, also the corresponding acid addition and metal salts.



   The new compounds of the present patent can optionally also exist in the form of their tautomers.



   The new compounds have valuable pharmacological properties. They are very effective against tubercle bacilli. Furthermore, they are also highly effective against staphylococci. They are less toxic than the corresponding 25-acetylated derivatives and, as already mentioned above, are significantly more soluble in water and therefore also in physiological fluid, which makes them particularly suitable as antibacterial chemotherapeutic agents, especially for parenteral administration.



   However, the new compounds are also valuable intermediates for the preparation of other useful substances, in particular pharmacologically active compounds.



   The new compounds can also be used as disinfectants, feed additives and for the preservation of food.



   Of the process products, the following should be mentioned in particular: 25-deacetyl-3-pyrrolidinoiminomethyl-rifamycin SV, 25-deacetyl-3-dimethylhydrazono-methyl-rifamycin SV, 25-deacetyl-3-morpholinoiminomethyl-rifamycin SV, 25-deacetyl -3- (4'-methyl-piperazinyliminomethyl) -rifamycin SV.



   The new compounds can e.g. find use in the form of pharmaceutical preparations. These contain the compounds in a mixture with a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for enteral, topical or parenteral administration. For the formation of the same, substances come into question that do not react with the new compounds, e.g. Water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, propylene glycol, polyalkylene glycols, petrolatum, cholesterol or other known excipients. The pharmaceutical preparations can e.g. as tablets, dragees, ointments, creams, capsules or in liquid form as solutions, suspensions or emulsions.

  If necessary, they are sterilized and / or contain auxiliary substances such as preservatives. Stabilizers, wetting agents or emulsifiers, solubilizers or salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The preparations are obtained by customary methods.



   The new compounds can also be used in veterinary medicine, e.g. can be used in any of the above forms.

 

   The invention is described in the following example. The temperatures are given in degrees Celsius.



   example
A mixture of 13 g of 25-deacetyl-rifamycin S, 8 ml of tert-butylamine, 3.1 ml of 39% aqueous formaldehyde, 4.2 g of manganese dioxide and 120 ml of tetrahydrofuran is then heated for 12 hours at 45-50 " a further 1.5 ml of 39% formaldehyde is added and the mixture is heated for a further 8 hours at 45-50 ".

 

   It is filtered and the filtrate is poured into 350 ml of ethyl acetate and 180 ml of water, the pH is adjusted to approx. 7 with dilute sulfuric acid and the organic phase is then washed several times with water, dried and evaporated in vacuo to approx.



  a volume of 100 ml. 4.8 g of l-amino-4-methylpiperazine are now added and the mixture is left to stand for 2 hours at room temperature. The addition of petroleum ether separates the tert-butylamine salt of 25-deacetyl-3 (4-methyl-piperazinyl-iminomethyl) -rifamycin SV, from which the free 25-deacetyl-3 - (4-methyl-piperazinyl) -iminomethyl) -rifamycin SV isolated by known methods.

 

Claims (1)

PATENT CLAIM Process for the preparation of 25-deacetyl-rifamycin SV substituted in the 3-position by a free or substituted hydrazonomethyl group, characterized in that a Schiff's base of a primary aliphatic amine with 3-formyl-25-deacetyl-rifamycin S with approx 2 molar equivalents of hydrazine or an N-substituted hydrazine is converted. SUBCLAIMS 1. The method according to claim, characterized in that a Schiff's base of 25-deacetyl-3-formyl-rifamycin S is used with the primary amine in the form of the crude reaction product, as is obtained when 25-deacetyl-rifamycin S, -SV, 0 or B with 1 to 2 moles of formaldehyde and 2-4 moles of a primary aliphatic amine in the presence of an oxidizing agent. 2. The method according to claim or dependent claim 1, characterized in that the 25-deacetyl-3-dimethyl-hydrazono-methyl-rifamycin SV is produced. 3. The method according to claim or dependent claim 1, characterized in that the 25-deacetyl-3 (4'-methyl-piperazinyl) -iminomethyl-rifamycin SV is produced.