Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
  • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
  • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
  • C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the invention relates to new pseudotrisaccharides, processes for their preparation and their use as medicaments.
• the invention relates to new, antibacterial aminoglycoside antibiotics of the 4,6-di-O- (aminoglycosyl) -1,3-diaminocyclitole type.
• Aminoglycoside antibiotics are important substances for the effective fight against bacterial infections. In many cases, however, the emergence of resistant germs reduces their broad applicability; further side effects such as ototoxicity and nephrotoxicity can occur. In some cases, derivatization can overcome these disadvantages.
• alkenyl and alkynyl radicals preferably have 2 to 6 carbon atoms. Examples include: allyl, crotyl, methallyl, ⁇ -methyl- ⁇ -butenyl, propyn (2) yl, butyn (2) yl. If they are substituted, they preferably carry one of the substituents listed above for alkyl.
• Cycloalkyl and cycloalkenyl preferably denote a cyclic radical having preferably 3 to 10, in particular 3 to 6, carbon atoms, which has 1 to 3, in particular 1 or 2, may have the same or different of the substituents mentioned above for alkyl.
• Cycloalkylalkyl and cycloalkenylalkyl preferably represent cycloalk (en) ylmethyl or cycloalk (en) ylethyl, the cycloalk (en) yl radical being defined as previously indicated.
• Suitable cycloalk (en) yl and cycloalk (en) ylalkyl radicals are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexenylmethyl.
• Aryl preferably denotes a phenyl or naphthyl radical.
• the aryl group may have 1 to 3 identical or different substituents such as alkyl preferably having 1 to 4 carbon atoms s, preferably fluorine, chlorine or bromine, nitro, amino, monoalkyl and dialkylamino each having 1 to 4-K hlenstoffatomen per alkyl group, H ydroxy, Wear alkyloxy and alkylthio with 1 to 4 carbon atoms per alkyl group.
• substituents such as alkyl preferably having 1 to 4 carbon atoms s, preferably fluorine, chlorine or bromine, nitro, amino, monoalkyl and dialkylamino each having 1 to 4-K hlenstoffatomen per alkyl group, H ydroxy, Wear alkyloxy and alkylthio with 1 to 4 carbon atoms per alkyl group.
• aryl radicals are: o-ethylphenyl, m-ethylphenyl, p-ethylphenyl, p-hydroxyphen
• the aralkyl radicals are preferably phenylmethyl or phenylethyl radicals which can carry the substituents mentioned above for aryl. Examples include: ⁇ -phenylethyl, B-tolylethyl.
• aminoglycoside antibiotics which are derived from the antibiotics gentamicin A, gentamicin B, gentamicin B 1 gentamicin C 1 , gentamicin C 1a , gentamicin C 2 , gentamicin C 2a ' gentamicin C 2b' gentamicin X 2 , sisomicin, JI-20A, JI-20B, verdamicin G52, G418, 66-40B, 66-40D, mutamicin 1, mutamicin 2, mutamicin 4, mutamicin 5 and mutamicin 6, thereby derived propyl, t-butyl, ß-propylpentyl, ⁇ -ethylhexyl, ß-dimethylpropyl, ß-hydroxypropyl, ß, ⁇ -dihydroxypropyl, ⁇ -hydroxypentyl.
• alkenyl and alkynyl radicals preferably have 2 to 6 carbon atoms. Examples include: allyl, crotyl, methallyl, ⁇ -methyl- ⁇ -butenyl, propyn (2) yl, butyn (2) yl. If they are substituted, they preferably carry one of the substituents listed above for alkyl.
• Cycloalkyl and cycloalkenyl designate preferably a c y clischen radical having preferably 3 to 10, especially 3 to 6 carbon atoms, 1 to 3, in particular 1 or 2, 3 "-N-Demethyl-3" -N-heptylsisomicin 3 "-N-Demethyl-3" -N- (ß-dimethylpropyl) -sisomicin 3 "-N-Demethyl-3” -N-allylsisomicin 3 "-N- Demethyl-3 "-N- (ß-butenyl) -sisomicin 3" -N-demethyl-3 "-N-tolylethylsisomicin 3" -N-demethyl-3 "-N- (ß-aminoethyl) -sisomicin 3" -H -Demethyl-3 "-N- (ß-methoxyethyl) -sisomicin 3" -N-Demethyl-3 "-N- (1-methoxy
• the invention further encompasses the acid addition salts, in particular the pharmaceutically usable salts of the new aminoglycoside antibiotics, of which the addition salts with hydrogen chloride, sulfur, phosphorus, saltpetre, hydrogen bromide, benzenesulfone, ants, vinegar, propion, Maleic, ascorbic or citric acid may be mentioned as examples.
• the pharmaceutically usable salts of the new aminoglycoside antibiotics of which the addition salts with hydrogen chloride, sulfur, phosphorus, saltpetre, hydrogen bromide, benzenesulfone, ants, vinegar, propion, Maleic, ascorbic or citric acid may be mentioned as examples.
• the invention further relates to processes for the preparation of the pseudotrisaccharides represented by formula (I).
• sisomicin derivatives represented by formula (II) are those R has the meaning given above, particularly valuable.
• Amino protective groups R ' which can be used are all protective groups which are stable under the oxidation conditions of the process described above and which are customary in the field of aminosugar and peptide chemistry. Such protecting groups and the processes for their preparation are known (see, for example, Houben-Weyl, Methods of Organic Chemistry, Volume XV, 1, Georg Thieme Verlag, Stuttgart, 1974).
• the starting materials used according to the invention are aminotrisaccharides of the general formula (IV) which are known per se from the literature
• the invention also encompasses processes by which the selectively protected pseudotrisaccharides of the formula (VII) are N-alkylated on the 3 "-methylamino group, whereby 3" -N- A alkyl derivatives of the formula (III) with the meaning of the newly occurred Rest of R receives.
• 1.2 ', 3,6'-tetra-N-ethoxycarbonylsisomicin of the formula (VI) is obtained quantitatively by reaction in aqueous ethanol.
• the process is usually carried out in an inert solvent.
• the solvent can be an organic or inorganic one in which the selectively protected 4,6-di-O- (aminoglycosyl) -1,3-diaminocyclitol and the other reagents are soluble and which, if possible, reduces or prevents side reactions under the reaction conditions.
• anhydrous aprotic solvents can be used to advantage (e.g.
• a protic solvent is usually used.
• the process is usually carried out in a pH range from 1 to 11 and preferably at pH 4 to 8.
• Typical aldehydes of the formula R "CHO, wherein R" is as defined above, which can be used in the process, include straight or branched chain alkyl aldehydes such as acetaldehyde, n-propanal, n-butanal, 2-methylpropanal, n-pentanal, 2 -Methylbutanal, 3-methylbutanal, 2,2-dimethylpropanal, n-hexanal, 2-ethylbutanal, n-heptanal and n-octanal; Alkenyl aldehydes such as propenal, 2-methylpropenal, 2-butenal, 2-methyl-2-butenal, 2-ethyl-2-hexenal; Cyclic aldehydes such as cyclopropane carbaldehyde, cyclopentane carbaldehyde, cyclopentane acetaldehyde, cyclohexane carbaldehyde;
• This process in which the 3 "amino group in a 4,6-di-0- (aminoglycosyl) -1,3-diaminocyclitol reacts with an aldehyde and is simultaneously reduced in situ, is usually carried out at room temperature in the presence of air, although it may be more convenient to carry out the reaction under inert gas (argon, nitrogen)
• inert gas argon, nitrogen
• the reaction is usually very rapid, often in less than 60 minutes, which can be determined by thin layer chromatography.
• Hydrogen donor reducing agents used in this process include dialkylaminoborane (e.g. dimethylaminoborane, and preferably morpholinoborane), tetraalkylammonium cyanoborohydride (e.g. tetrabutylammonium cyanoborohydride), alkali metal borohydride (e.g. sodium borohydride), and preferably sodium borohydride (e.g.
• the process is preferably carried out in such a way that a solution of 4,6-di-0- (aminoglycosyl) -1,3-diaminocyclitol, which contains amino protective groups in all positions except in position 3 "(for example 1,2 ', 3,6'-Tetra-N-ethoxycarbonyl-sisomicin) in aqueous methanol gives 1-10 equivalents of the respective aldehyde (eg acetaldehyde) and then (after about 0.5 hours) approximately 1.3 equivalents of alkali metal cyanoboranate (eg sodium cyanoboranate).
• Working up according to customary methods provides the desired 3 "NR derivative of the corresponding protected pseudotrisaccharide (eg 3" N ethyl 1,2 ', 3,6' tetra N ethoxy carbonylsisomicin).
• Hydroxy substituted straight and branched chain alkyl aldehydes such as 5-hydroxypentanal, 2-hydroxy-3-methylbutanal, 2-hydroxy-2-methylpropanal, 4-hydroxybutanal, 2-hydroxypropanal and 8-hydroxyoctanal as well as glyceraldehyde; straight-chain and branched-chain alkyl aldehydes substituted by amino, such as 5-aminopentanal, 2-aminopropanal, 3-aminopropanal, 4-aminobutanal, 2-amino-3-methylbutanal, 8-aminooctanal and mono-N-alkyl derivatives thereof; and straight and branched chain alkyl aldehydes disubstituted by amino and hydroxy, such as 2-hydroxy-5-aminopentanal, 3-hydroxy-3-methyl-4-amino-bu-tanal, 2-hydroxy-4-aminobutanal, 2-hydroxy-3- aminopropanal, 2-hydroxy-2-methyl-3-amino
• each enantiomer can be separated or the racemate can be used and the corresponding diastereoisomers or a mixture thereof are obtained.
• the aldehydes used in the process are either known compounds or can be easily prepared from known compounds by standard procedures.
• aldehyde which has an amino group on this amino group, for example as acetamido, phthalimido or ethoxycarbonyl derivative, and to release the amino group after completion of the reaction. It may also be advantageous to protect any hydroxy groups in aldehydes, but this is generally not necessary.
• the invention further encompasses processes for the selective removal of the methyl group from the 3 "-N (CH 3 ) R-trisaccharides of the formula (III) obtained with the aid of the alkylation methods described above.
• One of the preferred methods of cleavage according to the invention is the oxidative demethylation of the tertiary 3 "amino group.
• oxidizing agents are heavy metal salts, peroxides, halogens, halogen oxyacids and their salts, nitrogen oxides and molecular oxygen.
• Preferred oxidizing agents are permanganates, manganates, manganese dioxide, chromium trioxide, bichromates, chromates, alkyl chromates, chromyl chloride, selenium dioxide, cobalt (III) salts, cerium (IV) salts, potassium hexacyanoferrate (III), copper oxide, lead oxide, mercury oxide, and mixtures of hydrogen peroxide Iron (II) salts, iron (III) salts, selenium dioxide, osmium tetroxide, vanadates, tungstic acid and / or chromium Hal means halogen, such as chlorine, bromine or iodine.
• auxiliary base to capture the hydrogen halide liberated in the reaction.
• corresponding bases are alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, alkaline earth metal oxides, carbonates and oxides of heavy metals such as e.g. Lead carbonate and silver carbonate as well as mercury oxide or silver oxide.
• all compounds which are stable under the reaction conditions and are able to trap the hydrogen halide formed can be used as auxiliary bases.
• the reaction according to the invention is carried out at temperatures from about -20 to + 80 °, preferably from 0 ° to 30 °.
• the reaction time is normally 1-48 hours and the process is generally carried out under normal pressure.
• Bases are ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal alcoholates and alkali and alkaline earth metal salts of carboxylic acids.
• the pH can be adjusted either from the start of the reaction or during the reaction.
• the reaction according to the invention is carried out at temperatures from about -20 ° to about 100 ° C, preferably from about -5 ° to about 70 ° C.
• the reaction time is half an hour to 50 hours. In general, the reaction is carried out at normal pressure.
• the protective groups present in the molecule after the reaction can be split off in a known manner by alkaline or acidic hydrolysis, hydrogenolysis or displacement reactions. If compounds which contain acyl protective groups of type (1) or (2) are used for the cleavage, these can preferably be cleaved off with aqueous alkalis of alkali metal or alkaline earth metal hydroxides.
• oxidizing agents are manganese dioxide, potassium hexacyanoferrate (III) and potassium permanganate.
• potassium hexacyanoferrate III is the oxidizing agent and ammonium hydroxide is the auxiliary base
• copper (II) sulfate can be added to the solution to be oxidized. The hexacyanoferrate-II formed during the oxidation then precipitates out as a poorly soluble copper salt.
• the cleavage reaction is preferably carried out in the presence of a diluent which is inert under the reaction conditions, preferably one in which the reactants dissolve.
• a diluent which is inert under the reaction conditions, preferably one in which the reactants dissolve.
• Suitable diluents of the type mentioned are water or mixtures of water with methanol, ethanol, i-propanol, tetrahydrofuran, dimethylformamide, dioxane, pyridine, ethylene glycol dimethyl ether and acetone.
• the reaction according to the invention is carried out at a pH of 3 to 12.
• the pH can be adjusted by adding an appropriate acid or base.
• acids or bases are to be used which do not decompose the starting compounds or the end products and which do not cause a reduction in the activity of the oxidizing agents. Rather, it is desirable that they increase the activity of the oxidizing agents.
• Hydrochloric acid or sulfuric acid for example, can be used as inorganic acids and acetic acid or formic acid, for example, can be used as organic acids.
• the inorganic salts are precipitated by adding acetone, and the solution which remains is isolated the 3 "-N-demethyl compound (X) in high yield.
• the acetyl protective groups are split off by heating in an aqueous barium hydroxide solution and the previously unknown 3 "-N-ethyl-3" -N-demethylslsomicin is thus obtained.
• the 3 "-N-methyl group can also be split off by adding 3" -N-derivatives of the formula - III according to the known methods - e.g. B. oxidized with hydrogen peroxide on the tertiary 3 "amino group to the corresponding N-oxide and this product by treatment with acetic anhydride in the corresponding 3" -N-acetyl-3 "-N-alkyl-3" -N-desmethyl-l, 2 ', 3.6'- wherein the amino groups present in the molecule are in free form.
• A, B, U, V, W, X, Z and R have the meaning given above in (XII).
• the compounds according to the invention are antimicrobial agents with a broad spectrum of activity and particular activity against gram-negative bacteria. These properties enable them to be used as pharmaceuticals in combating bacterial diseases in humans and animals. They are well suited for the prophylaxis and chemotherapy of local and systemic infections, in particular infections of the genitourinary system in human and veterinary medicine, which are caused by gram-negative bacteria, for example E. coli, Proteus, Klebsiella and Pseudomonas.
• the dose of the compounds of the invention to be administered will depend on the age and weight of the subject, the mode of administration, the type and the severity of the bacterial infection.
• the dosage of the Tetra-N-acyl compound transferred. After the acyl groups have been split off, the 3 "-N-alkyl-3" desmethyl derivatives according to the invention having free amino groups are obtained.
• R "' can be hydrogen or acyl.
• a slurry of 3 "-N-demethyl-ethylsisomicin, lactose and polyvinylpyrrolidone is prepared and these are spray dried.
• the corn starch and magnesium stearate are added, mixed and compressed into tablets.
• Compounds according to the invention are usually similar to the dosage of the 3 "-N-methyl compound.
• the dosage range is from 20 mg / day / person to 2000 mg / day / person, preferably 100 mg - 500 mg / day.
• the compounds of the invention can be administered orally.
• the administration can take place in single doses or in several doses. They can also be administered topically in the form of ointments, creams or lotions.
• Pharmaceutical excipients for these formulations include water, oils, fats, polyesters and polyols.
• Tablets, capsules or elixirs can be used for oral administration of the compound of this invention, but the compounds can also be admixed to animal feed.
• topical preparations contain about 0.1 to about 3.0 g of the compounds of the invention per 100 g of ointment, cream or lotion. Topical administration takes place about 2 to 5 times a day.
• the antibacterial agents of the invention may be in liquid form as solutions or suspensions for use in the ears and eyes or for parenteral administration in the form of intramuscular injections.
• Injection solutions or suspensions are usually administered in such a way that approximately 1 to 15 mg of active ingredient per kilogram of body weight reaches the infected organism in 2 to 4 doses per day. The exact dose depends on the type of infection, the sensitivity of the infecting germ and the individual characteristics of the person being treated.
• the product obtained according to Example 8 is dissolved in 30 ml of water and, after addition of 20 g of barium hydroxide hydrate, heated to reflux for 5 hours. For working up, the dissolved barium salts are precipitated as barium carbonate. It is filtered, the filtrate is evaporated to dryness in vacuo, the residue thus obtained is extracted with methanol / methylene chloride and the undissolved is filtered off. Evaporation of the filtrate gives the title compound as a colorless solid
• the crude product thus obtained is used for final purification acid to pH 1, heated to reflux for 10 minutes and then neutralized with dilute sodium hydroxide solution. Now add 400 mg of 1,2 ', 3,6'-tetra-N-acetyl-sisomicin, leave for 0.5 hours at room temperature and then add 100 mg of sodium cyanoboranate. After a further 5 hours the mixture is worked up as described in Example 10. Demethylation and removal of the protective groups are carried out as described in Example 10 and the title compound is obtained as a colorless solid.
• the solvent system for determining the Rf values is chloroform: methanol: 20% NH 3 / H 2 0 in a ratio of 1: 1: 1.
• Rf of sisomicin 0.18

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