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EP1907413A2 - Macrocycles d'amide vii antibacteriens - Google Patents

Macrocycles d'amide vii antibacteriens

Info

Publication number
EP1907413A2
EP1907413A2 EP06762521A EP06762521A EP1907413A2 EP 1907413 A2 EP1907413 A2 EP 1907413A2 EP 06762521 A EP06762521 A EP 06762521A EP 06762521 A EP06762521 A EP 06762521A EP 1907413 A2 EP1907413 A2 EP 1907413A2
Authority
EP
European Patent Office
Prior art keywords
hydrogen
formula
amino
independently
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06762521A
Other languages
German (de)
English (en)
Inventor
Rainer Endermann
Kerstin Ehlert
Martin Michels
Stefan Weigand
Guido Schiffer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aicuris GmbH and Co KG
Original Assignee
Aicuris GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aicuris GmbH and Co KG filed Critical Aicuris GmbH and Co KG
Publication of EP1907413A2 publication Critical patent/EP1907413A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids

Definitions

  • the invention relates to antibacterial amide macrocycles and processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of bacterial infections.
  • WO 03/106480, WO 04/012816, WO 05/033129 and WO 05/058943 describe antibacterial macrocycles of the biphenomycin B type with amide or ester substituents.
  • biphenomycin B is described as having antibacterial activity. Partial steps in the synthesis of biphenomycin B are described in Synlett (2003), 4, 522-526 and Org. Lett. (2005), (7), 2981-2984.
  • An object of the present invention is therefore to provide new and alternative compounds having the same or improved antibacterial activity for the treatment of bacterial diseases in humans and animals.
  • the invention relates to compounds of the formula
  • R 26 is hydrogen, halogen, hydroxy or methyl
  • R 7 is a group of the formula NH, S NH "
  • R 1 is hydrogen or hydroxy
  • A is a bond or phenyl
  • R 4 is hydrogen, amino or hydroxy
  • R 5 is a group of the formula
  • R 23 is hydrogen or a group of the formula * - (CH 2 J n -OH or * - (CH 2 ) o -NH 2 ,
  • n and o independently of one another are a number 1, 2, 3 or 4,
  • n is a number 0 or 1
  • d R 12 are independently of one another a group of the formula * -CONHR 14 or * -CH 2 CONHR 15 ,
  • R 14 and R 15 are independently a group of the formula
  • R 4a is hydrogen, amino or hydroxy
  • R 5a is hydrogen, methyl or aminoethyl
  • R 6a is hydrogen or aminoethyl
  • R 5a and R 6a together with the nitrogen atom to which they are attached form a piperazine ring
  • R 8a and R 12a are independently * - (CH 2 ) Zla -OH, * - (CH 2 ) z 2a -NHR 13a , * -CONHR 14a or * -CH 2 CONHR 15a ,
  • ZIa and Z2a are independently a number 1, 2 or 3,
  • R 13a is hydrogen or methyl
  • R 14a and R 15a are independently a group of the formula
  • R 4c is hydrogen, amino or hydroxy
  • R 5c is hydrogen, methyl or aminoethyl
  • R 6c is hydrogen or aminoethyl
  • kc is a number 0 or 1
  • Ic is a number 1, 2, 3 or 4,
  • R 9a and R 11a are independently hydrogen or methyl
  • R 10a is amino or hydroxy
  • R 16a is a group of the formula
  • R 4d is hydrogen, amino or hydroxyl
  • R 5d is hydrogen, methyl or aminoethyl
  • R 6d is hydrogen or aminoethyl
  • kd is a number 0 or 1
  • Id is a number 1, 2, 3 or 4,
  • ka is a number 0 or 1
  • Ia, wa, xa and ya are independently a number 1, 2, 3 or 4,
  • R 20 is hydrogen or * - (CH 2 ) i -NHR 22 ,
  • R 22 is hydrogen or methyl
  • i is a number 1, 2 or 3,
  • R 21 is hydrogen or methyl
  • f is a number 0, 1, 2 or 3,
  • g is a number 1, 2 or 3
  • h is a number 1, 2, 3 or 4, d R 7 independently represent a group of the formula
  • R 4b is hydrogen, amino or hydroxy
  • R sb is hydrogen, methyl or aminoethyl
  • R 6b is hydrogen or aminoethyl
  • R 8b and R 12b are independently * - (CH 2 ) Zlb -OH,
  • R 13b is hydrogen or methyl
  • ZIb and Z2b are independently a number 1, 2 or 3,
  • R 14b and R 15b are independently a group of the formula
  • R 4g is hydrogen, amino or hydroxy
  • R 5g is hydrogen, methyl or aminoethyl
  • R 6g is hydrogen or aminoethyl
  • kg is a number 0 or 1
  • Ig is a number 1, 2, 3 or 4,
  • R 9b and R llb are independently hydrogen or methyl
  • R 1Ob is amino or hydroxy
  • kb is a number 0 or 1
  • Ib, wb, xb and yb are independently a number 1, 2, 3 or 4,
  • R 18 is hydrogen, amino or hydroxy
  • R 19 is hydrogen, methyl or a group of the formula
  • R 25 is hydrogen or * - (CH 2 ) u -NHR 29 ,
  • R 29 is hydrogen or methyl
  • u is a number 1, 2 or 3,
  • R 28 is hydrogen or methyl
  • s is a number 0, 1, 2 or 3
  • t is a number 1, 2 or 3,
  • R 24 is hydrogen or aminoethyl
  • d is a number 1, 2 or 3
  • k and q are independently a number 0 or 1
  • 1, r, w and y are independently a number 1, 2, 3 or 4,
  • L jw, r or y can independently of one another carry a hydroxyl group at w, r or y equal to 3,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, and the compounds of formula (I), hereinafter referred to as the exemplary embodiment (e) and their salts, solvates and solvates of the salts, insofar as the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers can be isolated by known methods such as chromatography on chiral phase or crystallization with chiral amines or chiral acids, the stereoisomerically uniform components in a known manner.
  • the invention also relates to tautomers of the compounds, depending on the structure of the compounds.
  • physiologically acceptable salts of the compounds according to the invention are preferred in the context of the invention.
  • Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, trifluoroacetic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds (I) also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, i-f-methylmorpholine, dihydroazylethylamine, arginine, lysine, ethylenediamine and methylpiperidine.
  • Solvates in the context of the invention are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • Halogen is fluorine, chlorine, bromine and iodine.
  • a symbol # on a carbon atom means that the compound is in enantiomerically pure form with regard to its configuration at this carbon atom, which in the context of the present invention is understood to mean an enantiomeric excess of more than 90% (> 90% ee ).
  • R 26 is hydrogen, halogen, hydroxy or methyl
  • R 1 is hydrogen or hydroxy
  • R 2 is hydrogen or methyl
  • R 3 is as defined above
  • R 26 is hydrogen, chlorine, hydroxyl or methyl.
  • R 26 is hydrogen or hydroxy
  • R 1 is hydrogen or hydroxy
  • R 2 is hydrogen
  • R 3 is a group of the formula
  • R 4 is hydrogen, amino or hydroxy
  • R 5 is a group of the formula
  • R 23 is hydrogen or a group of the formula * - (CH 2 ) n -OH or * - (CH 2 ) o -NH 2 , wherein
  • n and o independently of one another are a number 1, 2, 3 or 4,
  • n is a number 0 or 1
  • R 14 and R 15 are independently a group of the formula
  • R 4a is hydrogen, amino or hydroxy
  • R 5a is hydrogen, methyl or aminoethyl
  • R 6a is hydrogen or aminoethyl
  • R 5a and R 6a together with the nitrogen atom to which they are attached form a piperazine ring
  • R 8a and R 12a are independently * - (CH 2 ) zla -OH, * - (CH 2 ) z 2a -NHR 13a , * -CONHR 14a or * -CH 2 CONHR 15a ,
  • ZIa and Z2a are independently a number 1, 2 or 3,
  • R 13a is hydrogen or methyl
  • R 14a and R 15a are independently a group of the formula
  • R 4c is hydrogen, amino or hydroxy
  • R 5c is hydrogen, methyl or aminoethyl
  • R 6c is hydrogen or aminoethyl
  • k ⁇ is a number 0 or 1
  • Ic is a number 1, 2, 3 or 4,
  • R 9a and R 11a are independently hydrogen or methyl, R 10a is amino or hydroxy,
  • R 16a is a group of the formula
  • R 4d is hydrogen, amino or hydroxy
  • R 5d is hydrogen, methyl or aminoethyl
  • R 6d is hydrogen or aminoethyl
  • kd is a number 0 or 1
  • Id is a number 1, 2, 3 or 4,
  • ka is a number 0 or 1 and
  • Ia, wa, xa and ya are independently a number 1, 2, 3 or 4,
  • R 20 is hydrogen or * - (CH 2 J 1 -NHR 22 ,
  • R 22 is hydrogen or methyl
  • i is a number 1, 2 or 3,
  • R 21 is hydrogen or methyl, f is a number 0, 1, 2 or 3,
  • g is a number 1, 2 or 3
  • h is a number 1, 2, 3 or 4,
  • R 4b is hydrogen, amino or hydroxy
  • R 5b is hydrogen, methyl or aminoethyl
  • R 6b is hydrogen or aminoethyl
  • R 5b and R 6b together with the nitrogen atom to which they are attached form a piperazine ring
  • R 8b and R 12b are independently * - (CH 2 ) zlb -OH,
  • R 13b is hydrogen or methyl
  • ZIb and Z2b are independently a number 1, 2 or 3,
  • R 14b and R 15b are independently a group of the formula
  • R 4g is hydrogen, amino or hydroxy
  • R 5g is hydrogen, methyl or aminoethyl
  • R 6g is hydrogen or aminoethyl
  • kg is a number 0 or 1
  • Ig is a number 1, 2, 3 or 4,
  • R 9b and R llb are independently hydrogen or methyl
  • R 1Ob is amino or hydroxy
  • kb is a number 0 or 1
  • Ib, wb, xb and yb are independently a number 1, 2, 3 or 4,
  • R 1B is hydrogen, amino or hydroxy, equal to hydrogen, methyl or a group of the formula
  • R 25 is hydrogen or * - (CH 2 ) U -NHR 29 ,
  • R is hydrogen or methyl
  • u is a number 1, 2 or 3,
  • R 28 is hydrogen or methyl
  • s is a number 0, 1, 2 or 3
  • t is a number 1, 2 or 3
  • R 24 is hydrogen or aminoethyl
  • d is a number 1, 2 or 3
  • k and q are independently a number 0 or 1
  • 1, r and w are independently of one another a number 1, 2, 3 or 4,
  • L jw or r can independently of one another carry a hydroxy group at w or r equal to 3,
  • R 26 is hydrogen or hydroxy
  • R 1 is hydrogen or hydroxy
  • R 2 is hydrogen
  • R 3 is a group of the formula
  • R 4 is hydrogen, amino or hydroxy
  • R 5 is a group of the formula
  • R 23 is hydrogen or a group of the formula * - (CH 2 J n -OH or * - (CH 2 ) O -NH 2 , wherein
  • n and o independently of one another are a number 1, 2, 3 or 4,
  • n is a number 0 or 1
  • R 14 and R 15 are independently a group of the formula
  • R 4a is hydrogen, amino or hydroxy
  • R 5a is hydrogen
  • R 6a is hydrogen
  • R 12a is * - (CH 2 ) zla -OH or * -CH 2 CONHR 15a
  • ZIa is a number 1, 2 or 3
  • R 15a is a group of the formula
  • R 4c is hydrogen, amino or hydroxy
  • R 5c is hydrogen
  • R 6c is hydrogen
  • kc is a number 0 or 1
  • Ic is a number 1, 2, 3 or 4,
  • ka is a number 0 or 1
  • Ia and ya are independently of one another a number 1, 2, 3 or 4,
  • R 9 is hydrogen
  • R 17 is a group of the formula
  • R 4b is hydrogen, amino or hydroxy
  • R 5b is hydrogen
  • R 6b is hydrogen
  • kb is a number 0 or 1
  • Ib is a number 1, 2, 3 or 4,
  • R 18 is hydrogen, amino or hydroxy
  • R 19 is hydrogen
  • R 24 is hydrogen
  • d is a number 1, 2 or 3
  • k and q are independently a number 0 or 1
  • 1, r and w are independently of one another a number 1, 2, 3 or 4,
  • L jw or r can independently of one another carry a hydroxy group at w or r equal to 3,
  • the invention furthermore relates to a process for the preparation of the compounds of the formula (I) or their salts, their solvates or the solvates of their salts, according to processes
  • R 2 , R 7 and R 26 have the abovementioned meaning and boc is the same as tez-t-butoxycarbonyl
  • R 3 has the meaning given above
  • R 2 , R 7 and R 26 have the abovementioned meaning and Z is benzyloxycarbonyl
  • R 3 has the meaning given above
  • the free base of the salts can be obtained, for example, by chromatography on a reversed-phase column with an acetonitrile-water gradient with addition of a base, in particular by using a RP18 Phenomenex Luna C18 (2) column and diethylamine as base.
  • Another object of the invention is a process for the preparation of the compounds of formula (I) or their solvates according to claim 1, in which salts of the compounds or solvates of the salts of the compounds are converted by chromatography with the addition of a base in the compounds.
  • the hydroxy group on R 1 is optionally protected during the reaction with compounds of the formula (III) with a tert-butyldimethylsilyl group, which is cleaved off in the second reaction step.
  • the reaction of the first stage of the processes [A] and [B] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to 40 ° C. under atmospheric pressure.
  • Suitable dehydrating reagents in this case for example, carbodiimides such as iV, i ⁇ T'-diisopropyl, A ⁇ -V'-dicyclohexylcarbodiimide, N- (3-dimethyl-aminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), yy-cyclohexylcarbodiimide-iV'-propyloxymethyl-polystyrene (PS - Carbodiimid) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxy carbonyl-1,2-dihydroquinoline, or propanephosphonic
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, JV-methylmorpholine, ⁇ T-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate, or bicarbonate
  • organic bases such as trialkylamines e.g. Triethylamine, JV-methylmorpholine, ⁇ T-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • the condensation is preferably carried out with HATU in the presence of a base, in particular diisopropylethylamine, or with EDC and HOBt in the presence of a base, in particular triethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbon such as benzene, or nitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.
  • the reaction with an acid in the second stage of the processes [A] and [B] is preferably carried out in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • Suitable acids in this case are hydrogen chloride in dioxane, hydrogen bromide in acetic acid or trifluoroacetic acid in methylene chloride.
  • the hydrogenolysis in the second stage of the process [B] is generally carried out in a solvent in the presence of hydrogen and palladium on activated carbon, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • Solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol, in a mixture with water and glacial acetic acid; preference is given to a mixture of ethanol, water and glacial acetic acid.
  • R, R 7 and R 26 have the abovementioned meaning
  • reaction is generally carried out in a solvent, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • bases examples include alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or other bases such as DBU, triethylamine or diisopropylethylamine, preference being given to sodium hydroxide or sodium carbonate.
  • Solvents are, for example, halogenated hydrocarbons such as methylene chloride or 1,2-dichloroethane, alcohols such as methanol, ethanol or isopropanol, or water.
  • the reaction is carried out with sodium hydroxide in water or sodium carbonate in methanol.
  • the compounds of the formula (V) are known or can be prepared by reacting compounds of the formula
  • R 2 , R 7 and R 26 have the meaning given above, and
  • R 27 is benzyl, methyl or ethyl, with an acid or by hydrogenolysis as described for the second step of process [B], optionally followed by reaction with a base to saponify the methyl or ethyl ester.
  • the saponification can be carried out, for example, as described in the reaction of compounds of the formula (VI) to give compounds of the formula (IV).
  • the compounds of the formula (IV) are known or can be prepared by saponifying in compounds of the formula (VI) the benzyl, methyl or ethyl ester.
  • the reaction is generally carried out in a solvent, in the presence of a base, preferably in a temperature range from 0 ° C. to 40 ° C. under atmospheric pressure.
  • Bases are, for example, alkali metal hydroxides such as lithium, sodium or potassium hydroxide, lithium hydroxide is preferred.
  • Solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, ethers such as tetrahydrofuran or dioxane, or alcohols such as methanol, ethanol or isopropanol, or dimethylformamide. It is likewise possible to use mixtures of the solvents or mixtures of the solvents with water. Particularly preferred are tetrahydrofuran or a mixture of methanol and water.
  • the compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula
  • R 2 , R 7 , R 26 and R 27 are as defined above,
  • the reaction with bases is generally carried out in a solvent, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • Bases are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or other bases such as DBU, triethylamine or diisopropylethylamine, triethylamine is preferred.
  • alkali metal hydroxides such as sodium or potassium hydroxide
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate
  • other bases such as DBU, triethylamine or diisopropylethylamine, triethylamine is preferred.
  • Solvents are, for example, halogenated hydrocarbons such as chloroform, methylene chloride or 1, 2-dichloroethane, or tetrahydrofuran, or mixtures of the solvents, preferably methylene chloride or tetrahydrofuran.
  • halogenated hydrocarbons such as chloroform, methylene chloride or 1, 2-dichloroethane, or tetrahydrofuran, or mixtures of the solvents, preferably methylene chloride or tetrahydrofuran.
  • the compounds of formula (VII) are known or can be prepared by reacting compounds of the formula (VII)
  • the reaction is preferably carried out with DMAP and EDC in dichloromethane in a temperature range from -40 0 C to 40 0 C at atmospheric pressure.
  • R 2 , R, R 2 and R have the abovementioned meaning, be reacted with fluoride, in particular with tetrabutylammonium fluoride.
  • the reaction is generally carried out in a solvent, preferably in a temperature range from -10 0 C to 3O 0 C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane, or hydrocarbons, such as benzene or toluene, or ethers, such as tetrahydrofuran or dioxane, or dimethylformamide. It is likewise possible to use mixtures of the solvents. Preferred solvents are tetrahydrofuran and dimethylformamide.
  • R 7 has the meaning indicated above
  • the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum.
  • the compounds according to the invention can be used alone or in combination with other active compounds for the treatment and / or prophylaxis of infectious diseases, in particular of bacterial infections.
  • Gram-positive cocci e.g. Staphylococci (Staph aureus, Staph epidermidis) and streptococci (Strept agalactiae, Strept faecalis, Strept pneumoniae, Strept pyogenes); Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rods such as Enterobacteriaceae, e.g. Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob.friendii, Citrob. Divernis), Salmonella and Shigella; Klebsiella (Klebs. pneumoniae, Klebs. oxytocy), Enterobacter (Ent.
  • Staphylococci Staph aureus, Staph epidermidis
  • streptococci Strept agalactiae, Strept faecalis, Strept pneumoniae, Strept pyogenes
  • the antibacterial spectrum comprises the genus Pseudomonas (Ps. Aeruginosa, Ps. Maltophilia) as well as strictly anaerobic bacteria such as e.g. Bacteroides fragilis, representatives of the genus Pepoccocus, Peptostreptococcus and the genus Clostridium; mycoplasmas (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, e.g. Mycobacterium tuberculosis.
  • Pseudomonas Ps. Aeruginosa, Ps. Maltophilia
  • strictly anaerobic bacteria such as e.g. Bacteroides fragilis, representatives of the genus Pepoccocus, Peptostreptococcus and the genus Clostridium
  • mycoplasmas M. pneumoniae, M. hominis, M. urealyticum
  • mycobacteria
  • pathogens are merely exemplary and by no means limiting.
  • diseases which are caused by the named pathogens or mixed infections and which can be prevented, ameliorated or cured by the topically applicable preparations according to the invention are:
  • Infectious diseases in humans such. As septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the Mouth area, infections after dental surgery, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.
  • bacterial infections can also be treated in other species. Examples include:
  • Pig coli-diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalactiae syndrome, mastitis;
  • Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;
  • Horse bronchopneumonia, foal disease, puerperal and postpuerperal infections, salmonellosis;
  • Dog and cat bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;
  • Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.
  • bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, the antibacterial spectrum on the aforementioned pathogens on other pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema , Nocardia, Rikettsie, Yersinia, expanded.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of bacterial diseases, in particular of bacterial infections.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an antibacterially effective amount of the compounds of the invention.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • suitable administration forms for the oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or morphed and / or dissolved form, such as tablets (uncoated or coated tablets , for example, with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets in the oral cavity , Powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets , for example, with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention
  • rapidly disintegrating tablets or films / wafers films / lyophilisates
  • capsules eg hard or soft gelatin
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalant medicines including powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, but are not limited to, excipients (eg, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxy sorbitan oleate), binders (e.g., polyvinyl pyrrolidone), synthetic and natural polymers (eg, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odor remedies.
  • excipients eg, microcrystalline cellulose, lactose, mannitol
  • solvents eg, liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxy sorbitan oleate
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • Method 2 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A - ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 4 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 100% A -> 2.9 min 30% A -> 3.1 min 10% A -> 5.5 min 10% A; Flow: 0.8 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • a solution of 8.0 g (31.1 mmol) of 3-amino-4- (3-bromophenyl) butanoic acid in 100 ml of water is combined with 62 ml of 1N sodium hydroxide solution. While stirring, a solution of 20 g (93 mmol) of di-tert-butyl dicarbonate in 100 ml of methanol at RT is added and stirred for 2 h. By addition of 0. IN hydrochloric acid is adjusted to pH 3 and extracted twice with ethyl acetate. The organic phases are combined, dried with magnesium sulfate and evaporated to dryness in vacuo. The remaining solid is used without further purification.
  • a solution of 0.58 g (0.99 mmol) of the compound from Example 10A in 10 ml of water is mixed with 5 ml of 1N sodium hydroxide solution. With stirring, a solution of 0.65 g (2.96 mmol) of di-tert-butyl dicarbonate in 3.7 ml of methanol at RT is added and for Stirred for 2 h. The mixture is added to 25 ml of water, with 0.1N hydrochloric acid is adjusted to pH 3 and shaken out three times with ethyl acetate. The organic phases are combined, dried with magnesium sulfate and evaporated to dryness in vacuo. The remaining solid is purified in a high vacuum to constant weight.
  • a solution of 91 mg (0.10 mmol) of the compound from Example 18A in 10 ml of ethanol is hydrogenated after addition of 10 mg of palladium on activated carbon (10%) for 12 h at RT and normal pressure. It is filtered through kieselguhr and the residue is washed with ethanol. The filtrate is concentrated to dryness in vacuo. The product is reacted without further purification.
  • the solution is concentrated in vacuo and the residue is taken up in ethyl acetate.
  • the organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried under high vacuum to constant weight.
  • tert -butyl [(45,105,155) -10,15-bis [( ⁇ - ⁇ -butoxycarbonyl) amino] -4- ( ⁇ [(85, 115, 145) -14- [(tert-butoxycarbonyl) amino ] -ll- ⁇ 3- [(tert-butoxycarbony1) amino] propyl ⁇ -17-hydroxy-10,13-dioxo-9,12-diacatricyclo [14.3.1.1 2 ' 6 ] henicosa-1 (20), 2 (21), 3, 5, 16, 18-hexa-8-yl] -acetyl ⁇ -amino) -22,22-dimethyl-5,12,20-trioxo-21-oxa-6,13,19-triazatricos- 1-yl] carbamate
  • cAMP 11.25 mg / ml
  • the test batch is 105 .mu.l, wherein 5 .mu.l of the substance to be tested in 5% DMSO are submitted.
  • the transcription template used is 1 ⁇ g / 100 ⁇ l batch of the plasmid pBESTLuc (Promega, Germany).
  • luciferin solution (20 mM Tricine, 2.67 mM MgSO 4, 0.1 mM EDTA, 33.3 mM DTT pH 7.8, 270 uM CoA, 470 uM luciferin, 530 uM ATP) is added and the resulting bioluminescence measured for 1 minute in a luminometer.
  • the IC 50 is the concentration of an inhibitor which leads to a 50% inhibition of the translation of firefly luciferase.
  • plasmid pBESTluc Promega Corporation, USA
  • E. coli tac promoter present in this plasmid in front of the firefly luciferase is exchanged for the capAl promoter with corresponding Shine-Dalgarno sequence from S. aureus.
  • the primer CAPFor contains the capAl promoter, the ribosome binding parts and the 5 'region of the luciferase gene. After PCR using pBESTluc as a template, a PCR product containing the firefly luciferase gene with the fused capAl promoter can be isolated.
  • BHI medium Six liters of BHI medium are inoculated with a 250 ml overnight culture of a S. aureus strain and grown at 37 ° C to an OD 50 nm of 2-4.
  • the cells are harvested by centrifugation and washed in 500 ml of cold buffer A (10 mM Tris-acetate, pH 8.0, 14 mM magnesium acetate, 1 mM DTT, 1 M KCl). After re-centrifugation, the cells in 250 ml of cold buffer A containing 50 mM KCl, and the resulting pellets at -20 0 C for 60 min to be frozen.
  • cold buffer A 10 mM Tris-acetate, pH 8.0, 14 mM magnesium acetate, 1 mM DTT, 1 M KCl
  • the pellets are thawed on ice in 30 to 60 minutes and taken up to a total volume of 99 ml in buffer B (10 mM Tris-acetate, pH 8.0, 20 mM magnesium acetate, 1 mM DTT, 50 mM KCl).
  • buffer B 10 mM Tris-acetate, pH 8.0, 20 mM magnesium acetate, 1 mM DTT, 50 mM KCl.
  • 1.5 ml of lysostaphin (0.8 mg / ml) in buffer B are precooled in 3 Centrifuge cup presented and mixed with 33 ml of the cell suspension. The samples are incubated at 37 ° C. for 45-60 minutes with occasional shaking before adding 150 ⁇ l of a 0.5 M DTT solution.
  • the lysed cells are centrifuged min at 4 0 C at 30,000 xg 30th
  • the cell pellet after uptake in Buffer B, is recentrifuged under the same conditions and the collected supernatants are pooled.
  • the supernatants are again centrifuged under the same conditions and to the upper 2/3 of the supernatant 0.25 volumes of buffer C (670 mM Tris-acetate, pH 8.0, 20 mM magnesium acetate, 7 mM Na 3 phosphoenolpyruvate, 7 mM DTT, 5.5 mM ATP, 70 ⁇ M amino acids (complete from Promega), 75 ⁇ g pyruvate kinase (Sigma, Germany)) / ml.
  • buffer C 670 mM Tris-acetate, pH 8.0, 20 mM magnesium acetate, 7 mM Na 3 phosphoenolpyruvate, 7 mM DTT, 5.5 mM ATP, 70 ⁇ M amino acids
  • the samples are incubated for 30 min at 37 0 C.
  • the supernatants are dialyzed overnight at 4 0 C against 2 1 dialysis buffer (10 mM Tris-acetate, pH 8.0, 14 mM magnesium acetate, 1 mM DTT, 60 mM potassium acetate) with a buffer change in a dialysis tube with 3500 Da exclusion ,
  • the dialysate is concentrated to a protein concentration ml of about 10 mg / by the dialysis tube with cold PEG 8000 powder (Sigma, Germany) is covered at 4 0 C.
  • the S30 extracts can be stored in aliquots at -70 0 C.
  • Inhibition of protein biosynthesis of the compounds can be demonstrated in an in vitro transcription-translation assay.
  • the assay is based on the cell-free transcription and translation of firefly luciferase using the template plasmid pla as template and cell-free S30 extracts obtained from S. aureus. The activity of the resulting luciferase can be detected by luminescence measurement.
  • the amount of S30 extract or plasmid pla to be used must be re-tested for each preparation in order to ensure an optimal concentration in the test. 3 ⁇ l of the substance to be tested dissolved in 5% DMSO are placed in an MTP. Then 10 .mu.l of a suitably concentrated plasmid solution pla are added.
  • luciferin solution (20 mM Tricine, 2.67 mM MgSO 4, 0.1 mM EDTA, 33.3 mM DTT pH 7.8, 270 uM CoA, 470 uM luciferin, 530 uM ATP), and the resulting bioluminescence for 1 min measured in a luminometer.
  • the IC 50 is the concentration of an inhibitor which leads to a 50% inhibition of the translation of firefly luciferase.
  • the minimum inhibitory concentration is the minimum concentration of antibiotic used to inhibit a test bacterium in its growth for 18-24 h.
  • the inhibitor concentration can be determined according to standard microbiological procedures (see, for example, The National Committee for Clinical Laboratory Standards, Methods for dilution, anti-microbial susceptibility tests for bacteria that grow aerobic, approved standard-fifth edition, NCCLS document M7-A5). ISBN 1-56238-394-9]. NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-98 USA, 2000).
  • the MIC of the compounds according to the invention is measured in the liquid dilution test in the 96 Microtiter plate scale determined.
  • the bacterial germs are isolated in a minimal medium (18.5 mM Na 2 HPO 4 , 5.7 mM KH 2 PO 4 , 9.3 mM NH 4 Cl, 2.8 mM MgSO 4 , 17.1 mM NaCl, 0.033 ⁇ g / ml thiamine hydrochloride, 1.2 ⁇ g / ml nicotinic acid, 0.003 ⁇ g / ml biotin, 1% glucose, 25 ⁇ g / ml of each proteinogenic amino acid except phenylalanine [H.P. Kroll, unpublished]) cultured with the addition of 0.4% BH broth (test medium).
  • a minimal medium (18.5 mM Na 2 HPO 4 , 5.7 mM KH 2 PO 4 , 9.3 mM NH 4 Cl, 2.8 mM MgSO 4 , 17.1 mM NaCl, 0.033 ⁇ g / ml thiamine hydrochloride, 1.2 ⁇
  • the lowest substance concentration at which no visible bacterial growth occurs is defined as MIC.
  • the minimum inhibitory concentration is the minimum concentration of antibiotic used to inhibit a test bacterium in its growth for 18-24 h.
  • the inhibitor concentration can be determined in accordance with standard microbiological procedures using a modified medium as part of an agar dilution test (see, for example, The National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. NCCLS document M7-A5 [ISBN 1-56238-394-9]. NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-98 USA, 2000). The bacteria are cultured on 1.5% agar plates containing 20% defibrinated horse blood.
  • test organisms which are incubated overnight on Columbia blood agar plates (Becton-Dickinson), are diluted in PBS, adjusted to a bacterial count of about 5 ⁇ 10 5 germs / ml and dropped onto test plates (1-3 ⁇ l).
  • the test substances contain different dilutions of the test substances (dilution stages 1: 2).
  • the cultures are incubated at 37 ° C. for 18-24 hours in the presence of 5% CO 2 .
  • the lowest substance concentration at which no visible bacterial growth occurs is defined as MIC and expressed in ⁇ g / ml.
  • Concentration data MIC in ⁇ g / ml; IC 50 in ⁇ M. Systemic infection with S. aureus 133
  • the suitability of the compounds according to the invention for the treatment of bacterial infections can be demonstrated in various animal models.
  • the animals are generally infected with a suitable virulent germ and then treated with the compound to be tested, which is present in a formulation adapted to the respective therapeutic model.
  • the suitability of the compounds of the invention for the treatment of bacterial infections in a sepsis model in mice after infection with S. aureus can be demonstrated.
  • S. aureus 133 cells are grown overnight in BH broth (Oxoid, Germany). The overnight culture was diluted 1: 100 in fresh BH broth and spun for 3 hours. The bacteria in the logarithmic growth phase are centrifuged off and washed twice with buffered, physiological saline. Thereafter, a cell suspension in saline solution with an extinction of 50 units is set on the photometer (Dr. Lange LP 2W). After a dilution step (1:15), this suspension is mixed 1: 1 with a 10% mucin suspension. 0.2 ml / 20 g mouse ip is administered from this infectious solution. This corresponds to a cell number of about 1-2 x 10 6 germs / mouse.
  • the spontaneous resistance rates of the compounds according to the invention are determined as follows: the bacterial germs are dissolved in 30 ml of a minimal medium (18.5 mM Na 2 HPO 4 , 5.7 mM KH 2 PO 4 , 9.3 mM NH 4 Cl, 2.8 mM MgSO 4 , 17.1 mM NaCl, 0.033 ⁇ g / ml thiamin hydrochloride, 1.2 ⁇ g / ml nicotinic acid, 0.003 ⁇ g / ml biotin, 1% glucose, 25 ⁇ g / ml of each proteinogenic amino acid with the addition of 0.4% BH broth) at 37 ° C overnight, 10 min Centrifuged at ⁇ .OOOxg and resuspended in 2 ml of phosphate-buffered physiological NaCl solution (about 2x10 9 germs / ml).
  • 100 ⁇ l of this cell suspension or 1:10 and 1: 100 dilutions are diluted on predried agar plates (1.5% agar, 20% defibrinated horse blood or 1.5% agar, 20% bovine serum in 1/10 Müller-Hinton medium diluted with PBS), which contains the compound of the invention to be tested in a concentration corresponding to 5xMHK or 1OxMHK, plated and incubated at 37 0 C for 48 h. The resulting colonies (cfu) are counted.
  • the S. aureus strain RN4220Bi R is isolated in vitro.
  • 100 ⁇ l of a S. aureus RN4220 cell suspension (approximately 1.2 ⁇ 10 8 cfu / ml) are applied to an antibiotic-free agar plate (18.5 mM Na 2 HPO 4 , 5.7 mM KH 2 PO 4 , 9.3 mM NH 4 Cl, 2.8 mM MgSO 4 , 17.1 mM NaCl, 0.033 ⁇ g / ml thiamine hydrochloride, 1.2 ⁇ g / ml nicotinic acid, 0.003 ⁇ g / ml biotin, 1% glucose, 25 ⁇ g / ml of each proteinogenic amino acid with the addition of 0.4% BH broth and 1% agarose) and a Agar plate containing 2 ⁇ g / ml Biphenomycin B (10xMHK) and incubated overnight at 37 ° C.
  • the S. aureus strain T17 is isolated in vivo. CFWl mice are challenged with 4x10 ⁇ S. aureus 133 cells per mouse intraperitoneally. 0.5 hours after infection, the animals are treated with 50 mg / kg biphenomycin B intravenously. The survivors are removed from the kidneys on day 3 post-infection. After homogenization of the organs, the homogenates, as described in RN4220Bi R , on antibiotic-free and antibiotic-containing agar plates, plated and incubated overnight at 37 0 C incubated. About half of the colonies isolated from the kidney show growth on the antibiotic-containing plates (2.2 ⁇ 10 6 colonies), which demonstrates the accumulation of biphenomycin B-resistant S. aureus cells in the kidney of the treated animals. Approximately Twenty of these colonies are tested for biphenomycin B MIC and a colony with a MIC> 50 ⁇ M is selected for further culture and the strain is designated T17.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the compound of the present invention is dissolved in the water with stirring together with polyethylene glycol 400.
  • the solution is sterile-filtered (pore diameter 0.22 ⁇ m) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

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Abstract

L'invention concerne des macrocycles d'amide antibactériens, leur procédé de préparation, leur utilisation pour le traitement et/ou la prophylaxie de maladies, ainsi que leur utilisation pour la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier d'infections bactériennes.
EP06762521A 2005-07-14 2006-07-11 Macrocycles d'amide vii antibacteriens Withdrawn EP1907413A2 (fr)

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DE102005032781A DE102005032781A1 (de) 2005-07-14 2005-07-14 Antibakterielle Amid-Markozyklen VII
PCT/EP2006/006770 WO2007006548A2 (fr) 2005-07-14 2006-07-11 Macrocycles d'amide vii antibacteriens

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DE10226921A1 (de) * 2002-06-17 2003-12-24 Bayer Ag Antibakterielle Amid-Makrozyklen
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DE10358824A1 (de) * 2003-12-16 2005-07-21 Bayer Healthcare Ag Antibakterielle Makrozyklen mit substituiertem Biphenyl
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DE102004025731A1 (de) * 2004-05-26 2005-12-15 Bayer Healthcare Ag Antibakterielle Amid-Makrozyklen III
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DE102005014247A1 (de) * 2005-03-30 2006-10-05 Aicuris Gmbh & Co. Kg Antibakterielle Amid-Makrozyklen VI
DE102005014245A1 (de) * 2005-03-30 2006-10-05 Aicuris Gmbh & Co. Kg Antibakterielle Amid-Makrozyklen V

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US20080306040A1 (en) 2008-12-11
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