EP1869068A1 - Amides macrocycliques antibacteriens v - Google Patents

Amides macrocycliques antibacteriens v

Info

Publication number
EP1869068A1
EP1869068A1 EP06723614A EP06723614A EP1869068A1 EP 1869068 A1 EP1869068 A1 EP 1869068A1 EP 06723614 A EP06723614 A EP 06723614A EP 06723614 A EP06723614 A EP 06723614A EP 1869068 A1 EP1869068 A1 EP 1869068A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
amino
independently
methyl
attachment
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Withdrawn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
EP06723614A
Other languages
German (de)
English (en)
Inventor
Rainer Endermann
Kerstin Ehlert
Siegfried Raddatz
Martin Michels
Yolanda Cancho-Grande
Stefan Weigand
Karin Fischer
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 EP1869068A1 publication Critical patent/EP1869068A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • A61K38/07—Tetrapeptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link

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 and WO 04/012816 describe antibacterial macrocycles of the biphenomycin B type with amide or ester substituents.
  • the natural substances do not correspond in their properties to the requirements placed on antibacterial drugs. Although structurally different antibacterial agents are present on the market, development of resistance can regularly occur. New means for a good and more effective therapy are therefore desirable.
  • 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, amino or methyl
  • R 7 is a group of the formula
  • R 1 is hydrogen or hydroxy
  • R 2 is hydrogen or methyl
  • R 3 is a group of the formula
  • 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 ) "- OH or * -CCH 2 ) 0 - NH 2 ,
  • n and o independently of one another are a number 1, 2, 3 or 4,
  • n is a number 0 or 1
  • R 8 and R 12 are independently a group of 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 ⁇ a 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 * - (C ⁇ 2 ) zi a -OH, * _ (CH 2 ) Z 2a -NHR 13a , * -CONHR Ua or * -CH 2 CONHR 15a , embedded image in which
  • ZIa and Z2a are independently a number 1, 2 or 3,
  • R 1 Yes is hydrogen or methyl
  • R a and R a independently represent a group of the formula
  • R c is hydrogen, amino or hydroxy
  • R c is hydrogen, methyl or aminoethyl
  • R ° is hydrogen or aminoethyl
  • kc is a number 0 or 1
  • Ic is a number 1, 2, 3 or 4,
  • R 9a and R 1 la independently of one another are hydrogen or methyl
  • R IOa 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,
  • R 18a and R I9a are independently hydrogen or a group of
  • R 4h is hydrogen, amino or hydroxy
  • R 5h is hydrogen, methyl or aminoethyl
  • R 6h is hydrogen or aminoethyl
  • kh is a number 0 or 1
  • Ih is a number 1, 2, 3 or 4,
  • ka is a number 0 or 1
  • ea is a number 1, 2 or 3
  • 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 and
  • h is a number 1, 2, 3 or 4,
  • R 8 is * - (CH 2 ) zi-OH
  • Zl is a number 1, 2 or 3
  • R 9 is a group of the formula
  • h is a number 1, 2, 3 or 4,
  • R 10 is amino or hydroxy
  • R 16 and R 17 independently represent a group of the formula
  • 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 sb and R 12b are independently * - (CH 2 ) zi b -OH, * - ⁇ CH 2 ) Z 2b -NHR 13b , * -CONHR I4b or * -CH 2 CONHR 15b ,
  • R 13b is hydrogen or methyl
  • ZIb and Z2b are independently a number 1, 2 or 3,
  • R I4b and R 15b are independently a group of the formula
  • R 4 ⁇ is hydrogen, amino or hydroxy
  • R 5 ⁇ 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 1 lb independently of one another are 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 19 are independently hydrogen or a group of the formula
  • R 4e is hydrogen, amino or hydroxy
  • R 5e is hydrogen, methyl or aminoethyl
  • R 6e is hydrogen or aminoethyl
  • R 8e and R 12e independently of each other * - (CH 2) z, -OH e o r * - (CH 2) Z2e -NHR 13e,
  • R 13e is hydrogen or methyl
  • ZIe and Z2e are independently a number 1, 2 or 3,
  • R 9e and R 1 are independently of one another hydrogen or methyl
  • R 1Oe is amino or hydroxy
  • ke is a number 0 or 1
  • Ie we, xe and ye are independently a number 1, 2, 3 or 4,
  • R 25 is a group of the formula
  • R 4f is hydrogen, amino or hydroxy
  • R 5f is hydrogen, methyl or aminoethyl
  • R 6f is hydrogen or aminoethyl
  • R 8f and R 12f ⁇ independently - (CH 2) r OH ZI or * - (CH 2) Z2 RNHR are 13f
  • R 13f is hydrogen or methyl
  • ZIf and Z2f are independently a number 1, 2 or 3,
  • R 9f and R 1 are independently of one another hydrogen or methyl, R 1Of is amino or hydroxy,
  • kf is a number 0 or 1
  • wf, xf and yf are independently a number 1, 2, 3 or 4,
  • d and e are independently a number 1, 2 or 3
  • k is a number 0 or 1
  • 1, w, x and y are independently of one another a number 1, 2, 3 or 4,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as the compounds encompassed by formula (I), hereinafter referred to as embodiment (e) and their salts, solvates and solvates of the salts, as far as the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may 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 (T) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, eg salts of hydrochloric acid, bromine water tartaric, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic, trifluoroacetic and benzoic acids.
  • Physiologically acceptable salts of compounds (I) also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (e.g., sodium and potassium salts), alkaline earth salts
  • ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine,
  • 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 respect to the configuration at this carbon atom, which in the context of the present invention is understood to have an enantiomeric excess of more than 90% (> 90% ee).
  • R 26 is hydrogen, halogen, amino or methyl
  • R 7 is a group of the formula
  • R 1 is hydrogen or hydroxy
  • R is hydrogen or methyl
  • R 3 is a group of the formula
  • 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 ) n -OH or
  • n and o independently of one another are a number 1, 2, 3 or 4,
  • n is a number 0 or 1
  • R 8 and R 12 are independently a group of formula * -CONHR 14 or * -CH 2 CONHR 15 ,
  • R 14 and R IS independently of one another are 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 ) zi a -OH,
  • 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 4 ° is hydrogen, amino or hydroxy
  • R 5c is hydrogen, methyl or aminoethyl
  • R ⁇ c is hydrogen or aminoethyl
  • kc is a number 0 or 1
  • Ic is a number 1, 2, 3 or 4,
  • R 9a and R 1 la independently of one another are 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
  • 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,
  • R 8 is equal to * - (CH 2 ) zl -OH i st ,
  • Zl is a number 1, 2 or 3
  • R 9 is a group of the formula
  • h is a number 1, 2, 3 or 4,
  • R 10 is amino or hydroxy
  • R 16 and R 17 independently represent a group of the formula
  • 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 * independently 12b - (CH 2) b Z i -OH, * _ (CH 2) Z2 are b-NHR I3b, * -CONHR 14b or * -CH 2 CONHR 15 b,
  • 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 1b 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 19 are independently hydrogen or a group of the formula
  • R 4e is hydrogen, amino or hydroxy
  • R 5e is hydrogen, methyl or aminoethyl
  • R 6e is hydrogen or aminoethyl
  • R Se and R 12e are independently * - (CH 2 ) Z i e -OH or ⁇ CH 2 ) Z 26 -NHR 13e
  • R 13e is hydrogen or methyl
  • ZIe and Z2e are independently a number 1, 2 or 3,
  • R 9e and R 1 le are independently hydrogen or methyl
  • R IOe is amino or hydroxy
  • ke is a number 0 or 1
  • Ie we, xe and ye are independently a number 1, 2, 3 or 4,
  • R 25 is a group of the formula
  • R 4f is hydrogen, amino or hydroxy
  • R 5f is hydrogen, methyl or aminoethyl
  • R 6f is hydrogen or aminoethyl
  • R 8f and R I2f independently of one another or * - (CH 2 ) Z2 rNHR I3f ,
  • R 13f is hydrogen or methyl
  • ZIf and Z2f are independently a number 1, 2 or 3,
  • R 9f and R 1 if independently of one another are hydrogen or methyl
  • R IOf is amino or hydroxy
  • kf is a number 0 or 1
  • wf, xf and yf are independently a number 1, 2, 3 or 4,
  • d and e are independently a number 1, 2 or 3
  • k is a number 0 or 1
  • 1, w, x and y are independently of one another a number 1, 2, 3 or 4,
  • R 26 is hydrogen, halogen, amino 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 or methyl.
  • R 3 is a group of the formula
  • R 4 is hydrogen, amino or hydroxy
  • R s is a group of the formula
  • R 23 is hydrogen or a group of the formula * - ⁇ CH 2 ) n -OH or * -
  • n and o independently of one another are a number 1, 2, 3 or 4,
  • n is a number 0 or 1
  • R 8 is 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 independently of one another are MCH 2 WOH, * - (CH 2 ) Z 2a -NHR I 3a , * -CONHR 14a or * -CH 2 CONHR 15a ,
  • Zla 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
  • R 9a and R 1 la independently of one another are hydrogen or methyl
  • R IOa 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
  • Ia, wa, xa and ya are independently a number 1, 2, 3 or 4,
  • R 20 is hydrogen or MCH 2 VNHR 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 8 is * - (CH 2 ) Z 1 -OH
  • Zl is a number 1, 2 or 3
  • R 9 is a group of the formula
  • h is a number 1, 2, 3 or 4,
  • R 10 is amino or hydroxy
  • R 24 is a group of the formula * -CONHR 25 ,
  • R -.25 is a group of the formula
  • R, 4f is hydrogen, amino or hydroxy
  • R 5f is hydrogen, methyl or aminoethyl
  • R 6f is hydrogen or aminoethyl
  • R and R are independently * - (CH 2 ) zirOH or
  • ZIf and Z2f are independently a number 1, 2 or 3,
  • R and R independently of one another are hydrogen or methyl
  • R is amino or hydroxy
  • 20 kf is a number 0 or 1 and
  • wf, xf and yf are independently a number 1, 2, 3 or 4,
  • k is a number 0 or 1
  • 1, w and x are independently a number 1, 2, 3 or 4,
  • a hydroxy group can carry,
  • 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 ) 0 -NH 2 ,
  • n and o independently of one another are a number 1, 2, 3 or 4,
  • n is a number 0 or 1
  • k is a number 0 or 1
  • 1 is a number 1, 2, 3 or 4,
  • R 3 is a group of the formula
  • R 8 is 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 Sa 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 ) Z i a -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 I4a 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
  • R 9a and R 1 la independently of one another are 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 O 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 MCH 2 VNHR 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 8 is MCH 2 ) Zi-OH
  • Zl is a number 1, 2 or 3
  • R 9 is a group of the formula
  • h is a number 1, 2, 3 or 4,
  • R 10 is amino or hydroxy
  • R 24 is a group of the formula * -CONHR 25 ,
  • R 25 is a group of the formula
  • R 4f is hydrogen, amino or hydroxy
  • R 5f is hydrogen, methyl or aminoethyl
  • R ⁇ f is hydrogen or aminoethyl
  • R 8f and R 12f independently represent * - (CH 2) Z iroh * or - ⁇ CH 2) r NHR Z2 are i3F,
  • R I3f is hydrogen or methyl
  • ZIf and Z2f are independently a number 1, 2 or 3,
  • R 9f and R 1 ' f independently of one another are hydrogen or methyl
  • R 1Of is amino or hydroxy
  • 20 kf is a number 0 or 1 and
  • wf, xf and yf are independently a number 1, 2, 3 or 4,
  • w and x independently of one another are a number 1, 2, 3 or 4,
  • R 3 is a group of the formula
  • R 12 is 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 independently of each other * - ⁇ CH 2) a -OH zi, MCH 2) Z23 - NHR 13a, * -CONHR 14a or * -CH 2 CON ⁇ R I5a are
  • ZIa and Z2a are independently a number 1, 2 or 3,
  • R 13a is hydrogen or methyl
  • R 14a and R 15a independently represent 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
  • R 9a and R Ua 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
  • Ia, wa, xa and ya are independently a number 1, 2, 3 or 4,
  • y is a number 1, 2, 3 or 4,
  • R 3 is a group of the formula
  • A is a bond or phenyl
  • R 16 and R 17 independently represent a group of the formula
  • R, 4b is hydrogen, amino or hydroxy
  • R 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 is hydrogen or methyl
  • ZIb and Z2b are independently a number 1, 2 or 3,
  • R and R independently of one another are hydrogen or methyl
  • R 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,
  • a number is 1, 2 or 3
  • R 3 is a group of the formula
  • R is independently hydrogen or a group of the formula
  • R 4e is hydrogen, amino or hydroxy
  • R 5e is hydrogen, methyl or aminoethyl
  • R 6e is hydrogen or aminoethyl
  • R 8 ⁇ and R 12e are independently * - (CH 2 ) zi e -OH or MCH 2 K-NHR 136 ,
  • R l3e is hydrogen or methyl
  • ZIe and Z2e are independently a number 1, 2 or 3,
  • R 9e and R ll ⁇ independently of one another are hydrogen or methyl
  • R 1Oe is amino or hydroxy
  • ke is a number 0 or 1
  • Ie we, xe and ye are independently a number 1, 2, 3 or 4,
  • e is a number 1, 2 or 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 equal to te / 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 RPl 8 Phenomenex Luna Cl 8 (2) column and diethylamine as base.
  • the invention further provides a process for the preparation of the compounds of the 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 into the compounds by chromatography with addition of a base.
  • 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 in the second reaction step.
  • Reactive functionalities in the radical R 3 of compounds of the formula (IH) are already protected in the synthesis, preference is given to acid-labile protective groups (eg boc).
  • the protective groups can be eliminated by deprotection reaction. This is done by standard methods of protecting group chemistry. Deprotection reactions under acidic conditions or by hydrogenolysis are preferred.
  • 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 4O ° C at atmospheric pressure.
  • Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g. N, N-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl-I) -N-ethylcarbodiimide hydrochloride (EDC) , N-cyclohexylcarbodiimide-N'-propyloxy-methyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2- tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-e
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate, or bicarbonate
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-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 omitromethane, 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 ° C to 40 ° 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 ° C to 40 ° 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, preferably a mixture of ethanol, water and glacial acetic acid.
  • R 2 , R 7 and R 26 have the abovementioned meaning
  • the reaction is generally carried out in a solvent, preferably in a temperature range of 0 ° C to 4O ° 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, preferably 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 (VI)
  • R 2 , R 7 and R 26 have the meaning given above, and
  • R 27 is benzyl, methyl or ethyl
  • 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.degree. C. to 4.degree. C. under normal 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 (V ⁇ )
  • R, 2, r 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 ° C to 40 ° 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 being 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.
  • R, R 7 , R and R have the abovementioned meaning, with pentafluorophenol in the presence of dehydrating reagents as described for the first step of processes [A] and [B].
  • the reaction is preferably carried out with DMAP and EDC in dichloromethane in a temperature range from -4O ° C to 40 ° C at atmospheric pressure.
  • R 2 , R 7 , R 26 and R 27 are as defined above,
  • fluoride in particular with tetrabutylammonium fluoride.
  • the reaction is generally carried out in a solvent, preferably in a temperature range from -1O ° C to 3O ° 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 eg staphylococci (Staph aureus, Staph epidermidis) and streptococci (Strept agalactiae, Strept faecalis, Strept pneumoniae, Strept pyogenes); Gram-negative cocci (Neisseria gonorrhoeae) as well as Gram-negative rods such as Enterobacteriaceae, eg Escherichia coli, Hemophilus influenzae, Citrobacter (Citrobanthusii, Citrob. divernis), Salmonella and Shigella; also Klebsiella (Klebs. pneumoniae, Klebs. oxytocy), Enterobacter (Ent. aerogenes, 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 Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, eg Mycobacterium tuberculosis.
  • Pseudomonas Ps. aeruginosa, Ps. maltophilia
  • strictly anaerobic bacteria such as Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium
  • mycoplasma M. pneumoniae, M. hominis, M. urealyticum
  • mycobacteria eg Mycobacterium tubercul
  • 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, 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-agactiae 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, conjunctivae otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • Tablets uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings containing the
  • Soft gelatin capsules Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include 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)
  • milk Pastes, foams, scattering powders, implants or stents.
  • 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.
  • These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin ), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odor remedies.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • compositions containing at least one inventive compound are pharmaceutical compositions containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • Method 1 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; 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: 5O ° C; UV detection: 208-400 nm.
  • 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: 5O ° C; UV detection: 210 nm.
  • Method 4 (LC-MS); Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 1 liter of water + 1 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 1 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 -> 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.
  • Method 7 (LC-MS); Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE 50 mm ⁇ 2 mm, 3.0 ⁇ m; Eluent A: water + 500 ⁇ l of 50% formic acid; Eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0 min 5% B -> 2.0 min 40% B - »4.5 min 90% B -> 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min -> 4.5 min 0.75 ml / min 5.5 min -> 5.5 min 1.25 ml / min; UV detection: 210 nm.
  • Method 8 (LC-MS); Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo HyPURITY Aquastar 3 ⁇ 50 mm x 2.1 mm; 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; Oven: 5O ° C; Flow: 0.8 ml / min; UV detection: 210 nm.
  • Method 9 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE 50 ⁇ 2 mm, 3.0 ⁇ m; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 70% B -> 4.5 min 90% B -> 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min -> 4.5 min 0.75 ml / min - »5.5 min 1.25 ml / min; UV detection: 210 nm.
  • Method 10 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD-3 ⁇ 20 x 4 mm; 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; Oven: 5O ° C; Flow: 0.8 ml / min; UV detection: 210 nm.
  • Method 11 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; Eluent A: 5 ml HC1O 4/1 water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
  • Method 12 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; Eluent A: 5 ml HC1O 4/1 water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 15 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
  • Example 3A is prepared from the corresponding starting materials:
  • Example 5A is prepared from the corresponding starting materials:
  • Pentafluorophenyl 1- (25) -3- ⁇ 4- (benzyloxy) -3 '- [(2 $) - 2 - ( ⁇ (2S) -5- ⁇ [(benzyloxy) carbonyl] amino ⁇ -2- [( ⁇ / (butoxycarbonyl) amino] pentanoyl ⁇ amino) -3-methoxy-3-oxopropyl] biphenyl-3-yl ⁇ -2- ⁇ [(benzyloxy) carbonyl] amino ⁇ propanoate

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Abstract

L'invention concerne des amides macrocycliques antibactériens de formule (I) dans laquelle R<SUP>26</SUP> représente hydrogène, halogène, amino ou méthyle, R<SUP>7</SUP> représente un groupe de formules (II), (III), (IV) ou (V), dans lesquelles R<SUP>1</SUP> représente hydrogène ou hydroxy, *représente le site de liaison à l'atome de carbone, R<SUP>2</SUP> représente hydrogène ou méthyle. L'invention concerne également des procédés de production de ces amides macrocycliques, leur utilisation pour le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation pour la production de médicaments servant au traitement et/ou à la prophylaxie de maladies, notamment d'infections bactériennes.
EP06723614A 2005-03-30 2006-03-22 Amides macrocycliques antibacteriens v Withdrawn EP1869068A1 (fr)

Applications Claiming Priority (2)

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DE102005014245A DE102005014245A1 (de) 2005-03-30 2005-03-30 Antibakterielle Amid-Makrozyklen V
PCT/EP2006/002617 WO2006103015A1 (fr) 2005-03-30 2006-03-22 Amides macrocycliques antibacteriens v

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DE10358824A1 (de) 2003-12-16 2005-07-21 Bayer Healthcare Ag Antibakterielle Makrozyklen mit substituiertem Biphenyl
DE102005032781A1 (de) * 2005-07-14 2007-01-18 Aicuris Gmbh & Co. Kg Antibakterielle Amid-Markozyklen VII
JP2013539751A (ja) 2010-09-15 2013-10-28 ザ スクリプス リサーチ インスティチュート 広域抗生物質アリロマイシン類縁体
US10501493B2 (en) 2011-05-27 2019-12-10 Rqx Pharmaceuticals, Inc. Broad spectrum antibiotics
US20140249073A1 (en) * 2011-05-27 2014-09-04 Rqx Pharmaceuticals, Inc Broad spectrum antibiotics
WO2014081886A1 (fr) 2012-11-21 2014-05-30 Rqx Pharmaceuticals, Inc. Antibiotiques macrocycliques à large spectre
EP3145944B1 (fr) 2014-05-20 2021-05-05 RQX Pharmaceuticals, Inc. Antibiotiques macrocycliques à large spectre
WO2017084629A1 (fr) 2015-11-20 2017-05-26 Rqx Pharmaceuticals, Inc. Antibiotiques macrocycliques à large spectre
EP3388444A1 (fr) * 2017-04-10 2018-10-17 F. Hoffmann-La Roche AG Macrocycles peptidiques antibactériens et utilisation associée
EP3672939A1 (fr) 2017-08-21 2020-07-01 Celgene Corporation Procédés de préparation de (s)-tert-butyl 4,5-diamino-5-oxopentanoate
US11505573B2 (en) 2018-03-28 2022-11-22 Hoffmann-La Roche Inc. Peptide macrocycles against Acinetobacter baumannii
US11819532B2 (en) 2018-04-23 2023-11-21 Hoffmann-La Roche Inc. Peptide macrocycles against Acinetobacter baumannii
IL288294B (en) 2019-05-28 2022-09-01 Hoffmann La Roche A broad-spectrum macrocyclic antibiotic

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US3452136A (en) * 1968-04-17 1969-06-24 American Cyanamid Co Antibiotic af283 and production thereof
FR2720066B1 (fr) * 1994-05-20 1996-06-28 Rhone Poulenc Rorer Sa Peptides antagonistes de la neurotensine.
DE10226921A1 (de) * 2002-06-17 2003-12-24 Bayer Ag Antibakterielle Amid-Makrozyklen
DE10234422A1 (de) * 2002-07-29 2004-02-12 Bayer Ag Antibakterielle Ester-Makrozyklen
WO2005033129A1 (fr) * 2003-10-01 2005-04-14 Bayer Healthcare Ag Macrocycles d'amide antibacteriens
DE10358824A1 (de) * 2003-12-16 2005-07-21 Bayer Healthcare Ag Antibakterielle Makrozyklen mit substituiertem Biphenyl
DE102005014240A1 (de) * 2004-09-24 2006-03-30 Bayer Healthcare Ag Antibakterielle Amid-Makrozyklen IV

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IL185899A0 (en) 2008-12-29
BRPI0612219A2 (pt) 2009-01-13
JP2008534540A (ja) 2008-08-28
US20080275018A1 (en) 2008-11-06
UA91541C2 (ru) 2010-08-10
AU2006228751A1 (en) 2006-10-05
ZA200709336B (en) 2009-09-30
NO20075270L (no) 2007-12-18
WO2006103015A1 (fr) 2006-10-05
DE102005014245A1 (de) 2006-10-05
CN101228182A (zh) 2008-07-23
RU2007139760A (ru) 2009-05-10
NZ562003A (en) 2010-11-26
RU2409588C2 (ru) 2011-01-20
MX2007012146A (es) 2007-12-10
KR20070116169A (ko) 2007-12-06

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