Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to compounds, processes for their preparation, pharmaceutical compositions comprising them and their use in the treatment of diseases in humans or animals.
• R c is always hydrogen, R a is hepta-l, 3,5-trienyl, R b is hydrogen or R a is hepta-l, 3,5-trienyl, R b is methyl or R a is hepta-l , 3-dienyl, R b is methyl or R a is penta-1,3-dienyl, R is methyl or R a is penta-1,3-dienyl, R b is hydrogen or R a is penta-5 -Hydroxy-l, 3-dienyl, R is methyl) as antibacterial.
• JP 05 117 290 describes depsipeptides A and B, in which R a is a radical
• R b is hydrogen
• R c is hydrogen or methyl as antibacterial.
• An object of the present invention is to provide alternative compounds with comparable or improved antibacterial activity for the treatment of bacterial diseases in humans and animals.
• the present invention therefore relates to compounds of the general formula (I)
• R 1 is halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, amino,
• R 2 is hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino or alkylcarbonylamino
• R 3 is hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino or alkylcarbonylamino
• R 4 is hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino or alkylcarbonylamino,
• R 5 is hydrogen, C 1 -C 4 alkyl, fluorine or chlorine,
• R 6 is hydrogen, halogen or alkyl
• R 7 is alkyl or (cycloalkyl) alkyl
• R 8a is alkyl, alkylene, cycloalkyl or (cycloalkyl) alkyl,
• R 8a can be optionally substituted with 1, 2 or 3 substituents which are selected independently of one another from the group consisting of hydroxyl, alkoxy, a radical Carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, amino sulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, hetero- cyclylaminosulfonyl, heteroarylaminosulfonyl, aminocarbonylamino, hydroxy, carbonylamino, alkoxycarbonylamino, aminocarbonyloxy, in which R 8A_1 equal to an amino acid residue carbonylmagazinen .
• R 7 and R 8a together with the carbon atom to which R 8a is bonded and the nitrogen atom to which R 7 is bonded form a heterocyclyl ring which may optionally be substituted by 1, 2 or 3 substituents which are selected independently of one another are selected from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, azido, amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkanoyloxy,
• R 8b is hydrogen or alkyl
• R 9 is hydrogen, alkyl, hydroxyalkyl, carboxylalkyl or aminoalkyl
• R 9b is hydrogen or alkyl
• R 10a is hydrogen, alkyl or fluorine
• R 10b is hydrogen or fluorine
• R 1 x is hydrogen or alkyl
• R 12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, (cycloalkyl) alkyl, (cycloalkenyl) alkyl, (cycloalkyl) alkenyl (cycloalkenyl) alkenyl,
• R 12 may optionally be substituted with 1, 2 or 3 substituents which are selected independently of one another from the group consisting of halogen, hydroxy, alkoxy, fluoroalkoxy, aryloxy, alkanoyloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylamino sulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
• Form cycloalkyl which may optionally be substituted with 1 or 2 substituents which are selected independently of one another from the group consisting of halogen, hydroxy, alkoxy,
• R »13 is hydrogen or alkyl
• A represents a heterocycle which can optionally be substituted by 1, 2 or 3 substituents which are selected independently of one another from the group consisting of halogen, alkyl, trifluoromethyl, trifluoromethoxy, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkanoyloxy, Carboxyl, alkoxycarbonyl, azido, alkoxycarbonylamino,
• the compounds of the general formula (T) according to the invention can occur in various stereoisomeric forms which either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (diastereomers).
• the invention relates to both the enantiomers and the diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
• the substances of the general formula (I) according to the invention can also be present as salts.
• Pharmaceutically acceptable salts are preferred within the scope of the invention.
• salts can be salts of the compounds according to the invention with inorganic or organic acids.
• Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as, for example, acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid are preferred , Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
• Pharmaceutically acceptable salts can also be salts of the compounds according to the invention with bases, such as metal or ammonium salts.
• bases such as metal or ammonium salts.
• alkali metal salts for example sodium or potassium salts
• alkaline earth metal salts for example magnesium or calcium salts
• ammonium salts which are derived from ammonia or organic amines, such as, for example, ethyl in, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
• alkali metal salts for example sodium or potassium salts
• alkaline earth metal salts for example magnesium or calcium salts
• ammonium salts which are derived
• radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, regardless of the respectively specified combinations of the radicals.
• Alkyl and the alkyl parts in substituents such as alkoxy, mono- and dialkylamino,
• Alkylsulfonyl include linear and branched alkyl, for example C ⁇ -C 24 -, preferably CrC 12 - and C 7 -C 24 -, in particular C ⁇ C ⁇ - and C 1 -C 4 alkyl.
• CC 24 alkyl includes methyl, ethyl, n- and i-propyl, n-, i-, sec- and tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, 2-ethylhexyl, n-octyl, decyl Dodecyl
• C 1 -C 2 -alkyl includes methyl, ethyl, n- and i-propyl, n-, i-, sec- and tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, 2-ethylhexyl, n-octyl decyl
• Dodecyl C 1 -C 6 alkyl includes methyl, ethyl, n- and i-propyl, n-, i-, sec- and tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl,
• C 1 -C 4 alkyl includes methyl, ethyl, n- and i-propyl, n-, i-, sec- and tert-butyl,
• Alkenyl comprises linear and branched C 2 -C 24 -, preferably C 2 -C 12 -, in particular C 2 -C 6 - and C -C 4 - alkenyl, such as vinyl, allyl, Pro ⁇ -1-en-l-yl , Isopropenyl, but-1-enyls, but-2-enyls, buta-1,2-dienyls, buta-1,3-dienyls.
• Cycloalkyl comprises polycyclic saturated hydrocarbon residues with up to 14 C-
• Atoms namely C 3 -C 12 monocyclic, preferably C 3 -C 8 alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and polycyclic alkyl, ie preferably bicyclic and tricyclic, optionally spirocyclic C 7 -C 14 alkyl, such as, for example, bicyclo [2.2.1] hept-1-yl, bicyclo [2.2.1] hept-2-yl, bicyclo [2.2.1] hept-7-yl, bicyclo [2.2.2] oct-2-yl,
• Cycloalkenyl comprises polycyclic unsaturated, non-aromatic hydrocarbon radicals with up to 14 C atoms, namely monocyclic C 3 -C 12 , preferably C 3 -C 8 alkyl, such as, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
• (Cycloalkyl) alkyl represents an alkyl radical which is substituted by a cycloalkyl radical, cyclohexylmethyl may be mentioned by way of example.
• Cycloalkyl represents an alkyl radical which is substituted by a cycloalkyl radical, cyclohexylmethyl may be mentioned by way of example.
• Correspondingly means
• (Cycloalkenyl) alkyl an alkyl radical substituted with a cycloalkenyl ring, e.g. 2-cyclohexenyl.
• aryl stands for an aromatic radical having preferably 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• alkoxy preferably represents a straight-chain or branched alkoxy radical, in particular having 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
• a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred. Examples and preferably mentioned are: methoxy,
• Alkoxycarbonyl in the context of the invention preferably represents a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, which is linked via a carbonyl group.
• a straight-chain or branched is preferred
• Alkoxycarbonylrest with 1 to 4 carbon atoms The following may be mentioned as examples and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
• Alkanoyloxy in the context of the invention preferably represents a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 3 carbon atoms, which bears a double-bonded oxygen atom in the 1 position and which is linked via a further oxygen atom in the 1 position is.
• a straight-chain or branched alkanoyloxy radical having 1 to 3 carbon atoms is preferred. Examples include and are preferably: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.
• monoalkylamino represents an amino group with a straight-chain or branched alkyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
• a straight-chain or branched monoalamino radical having 1 to 4 carbon atoms is preferred.
• the following may be mentioned as examples and preferably: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino and n-hexylamino.
• dialkylamino stands for an amino group with two identical or different straight-chain or branched alkyl substituents which preferably each have 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
• Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred. Examples and preferably mentioned are: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N- isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N- Ethyl-Nn-pentylamino and
• mono- or dialkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents, each preferably having 1 to 4 or 1 to 2 carbon atoms ,
• the following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl and N-t-butyl-N-methylaminocarbonyl.
• alkylcarbonylamino represents an amino group having a straight-chain or branched alkanoyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms and is linked via the carbonyl group.
• a monoacylamino radical having 1 to 2 is preferred
• Carbon atoms The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
• Heterocyclyl stands for a mono- or polycyclic, heterocyclic radical with 4 to 10 ring atoms and up to 3, preferably 1 heteroatoms or hetero groups from the series ⁇ , O, S, SO, SO 2 . 4- to 8-membered heterocyclyl is preferred. Mono- or bicyclic heterocyclyl is preferred. Monocyclic heterocyclyl is particularly preferred. ⁇ and O are preferred as heteroatoms. The heterocyclyl residues can be saturated or partially unsaturated. Saturated heterocyclyl residues are preferred. The heterocyclyl radicals can be bonded via a carbon atom or a hetero atom. 5- to 7- are particularly preferred.
• a nitrogen heterocyclyl ring is a heterocycle that acts as heteroatoms only
• Heteroaryl stands for an aromatic, mono- or bicyclic radical with 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. 5- to 6-membered heteroaryls with up to 4 heteroatoms are preferred.
• the heteroaryl radical can be bonded via a carbon or heteroatom. Examples and preferably mentioned are: thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, hnidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
• alkoxycarbonylamino represents an amino group with a straight-chain or branched alkoxycarbonyl substituent which preferably has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and is linked via the carbonyl group.
• An alkoxycarbonylamino radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: methoxycarbonylamino, emoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.
• Aminosulfonyl stands for an -S (O) 2 NH 2 group. Accordingly, alkyl laminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl and heteroarylaminosulfonyl are on the amino group with the corresponding ones
• Residues substituted i.e. Alkyl, aryl etc.
• Carbonylbound amino acid residue stands for an amino acid residue which is beyond the
• Carbonyl group of the amino acid function is bound.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Fluorine or chlorine are preferred.
• R 1 is halogen, alkyl or trifluoromethyl
• R 2 is hydrogen, halogen or alkyl
• R 3 is hydrogen, halogen or alkyl
• R 4 is hydrogen, halogen or alkyl
• R 5 is hydrogen, methyl or fluorine
• R 6 is hydrogen or Ci-C 4 alkyl
• R 7 is alkyl
• R 8a is alkyl, alkylene, cycloalkyl or (cycloalkyl) alkyl,
• R 8a can optionally be substituted with 1 or 2 substituents which are selected independently of one another from the group consisting of hydroxy, Alkoxy, a radical -OR 8a , alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino,
• R 8a_1 is a carbonyl- bonded amino acid residue
• R 7 and R 8a together with the carbon atom to which R 8a is bonded and the nitrogen atom to which R 7 is bonded form a heterocyclyl ring which may optionally be substituted by 1 or 2 substituents which are selected independently of one another from the Group consisting of halogen, alkyl,
• R is hydrogen
• R, 9a is hydrogen, methyl or hydroxymethyl
• R is hydrogen
• R 10a means hydrogen
• R 10b is hydrogen
• R ⁇ is hydrogen
• R 12 is alkyl, alkenyl, (cycloalkyl) alkyl, (cycloalkenyl) alkyl, (cycloalkyl) alkenyl (cycloalkenyl) alkenyl,
• R 12 may optionally be substituted with 1 or 2 substituents which are selected independently of one another from the group consisting of halogen, hydroxy, alkoxy, or
• R 6 and R 12 together with the carbon atom to which they are attached form a cycloalkyl which may optionally be substituted with 1 or 2 substituents which are selected independently of one another from the
• R 13 is hydrogen
• A represents a heterocycle which can optionally be substituted by 1 or 2 substituents which are selected independently of one another from the group consisting of fluorine, alkyl, trifluoromethyl, alkoxycarbonylamino,
• R 1 is fluorine
• R 2 is hydrogen or fluorine
• R 3 is hydrogen
• R 4 is hydrogen
• R 5 is hydrogen or fluorine
• R 6 is hydrogen, R 7 is methyl,
• R 8a is C 1 -C 4 alkyl
• R 8a can be optionally substituted with 1 substituent selected from the group consisting of hydroxy and a radical -OR 8a_1 ,
• R 8a_1 is an aminomethylcarbonyl radical
• R 7 and R 8 together with the carbon atom to which R 8 is bonded and the nitrogen atom to which R 7 is bonded form a 5- to 6-membered nitrogen heterocyclyl ring which can contain up to 2 nitrogen atoms and which, if appropriate can be substituted with 1 substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, hydroxy,
• R 8b is hydrogen
• R 9a is hydrogen, alkyl or hydroxymethyl
• R 9b is hydrogen
• R 10a means hydrogen
• R 10b is hydrogen
• R 11 is hydrogen
• R 12 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, (cycloalkyl) alkyl, (cycloalkenyl) alkyl, (cycloalkyl) alkenyl (cycloalkenyl) alkenyl,
• R 12 can optionally be monosubstituted by hydroxy, or
• R 6 and R 12 together with the carbon atom to which they are attached form a 5- to 6-membered cycloalkyl which may optionally be monosubstituted by hydroxy,
• R, 13 is hydrogen
• A represents a 5-membered heterocycle which contains 1 nitrogen atom and which may optionally be monosubstituted by a substituent selected from the group consisting of fluorine, alkyl,
• R 1 to R 12 are as defined above, and R 14 is alkyl.
• R 1 is halogen and R 2 , R 3 and R 4 are identical or identical and are independently selected from the group consisting of hydrogen and halogen, especially where R 1 is fluorine and R 2 , R 3 and R 4 are the same or are different and are independently selected from the Group consisting of hydrogen and fluorine, in particular in which R 1 and R 2 are fluorine and are each meta to the benzylic methylene group, and R and R 4 are hydrogen.
• R 8a is methyl, hydroxymethyl or -OR 8a
• R 8a_1 is a carbonyl- bonded amino acid residue, in particular aminomethylcarbonyl or N-alkyl- or N, N-dialkylaminomethylcarbonyl and R represents hydrogen.
• R 12 is C 3 -C 8 alkyl, especially where R 12 is chain C 3 -C 5 alkyl, especially chain C 4 alkyl.
• the present invention further relates to a process for the preparation of the compounds of the general formula (I), in which compounds of the general formula (V)
• R to R, R to R, R and A have the meaning given above,
• carbodimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride
• EDC N-cyclohexyl-carbodiimide-N'-propyloxymethyl-polystyrene
• PS-carbodiimide N-cyclohexyl-carbodiimide-N'-propyloxymethyl-polystyrene
• carbonyl compounds such as carbonyldiimidazole
• 1,2-oxazolium compounds such as 2-ethyl-5 - phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate
• acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate , or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexa
• HATU -tettamethyl uronium hexafluorophosphate
• HOBt 1-hydroxybenzotriazole
• BOP Be_nzo azol-l-yloxy s (dimethylamino) - ⁇ hos ⁇ honiumhexafluorophosphate (BOP), or mixtures of these with Bases suitable.
• 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.
• halogenated hydrocarbons such as dichloromethane or trichloromethane
• hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Dimethylformamide is particularly preferred.
• the compounds of the general formula (XXV) are known or can be prepared from known carboxylic acids by processes known from the literature.
• R 1 to R 4 R R, 7 b-s R 11, R, 13 and A have the meaning given above,
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, dioxane, nitromethane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.
• Trifluoroacetic acid is particularly suitable as the acid, especially in aqueous solution, or hydrogen chloride in dioxane.
• the compounds of the general formula (VI) are new and can be prepared by compounds of the general formula (VII)
• R 7 to R 9 , R n , R 13 and A have the meaning given above,
• R to R and R » ⁇ o have the meaning given above are reacted in the presence of dehydration reagents.
• Suitable dehydrating reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, 'dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimemylaminoisopropyl) -N'-e ylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexyl-carbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) 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 acylamin
• 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 diisopropylethylamm.
• the condensation is preferably carried out with diisopropylethylamine.
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Dimethylformamide is particularly preferred.
• the compounds of the general formula (VII) can also be present in the form of their salts, in particular their hydrochlorides.
• the compounds of the general formula (VIII) are known or can be prepared from known amino acids by processes known from the literature.
• the compounds of the general formula (XXV) are known or can be prepared from known carboxylic acids by processes known from the literature.
• R 7 to R 9 , R 11 , R 13 and A have the meaning given above, optionally with the addition of acid, for example with hydrogen chloride in methanol, are hydrogenated.
• Suitable catalysts here are transition metals such as, for example, palladium, platinum or rhodium, preferably palladium, in an amount of 0.01 to 1 equivalent based on the mass of the compound of the general formula (IX) used, preferably 0.05 to 0 , 2 equivalents. Palladium is very particularly preferred, adsorbed on activated carbon.
• R 7 to R n , R 13 and A have the meaning given above, are cyclized.
• Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N * -dicyclohexyl-carbodiimide, ⁇ (S-dimethylaminoisopropy ⁇ - N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexyl-carbodiimide-N'-propyloxymethyl-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-methyl-isoxazolium perchlorate, or acyla
• 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 cyclization is likely to occur through the formation of the activated ester using the dehydration reagent (1.), the formation of the ester hydrochloride using the acid (2.), and the cyclization through slow release of the amine (3 .).
• R to R, R and A have the meaning given above,
• R 13 and A have the meaning given above, are reacted with dehydration reagents.
• Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, ⁇ (S-dimethylaminoisopropy ⁇ -N'-ethylcarbodiimide hydrochloride (EDC) , N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) 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-l-ethoxycarbonyl-l
• Bases are, for example, alkali carbonates, such as, for example, sodium or potassium carbonate, or hydrogen carbonate, or organic bases, such as trialkylamines, for example triethyl amine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
• alkali carbonates such as, for example, sodium or potassium carbonate, or hydrogen carbonate
• organic bases such as trialkylamines, for example triethyl amine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
• the condensation is preferably carried out with TPTU (2- (2-oxo-l (2H) - ⁇ yridyl) -l, 1,3,3-tetramethyluronium tetrafluoroborate) in the presence of HOBT and base, in particular Hünig base.
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.
• the compounds of the general formula (XIII) can also be present in the form of their salts, in particular their hydrochlorides.
• R and A have the meaning given above, acid, in particular hydrogen chloride in anhydrous organic solvents, in particular dioxane or tetrahydrofuran, are added.
• Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexyl-carbodiimide, ⁇ (S-dimethylaminoisopropy -N'-ethylcarbodiimide hydrochloride
• EDC N-cyclohexylcarbodiimide-N '-propyloxymethyl-polystyrene
• PS-carbodiimide carbonyl compounds such as carbonyldiimidazole
• 1,2-oxazolium- compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate
• acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2- dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazole-1-y ⁇ -NjNjNjNjNjNjNjN
• 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 EDC in the presence of DMAP.
• halogenated hydrocarbons such as dichloromethane or trichloromethane
• hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.
• R 7 to R 9 and R 11 have the meaning given above
• Suitable catalysts here are transition metals such as, for example, palladium, platinum or rhodium, preferably palladium, in an amount of 0.01 to 1 equivalent, based on the mass of the compound of the general
• Palladium is very particularly preferred, adsorbed on activated carbon.
• R 7 to R 9 and R 11 have the meaning given above, with N-Boc-proline, optionally in the presence of dehydration reagents.
• Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexyl-carbodiimide, ⁇ (S-dimethylaminoisopropy ⁇ -N'-ethylcarbodiimide hydrochloride
• EDC N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene
• PS-carbodiimide carbonyl compounds such as carbonyldiimidazole
• 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate
• acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis- (2-oxo -3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazole-1 -y ⁇ -NjNjN'jN'--
• 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 or with EDC in the presence of
• halogenated hydrocarbons such as dichloromethane or trichloromethane
• hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide or acetonitrile. It is also possible to mix the solvents. Dichloromethane or dimethylformamide is particularly preferred.
• R 7 to R 9 and R 11 have the meaning given above
• R 9 and R 11 have the meaning given above
• R 7 and R 8 have the meaning given above
• Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexyl-carbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride
• EDC N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene
• carbonyl compounds such as carbonyldiimidazole
• 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate
• acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis- (2-oxo -3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazole-1 -y ⁇ -NjNjN'jN'-te
• Bases are, for example, alkali carbonates, such as sodium or potassium carbonate, or bicarbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
• the condensation is preferably carried out with HATU or with EDC in the presence of HOBt.
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Dimethylformamide or dichloromethane is particularly preferred.
• R to R, R, R and have the meaning given above, optionally in the presence of dehydration reagents.
• Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexyl-carbodiimide, N- (3-dimethylaminoisopropy ⁇ -N'-ethylcarbodiimide hydrochloride
• EDC N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene
• PS-carbodiimide carbonyl compounds such as carbonyldiimidazole
• 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate
• acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2- oxo-3-oxazolidinyl) -phosphorylchlorid or Benzotri- azolyloxy-tri (dimethylammo) phosphonium hexafluorophosphate, or ⁇ - (benzotriazol-1 -y ⁇ j -NjN
• 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 using HATU.
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Dimethylformamide is particularly preferred.
• the compounds of the general formula (I) can epimerize on the carbon atom marked with an asterisk (*) in formula ((XXII) and can occur in the form of various diastereomers. In this case, undesired diastereomers are separated off by standard methods, for example by chromatography ,
• R 1 to R 4 and R 10 have the meaning given above,
• the acid function of the phenylamine in sistu is blocked as a silylester.
• the tert-butyl ester can be used in multiple stages.
• 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 reaction is preferably carried out with diisopropylethylamine.
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitro methane, dioxane, dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.
• the reactions described above generally take place in a temperature range from -78 ° C. to reflux temperature, preferably from -78 ° C. to + 20 ° C.
• the reactions can be carried out under normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at
• FIGS. 1 to 3 are intended to illustrate the processes:
• the active substance can act systemically and / or locally.
• it can be applied in a suitable manner, such as, for example, orally, parenterally, puhnonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctival, otically or as an implant.
• the active ingredient can be administered in suitable administration forms for these administration routes.
• Known application forms which release the active ingredient quickly and / or modified such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.
• Tablets non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings
• capsules dragees, granules, pellets, powders, emulsions, suspensions and solutions.
• Parenteral administration can be done by bypassing an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
• Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
• Inhalation drug forms e.g.
• the active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include Carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers
• the MIC is determined in the liquid dilution test. Overnight cultures of the test germs are 1: 5000 or S.aureus 133 1: 10000 in Müller Hinton Bouillon (manufacturer:
• the lowest substance concentration at which no visible bacterial growth occurred is defined as the MIC.
• the MIC values in ⁇ g / ml of some compounds according to the invention against a number of test germs are listed as examples in the table below. The compounds show very good antibacterial activity against most of the test germs and thus have a broad gram-positive effect.
• S. aureus 133 cells are grown overnight in BH broth (Oxoid). The overnight culture was diluted 1: 100 in fresh bra broth and turned up for 3 hours. The bacteria in the logarithmic growth phase are centrifuged off and washed twice with buffered, physiological saline. Then a cell suspension in saline with an absorbance 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. 0.25 ml / 20 g mouse is applied ip from this infection solution. This corresponds to a cell count of approximately 1 x 10E6 germs / mouse. The ip therapy takes place 30 minutes after the infection.
• mice Female CFW1 mice are used for the infection attempt. The survival of the animals is recorded over 6 days.
• the compounds according to the invention have a broad antibacterial spectrum, especially against gram-positive germs. These properties enable their use as chemotherapeutic agents in human and veterinary medicine. With their help, gram-positive germs can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.
• HATU 0- (7- Azabenzotriazol-1 -yl) -N, N, N ', N'-tetramethyluronium-
• UV detector DAD 208-400 nm
• UV detector DAD 208-400nm
• the residue is dissolved in 3.0 l of hot ethyl acetate and cooled to RT in an ice bath.
• the precipitated crystals are filtered off, washed with a little diethyl ether and dried in a high vacuum. 124.5 g (49% of theory) of the product are obtained.
• the mother liquor is concentrated in half, the precipitate is dissolved in the heat and cooled to 0 ° C. After suction and drying, a further 30.6 g (12% of theory) of product are isolated.
• the remaining mother liquor is evaporated to dryness, the residue is dissolved hot in 500 ml of ethyl acetate and again precipitated at 0 ° C.
• the aqueous phase is extracted twice with toluene, the combined organic phases are dried over sodium sulfate and, after filtration, evaporated to dryness.
• the product is obtained by silica gel chromatography on about 1500 ml of silica gel
• reaction can alternatively be carried out in dichloromethane and the product can be purified by silica gel chromatography with dichloromethane / methanol, then ethyl acetate.
• the mixture is evaporated to dryness in vacuo, the residue is taken up in diethyl ether and 2.5%. aqueous sodium bicarbonate solution (250 ml) extracted. The aqueous phase is extracted twice with ether and the combined organic phases are three times with
• the synthesis can be carried out using the proline benzyl ester and hydrogenolysis using palladium on carbon.
• Example 26A ((3S, 9S, 13S, 15R, 19S, 22S) -15,19-dimethyl-2,8,12,18,21-pentaoxo-ll-oxa-l, 7,17,20-tetraaza-tetracyclo [20.4.0.0 3.7 .0 13 '17 ] hexacos-9-yl) carbamic acid benzyl ester
• Pentafluorophenol are dissolved in dichloromethane (13 ml) and cooled to -20 ° C under argon. 1.14 g (5.95 mmol) of EDC are added, and the reaction mixture is stirred overnight with slow warming to RT. The reaction solution is evaporated to dryness and the residue is mixed with 4N hydrogen chloride solution in dioxane (80 ml) at 0.degree. It is stirred for 3 hours and that
• reaction can optionally also be carried out in dichloromethane.
• MS (ESI pos): m / z 661 [(M-TFA) + H] + .
• the reaction mixture is stirred under slow warming to RT overnight and remains at RT for two days.
• the mixture is evaporated to dryness in vacuo, the residue is taken up in diethyl ether and 2.5%. aq. Extracted sodium bicarbonate solution (250 ml).
• the aqueous phase is extracted twice with diethyl ether.
• the combined organic phases are extracted three more times with sodium hydrogen carbonate solution.
• the combined ethyl acetate phases are dried over sodium sulfate, filtered and the solvent is concentrated in vacuo.
• the residue (4.63 g) is stirred with diethyl ether and filtered. You get
• the acyl-phenylalanine side chain can first be built up analogously to Example 14A (see below). The hydrochloride from Example 11 A is then reacted with this acid to form the amide. The target compound of Example 1 still has to be separated from the (R) -phenylalanine epimer.
• Cyclohexylpropionic acid are placed under argon in anhydrous dimethylformamide (1 ml) at 0 ° C. and then 54.0 mg (0.14 mmol) of HATU and 0.025 ml (0.14 mmol) of ethyldiisopropylamine are added. After 30 minutes, a further 0.05 ml (0.29 mmol) of ethyldiisopropylamine is added to the reaction mixture. The reaction mixture is stirred overnight with slow warming to RT. The reaction solution is subjected directly to RP-HPLC with acetonitrile / water as the eluent. 50 mg (49% of theory) of a colorless solid are obtained.

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Priority Applications (6)

Applications Claiming Priority (2)

Publications (2)

Family

ID=7699507

Family Applications (1)

Country Status (8)

Cited By (4)

Families Citing this family (5)

Family Cites Families (5)

• 2001
  • 2001-09-19 DE DE10146104A patent/DE10146104A1/de not_active Withdrawn
• 2002
  • 2002-09-06 WO PCT/EP2002/009968 patent/WO2003024996A2/de not_active Ceased
  • 2002-09-06 JP JP2003528842A patent/JP4427326B2/ja not_active Expired - Fee Related
  • 2002-09-06 DE DE50209187T patent/DE50209187D1/de not_active Expired - Lifetime
  • 2002-09-06 CA CA002460646A patent/CA2460646A1/en not_active Abandoned
  • 2002-09-06 EP EP02764872A patent/EP1430075B1/de not_active Expired - Lifetime
  • 2002-09-06 ES ES02764872T patent/ES2280566T3/es not_active Expired - Lifetime
  • 2002-09-06 AU AU2002329267A patent/AU2002329267A1/en not_active Abandoned
  • 2002-09-06 US US10/490,192 patent/US7405201B2/en not_active Expired - Fee Related

Also Published As

Similar Documents

Legal Events