Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/40—2,5-Pyrrolidine-diones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to compounds, processes for their preparation, pharmaceutical compositions comprising them and their use in the treatment and / or prophylaxis of diseases in humans or animals, in particular bacterial units.
• Sulfonamide group or a carbamate group is replaced, are antibacterial.
• the present invention therefore relates to compounds of the general formula (I)
• R 1 is a group
• R, 1- " 1 is alkyl, cycloalkyl or aryl
• R 1 "1 can optionally be substituted with 1 to 3 substituents R 1" 1 "1 , where R 1" 1 "1 is selected independently of one another from the group consisting of halogen, alkyl, aryl, alkoxy, phenoxy, amino, monoalkylamino, Dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyl, heteroaryl and
• R 1 "2 and R 1" 3 are the same or different and denote hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl,
• R 1 "2 may optionally be substituted with 1 to 3 substituents R 1" 2 "1 , wherein
• R “" is independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, alkyl, monoalkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, phenoxy, carboxyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, Monoallcylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, heteroarylaminosulfonyl, aminocarbonylamino,
• aryl and heteroaryl can be substituted with 1 to 2 substituents which are selected independently of one another from the group consisting of halogen, hydroxy, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, monoalkylamino and dialkylamino, or
• R 1 "2 and R 1" 3 together with the nitrogen atom to which they are attached form a heterocycle which can optionally be fused to benzene,
• R 1 "4 is alkyl, alkenyl, alkynyl, cycloalkyl or aryl
• R 1 "4 may optionally be substituted with 1 to 3 substituents R 1" 4 "1 , wherein
• R 1 "4" 1 is selected independently from the group consisting of halogen, alkyl, aryl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyl, heteroaryl and heterocyclyl,
• R 2 is hydrogen or methyl
• R 3 is hydrogen or -CC alkyl
• R 4 is hydrogen or -Cralkyl
• R 5 is selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, monoalkylamino, dialkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aryl and heteroaryl,
• substituents R 5 together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl, where this cycloalkyl or heterocyclyl can be substituted with 0, 1 or 2 substituents R 5 "1 , the substituents R 5" 1 being selected independently of one another from the group consisting of halogen, alkyl, nitro, amino, trifluoromethyl, hydroxy and alkoxy,
• n is a number 0, 1, 2 or 3
• radicals R 5 may be the same or different
• R 6 is alkyl, cycloalkyl or heterocyclyl
• R can be substituted with 0, 1 or 2 substituents R " , the substituents R 6" 1 being selected independently of one another from the group consisting of halogen, nitro, amino, trifluoromethyl, hydroxy, alkyl and alkoxy,
• the compounds of the general formula (I) according to the invention can occur in various stereoisomeric forms which are either like images and mirror images
• 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.
• salts can be salts of the compounds according to the invention with inorganic or organic acids.
• Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid are preferred , 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, for example, metal or ammonium salts.
• bases such as, for example, 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, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-erphenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
• the compounds of the present invention are distinguished by a broad spectrum of activity against Gram-positive and Gram-negative bacteria, it also being possible to detect multi-resistant germs, in particular staphylococci, pneumococci and enterococci, including vancomycin-resistant strains.
• Alkyl and the alkyl parts in alkoxy, mono- and dialkylamino, alkylsulfonyl stands for straight-line or branched alkyl and, unless stated otherwise, comprises
• Alkenyl includes linear and branched C 2 -C 6 and C 2 -C 4 alkenyl, such as, for example, vinyl, allyl, prop-1-en-1-yl, isopropenyl, but-1-enyls, but-2-enyls, Buta-1,2-dienyls, buta-1,3-dienyls.
• Alkynyl includes linear and branched C 2 -C 6 and C 2 -C 4 alkynyl, such as, for example, ethynyl, n-prop-2-yn-1-yl, n-but-2-yn-yl.
• Cycloalkyl includes C 3 -C 8 monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
• 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 with 1 to is preferred
• 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 alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred.
• the following may be mentioned as examples and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
• monoalkylamino represents an amino group with a straight-chain or branched alkyl substituent, which is preferably 1 to 6, 1 to
• 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.
• N N-dimethyl-a ino
• N N-diethylamino
• N-ethyl-N-memylamino N-methyl-Nn-propyl__tnino
• N-isopropyl-Nn-propylamino Nt-butyl-N -memylamino
• N-ethyl-Nn-pentylamino Nn-hexyl-N-methy lamino.
• mono- or dialkylaminocarbonyl represents an amino
• the following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-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 carbon atoms is preferred. Examples include and are preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
• 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. Examples that may be mentioned are: methoxycarbonylamino, elhoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.
• Aminosulfonyl represents an -S (O) 2 NH 2 group.
• alkyllaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclyla inosulfonyl and heteroarylaminosulfonyl on the amino group are substituted with the corresponding radicals, ie alkyl, aryl etc.
• Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• Heteroaryl stands for a 5- to 10-membered aromatic heterocycle with up to 3 heteroatoms from the series S, O and / or N, for example for
• Heterocyclyl stands for a 3- to 8-membered saturated or unsaturated, non-aromatic, optionally bonded via a nitrogen atom
• Heterocycle which can contain up to 3 heteroatoms from the S, O and N series. It can be formed from two substituent groups together with the nitrogen atom to which they are attached and includes e.g. Morpholinyl, piperidinyl, piperazinyl, methylpiperazinyl, thiomorpholinyl or pyrrolidinyl and 3-, 7- and 8-membered heterocycles, such as e.g. Aziridines (e.g. 1-azacyclopropan-l-yl), azetidines
• the unsaturated representatives can contain 1 to 2 double bonds in the ring.
• Halogen represents fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred unless otherwise stated.
• benzannelated represents a phenyl which is bonded to a heterocycle or a cycloalkyl via two carbon atoms.
• the general or preferred radical definitions given above apply both to the end products of the formula (I) and correspondingly to the starting materials or intermediates required in each case for the preparation.
• 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.
• the invention relates to compounds of the general formula (I)
• R, 1-1 is alkyl, cycloalkyl or aryl
• R 1 "1 may optionally be substituted with 1 to 3 substituents R 1" 1 "1 , where R 1" 1 "1 is independently selected from the group consisting of
• R 1'2 and R 1 "3 are identical or different and are hydrogen, alkyl, alkenyl, cycloalkyl, aryl or heteroaryl,
• R 1 "2 may optionally be substituted with 1 to 2 substituents R 1" 2 "1 , where R 1" 2 "1 is independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, alkyl, monoalkylamino , Dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, phenoxy, alkylcarbonyl, aminocarbonyl,
• R 1 "2 and R 1" 3 together with the nitrogen atom to which they are attached form a heterocycle which can optionally be fused to benzene,
• R, 1-4 are alkyl, alkenyl or aryl
• R 1 "4 may optionally be substituted with 1 to 3 substituents R 1" , where R 1 "4" 1 is selected independently of one another from the group consisting of
• R 2 is hydrogen
• R 3 is hydrogen or methyl
• R 4 is methyl
• R 5 is selected from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, nitro, amino, monoalkylamino, dialkylamino, hydroxy,
• n is a number 0, 1 or 2
• radicals R 5 may be the same or different
• R> 6 is alkyl or cycloalkyl
• R 6 may be substituted with 0, 1 or 2 substituents R 6 "1 , the
• Substituents R 6 "1 are selected independently of one another from the group consisting of halogen, trifluoromethyl and alkoxy,
• the invention relates to compounds of the general formula (I)
• R .1-1 is C 1 -C 4 -alkyl, cyclopentyl, cyclohexyl, phenyl or naphthyl,
• R 1 "1 may optionally be substituted with 1 to 2 substituents R 1" 1 "1 , wherein
• R 1 "1" 1 is selected independently of one another from the group consisting of fluorine, chlorine, methyl, ethyl, phenyl, methoxy and ethoxy,
• R, 1- " 2 denotes alkyl, alkenyl, cycloalkyl, aryl or heteroaryl, 1 9 1 1 where R "can be optionally substituted with 1 substituent R "" , wherein R 1" 2 "1 is selected from the group consisting of fluorine, chlorine, trifluoromethyl, amino, alkyl, monoalkylamino, dialkylamino, alkylcarbonyl, aryl, Heteroaryl, hydroxy, methoxy and phenoxy, where aryl and heteroaryl can be substituted with 1 substituent selected from the group consisting of halogen, methoxy, trifluoromethyl and amino,
• R 1 "3 is hydrogen or methyl
• R 1 "2 and R 1" 3 together with the nitrogen atom to which they are attached form a heterocycle which can optionally be fused to benzene,
• R is alkyl, alkenyl or phenyl
• R may optionally be substituted by 1 substituent R " , where R is selected from the group consisting of fluorine, chlorine and phenyl,
• R 2 is hydrogen
• R 3 is hydrogen
• R 4 is methyl
• R 5 is selected from the group consisting of fluorine, chlorine, trifluoromethyl, alkoxy, methoxycarbonyl, C 1 -C 4 alkyl, phenyl and pyridyl,
• n is a number 0, 1 or 2, where n is 2, the radicals R 5 may be the same or different,
• R 6 is isopropyl, isobutyl, isopentyl or cyclopentyl
• R 1 to R 6 and n are as defined above.
• R 1 "2 is alkyl, alkenyl, cycloalkyl or aryl
• R 1 "2 can optionally be substituted by 1 to 2, in particular a sub-
• R 1 "2" 1 is selected from the group consisting of
• Halogen nitro, amino, alkyl, aryl, heteroaryl, hydroxy, alkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl and aminocarbonyl, in particular selected from the group consisting of alkyl, aryl, heteroaryl and
• the invention relates to compounds of the general formula (Ia)
• R 1 "2 and R 1" 3 are identical or different and denote hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl,
• R, 1- " 2 may optionally be substituted with 1 to 3 substituents
• R “" where R “" is independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, monoalkylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, monoalkyl - aminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,.
• R 2 is hydrogen or methyl
• R 3 is hydrogen or -Cralkyl
• R 4 is hydrogen or -CC 3 alkyl
• R 5 is selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, monoalkylamino, dialkylamino, hydroxy, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl,
• n is a number 0, 1, 2 or 3
• n 2 or 3
• the radicals R may be the same or different
• the invention relates to compounds of the general formula (Ia)
• R 1 "2 and R 1" 3 are the same or different and are hydrogen, alkyl, alkenyl, aryl or heteroaryl,
• R 1 "2 may optionally be substituted with 1 to 2 substituents
• R "" is independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, monoall_ylamino, dialkylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and aminosulfonyl, where aryl and heteroaryl may be substituted with 1 to 2 substituents which are independent of one another are selected from the group consisting of halogen, hydroxy, alkoxy, trifluoromethyl, trifluoromethoxy, nitro and amino,
• R 2 is hydrogen
• R 3 is hydrogen or methyl
• R 4 is equal to dC 3 alkyl
• R 5 is selected from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, nitro, amino, monoalkylamino, dialkylamino, hydroxy, alkoxy, aminocarbonyl,
• n is a number 0, 1 or 2
• radicals R 5 may be the same or different
• the invention relates to compounds of the general formula (Ia)
• R 1 "2 denotes alkyl, alkenyl, aryl or heteroaryl
• R " may optionally be substituted with 1 substituent R ""
• R 1" 2 "1 is selected from the group consisting of fluorine, chlorine, Trifluoromethyl, amino, monoalkylamino, dialkylamino, aryl, heteroaryl, hydroxy and methoxy, where aryl and heteroaryl can be substituted with 1 substituent selected from the group consisting of halogen, hydroxy, alkoxy, trifluoromethyl and amino,
• R 1 "3 denotes hydrogen or methyl
• R is hydrogen
• R 3 is hydrogen
• R 4 is methyl
• R 5 is selected from the group consisting of fluorine, chlorine, trifluoromethyl, amino, monoalkylamino, dialkylamino, hydroxy and alkoxy,
• n is a number 0, 1 or 2
• radicals R 5 may be the same or different
• R. 1- " 2 T b-.is R and n are as defined above.
• R 1 is a group
• R 1 "1 is dC 4 alkyl.
• R 1 is a group
• R 1 "1 is phenyl or naphthyl, where R 1" 1 may optionally be substituted with 1 to 2 substituents R 1 "1" 1 , where R 1 "1" 1 is selected independently of one another from the group consisting of fluorine and chlorine , Methyl, ethyl, phenyl, methoxy and ethoxy.
• R 1 "1" 1 is selected independently of one another from the group consisting of fluorine and chlorine , Methyl, ethyl, phenyl, methoxy and ethoxy.
• preference is also given to compounds of the general formula (I), (Ia), (Ib) or (Ic), in which
• R 1 is a group
• R 1 "2 is alkyl, alkenyl or aryl
• R 1 "2 may optionally be substituted by 1 to 2, in particular one
• R "" where R "" is selected from the group consisting of halogen, nitro, amino, aryl, heteroaryl, hydroxy, alkoxy, carboxyl, alkoxycarbonyl and aminocarbonyl, in particular selected from the group consisting of aryl, heteroaryl and alkoxy.
• R 1 is a group
• R is hydrogen or methyl
• R 1 is alkyl
• R 1 is a group
• R 1 "4 is alkenyl or phenyl, where R 1" 4 may optionally be substituted or must be substituted 11 R 11 "44”"11 ", where R 1 "4" 1 is selected from the group consisting of fluorine, chlorine and phenyl
• 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
• R 1 is a group
• R 1 is a group
• R 1 "3 is not hydrogen, or R " and R 1 "3 form a heterocycle
• R 1 is a group
• R 1 "1 has the meaning given above
• R 1 is a group
• R 1 "4 has the meaning given above and Hai 3 represents a halide or another leaving group
• reaction according to processes [A] to [D] is generally carried out in the presence of a solvent, if appropriate in the presence of a base.
• Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or potassium tert-butoxide . or tertiary amine bases such as triethylamine or diisopropylethylamine, or polymer-bound amine bases such as PS-DIEA, or other bases such as DBU, preference is given to triethylamine,
• Diisopropylethylamine or PS-DIEA Diisopropylethylamine or PS-DIEA.
• Inert organic solvents which do not change under the reaction conditions are suitable as solvents. These include halogenated hydrocarbons such as dichloromethane, trichloromethane or dichloroethane, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or
• Dioxane It is also possible to use mixtures of the solvents. Dichloromethane, dichloroethane, tetrahydrofuran or dimethylformamide are particularly preferred.
• the compounds of the general film (II) are known from the literature or new and can be prepared by compounds of the general film (Id)
• acid especially with hydrochloric acid or trifluoroacetic acid.
• Inert organic solvents are suitable as solvents, which do not change under the actual conditions.
• halogenated hydrocarbons such as dichloromethane or trichloromethane
• hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or dioxane. It is also possible to use mixtures of the solvents.
• hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane is particularly preferred.
• the compounds of the general formula (Id) represent a special embodiment of the compounds of the general formula (I).
• carbodimides such as, for example, N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N - (3-Dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-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 perch
• 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.
• Do not change reaction conditions include halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide or acetonitrile or ethers such as diethyl ether, tetrahydrofuran or dioxane. It is also possible to use mixtures of the solvents. One is particularly preferred
• R 3 , R 4 and R have the meaning given above,
• acid especially with hydrochloric acid or trifluoroacetic acid.
• 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, xylene,
• the use of hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane is particularly preferred.
• the compounds of the general formula (VI) are known or can be prepared according to regulations known from the literature. (For the representation of aromatic beta amino acids see: S. Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083).
• the compounds of the general formula (VE) are known or can be prepared by processes known from the literature. (See e.g. SG Davies, DJ Dixon, J Chem. Soc, Perkin Trans. 1, 1998, 17, 2635-2643.)
• Boc group can also be protected by other amino acid protecting groups.
• fluorenylmethoxycarbonyl Fmöc
• benzyloxycarbonyl be replaced, which can be removed by standard methods (Greene, TW, Wuts, GM, Protective Groups in Organic Synthesis, 3 rd Ed, Wiley 1999).
• 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 at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• the present invention further relates to compounds of the general formula (I) for combating diseases, in particular bacterial diseases, and to medicaments comprising compounds of the general formula (I) and auxiliaries and also to the use of compounds of the general formula (I) for the preparation a medicine to treat bacterial diseases.
• the preparations according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.
• Gram-positive cocci eg staphylococci (Staph. Aureus, Staph. Epidermidis), enterococci (E. faecalis, E. faecius) and streptococci (Strept. Agalactiae, Strept. Pneumoniae); gram-negative cocci (Neisseria gono ⁇ hoeae) and gram-negative Rods such as Enterobacteriaceen, for example Escherichia coli, Haemophilus influenzae, Citrobacter (Citrob. Freundii, Citrob. Divernis), Salmonella and Shigella; further Klebsiell (Klebs. pneumoniae, Klebs.
• the antibacterial spectrum includes strictly anaerobic bacteria such as Bacteroides fragilis, representatives of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) and mycobacteria, eg Mycobacterium tuberculosis.
• Infectious diseases in humans such as septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected infections, burns, mouth infections, 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
• Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections; Horse: bronchopneumonia, foal paralysis, 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 also be treated, the antibacterial spectrum extending beyond the previously mentioned eggs to other eggs such as e.g. Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema,
• the active substance can act systemically and / or locally.
• it can be applied in a suitable way, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as
• 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).
• absorption step intravenously, intraarterially, intracardially, intraspinally or intralumbally
• absorption intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
• suitable shape injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
• Parenteral, in particular intravenous, administration is preferred.
• Inhaled drug forms e.g. powder inhalers, nebulizers
• nasal drops / solutions, sprays e.g., nasal drops / solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, milk, pastes, powder or
• 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.
• Carriers e.g. microcrystalline cellulose
• solvents e.g. liquid polyethylene glycols
• emulsifiers e.g. sodium dodecyl sulfate
• dispersants e.g. polyvinylpy ⁇ olidone
• synthetic and natural biopolymers e.g. albumin
• stabilizers e.g. antioxidants such as ascorbic acid
• dyes e.g. inorganic pigments
• iron oxides e.g. inorganic pigments
• the MIC is determined in the liquid dilution test. Overnight cultures of the test germs are diluted to a cell count of 10 5 germs per ml in Isosensitest medium (manufacturer: Difco) and incubated with dilution of the test substances (dilution levels 1: 2). Exceptions are tests with S. pneumoniae G9A, which is in BHI broth (Difco) plus 20% bovine serum, and with H. influenzae, in BHI broth (Difco) plus 20% bovine serum, 10 ⁇ g / ml Haemin and 1% Isovital (Becton Dickinson) can be performed.
• the cultures are incubated at 37 ° C for 18-24 hours; S. pneumoniae and H. influenzae in the presence of 8 -10% CO 2 .
• the lowest substance concentration at which no visible bacterial growth occurred is defined as the MIC.
• the MIC values in ⁇ mol / l of only compounds according to the invention with respect to a number of test germs are listed in the table below as examples.
• Staphylococcus Haemophilus influenzae For example, Staphylococcus Haemophilus influenzae
• S.aureus 133 cells are grown overnight in BH broth (Oxoid).
• Overnight culture is 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.
• a cell suspension in saline with an absorbance of 50 units is set on the photometer (Dr. Lange LP 2W).
• this suspension is mixed 1: 1 with a 10% mucin suspension.
• 0.25 ml / 20 g mouse ip is applied from this infection solution. This corresponds to a cell count of approximately 1 x 10E 6 germs / mouse.
• the ip or iv therapy is given 30 minutes after the infection.
• Female CFW1 mice are used for the infection attempt. The survival of the animals is about 6
• PS-DIEA N N-diisopropylethylamine polystyrene (resin)
• eluent B water + 0.1% formic acid, gradient: 0.0 min 10% A ⁇ 4 min 90% A ⁇ 6 min 90% A
• Finnigan MAT 900S instrument Column: Symmetry C 18, 150 mm x 2.1 mm, 5.0 ⁇ m; Eluent B: water + 0.3g 35% HCl, eluent A: acetonitrile; Gradient: 0.0min 2% A - 2.5min 95% A - »5min 95% A; Oven: 70 ° C, flow: 1.2ml / min.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2790
• Eluent B acetonitrile + 0.05% formic acid
• eluent A water + 0.05% formic acid
• UV detection UV detection:
• Method 14 Instrument: Micromass Platform LCZ, HP1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A - 4.0 min 10% A - 6.0 min 10% A; Oven: 40 ° C, flow: 0.5 ml / min, UV detection: 208-400 nm.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2790
• Column Symmetry C 18, 50 mm x 2.1 mm, 3.5 ⁇ m
• Eluent B acetonitrile + 0.05% formic acid
• eluent A water + 0.05% formic acid
• Gradient 0.0min 5%
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2790; Column: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 ⁇ m; Eluent B: acetonitrile + 0.05%) formic acid, eluent A: water + 0.05%> formic acid; Gradient: 0.0min 5% B - 2.0min 40% B -> 4.5min 90% B- ⁇ 5.5min 90% B; Oven: 45 ° C, flow: O.Omin 0.75ml / min - 4.5min 0.75ml / min --_ 5.5min 1.25ml / min, UV detection: 210 nm
• Example 2A ((S) -2- ⁇ (S) -2-Methyl- 1 - [1 - ((3R, 4S) -4-methyl-2,5-dioxo-py ⁇ olidin-3-yl) -methanoyl] - propylcarbamoyl ⁇ - 1-phenyl-ethyl) -carbamic acid tert-butyl ester
• Example IA Analogously to Example IA, the following amines can be prepared in the form of their hydrochlorides from the corresponding tert-butoxycarbonylamino derivatives by treatment with hydrochloric acid in dioxane and directly reacted further:
• Beta-amino acid (1 eq.) [Synthesis according to regulations known from the literature (e.g. BS Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083; L. Läzär, T. Martinek , G. Bernath, F. Fülöp, Synth. Comm., 1998, 28, 219-224)] is placed in water (concentration approx. 0.3 - 1 mol / 1) and triethylamine (1.5 - 3 eq.) Is added.
• N- (tert-butoxycarbonyl) amino acid is placed in tetrahydrofuran (approx. 0.3 - 1 mol / 1) and treated with 1.1 eq N, N-carbonyldiimidazole. The mixture is stirred at room temperature for 2 h. Then 1 eq (3S) -l- (benzyloxy) -3-methyl-2,5-pyrrolidinedione (representation: SG Davies, DJ Dixon, J Chem. Soc, Perkin Trans. 1, 1998, 17, 2635 - 2643) added and the entire mixture is within
• the l-benzyloxy-2,5-py ⁇ olidindione (1 eq) is dissolved in methanol (approx. 0.02 mol / 1), a catalytic amount of palladium-carbon (10%) is added and the mixture is stirred for 1 h under a hydrogen atmosphere (normal pressure). Then the reaction mixture is filtered and concentrated. The residue is dissolved in acetonitrile (approx. 0.05 mol / 1) and added dropwise to a solution of 2-bromoacetophenone (1 eq) in acetonitrile (approx. 0.03 mol / 1) at room temperature. Then 1.5 eq of triethylamine in acetonitrile (about 0.35 mol / 1) are added dropwise to the reaction mixture over a period of 2 h. The reaction mixture is stirred at room temperature overnight, concentrated and that
• the crude product is purified by RP-HPLC (eluent: acetonitrile / water + 0.3 ml 37% hydrochloric acid / 1, gradient).
• the amine hydrochloride and triethylamine (1 eq.) In tetrahydrofuran (approx. 0.1 mol / 1) can be introduced and the isocyanate dissolved in a little tetrahydrofuran can be added at room temperature.
• the reaction mixture after stirring overnight, is diluted with dichloromethane and washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated.
• the crude product can be purified by RP-HPLC (eluent: water / acetonitrile,
• the amine hydrochloride and triethylamine (2 eq.) In tetrahydrofuran (approx. 0.1 mol / 1) can also be introduced and mixed with the chloramic acid derivative, if appropriate dissolved in a little tetrahydrofuran, at room temperature.
• the reaction mixture is concentrated after stirring overnight at temperatures between room temperature and 40 ° C., mixed with dichloromethane and washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated.
• the crude product can be purified by RP-HPLC (eluent: water / acetonitrile, gradient).
• Example 8 Morpholine-4-carboxylic acid - ((S) -2- ⁇ (S) -2-methyl- 1 - [1 - ((3R, 4S) -4-methyl-2,5-dioxopyolidin-3 - yl) -methanoyl] -propylcarbamoyl ⁇ - 1 -phenyl-ethyl) -amide
• the product can be obtained by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of the two methods.
• the implementation can also be carried out according to the following procedure: To a solution of the 3- [2-aminoalkanoyl] -2,5-pyrrolidinedione hydrochloride derivative (1 eq.) In absolute dichloromethane or a mixture (5: 1 to 1: 1) of absolute dichloromethane and N, N-dimethylformamide (approx. 0.1 to 0.3 mol / 1) the carboxylic acid derivative (1.1 - 1.5 eq.), triethylamine (3 eq.), HOBt (3 eq.) and finally 1.2 eq. Given EDC. The reaction mixture is stirred at room temperature (2 h to overnight) before being concentrated in vacuo.
• the residue is taken up in ethyl acetate or dichloromethane and the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
• the product can be purified by chromatography on silica gel (eluents: mixtures of cyclohexane / ethyl acetate or mixtures of dichloromethane and ethanol) or by RP-HPLC (eluents: variable gradients of water and acetonitrile), alternatively by a combination of both processes.
• the amine hydochloride is placed in tetrahydrofuran (approx. 0.1 mol / 1) and triethylamine (2 eq.) And the chloroformate (1.2 eq.) Are added.
• the reaction mixture is stirred at room temperature overnight. If the conversion has not yet taken place completely (TLC control), the mixture is stirred at 40 ° C. for a further night.
• the reaction mixture is then concentrated and the residue is taken up in dichloromethane and water and filtered through an Extrelut cartridge (Merck, Germany). The filtrate is concentrated and the residue is purified by RP-HPLC (eluent: variable gradients from acetonitrile and water + 0.3 ml of 37% hydrochloric acid / 1).
• the hydrochloride can be dissolved in N, N-dimethylformamide (approx. 0.1 mol / 1) and mixed with 2 eq triethylamine and 1 eq sulfonyl chloride. The reaction mixture is stirred overnight at room temperature, concentrated and then purified by RP-HPLC (eluent: water-acetonitrile, gradient).
• the synthesis is carried out according to the general rule K.
• the synthesis is carried out according to the general rule K.
• Example 47 (3 __ ⁇ - N - ((l__ -2-Methyl-l - ⁇ [(3R, 4S) -4-methyl-2,5-dioxo-3-pyrrolidinyl] carbonyl ⁇ - propyl) -3-phenyl- 3 - ( ⁇ [(_ 5 -2-phenylethenyl] sulfonyl ⁇ amino) propionicide
• the synthesis is carried out according to the general rule K.
• the synthesis is carried out according to the general rule K.
• the synthesis is carried out according to general rule A.
• the compounds according to the invention can be converted into pharmaceutical preparations as follows:
• Example 1 100 mg of the compound from Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
• a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
• Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stirred for about 6 hours.

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