EP1071664A1

EP1071664A1 - Substituted 2-oxo-alkanoic acid- 2-(indol-3-yl)-ethyl] amides

Info

Publication number: EP1071664A1
Application number: EP99917958A
Authority: EP
Inventors: Thomas Himmler; Franz Pirro
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1998-04-16
Filing date: 1999-04-03
Publication date: 2001-01-31
Also published as: CN1297437A; KR20010052236A; AU752273B2; HUP0102099A2; CA2328875A1; BR9909692A; DE19816780A1; AU3605099A; US6255335B1; HUP0102099A3; JP2002512226A; WO1999054301A1

Abstract

The invention relates to novel substituted 2-oxo- alkanoic acid-[2- (indol-3-yl)- ethyl] amides of general formula (I), wherein R1 represents optionally branched C¿1?-C8-alkyl or C4-C8-cycloalkyl, R?2¿ represents hydrogen, C¿1?-C4-alkyl, C1-C4-alkoxy, C1-C4-thioalkyl, phenyl or halogen independently of R?3, R3¿ represents hydrogen, C¿1?-C4-alkyl or halogen and R?4¿ represents optionally branched C¿1?-C6-alkyl or C4-C6-cycloalkyl, phenyl which has been optionally substituted once to three times by C1-C3-alkyl, C1-C3-alkoxy, C1-C3-thioalkyl, halogen, nitro or amino or benzyl which has been optionally substituted once to three times by C1-C3-alkyl, C1-C3-alkoxy, C1-C3-thioalkyl, halogen, nitro or amino. The invention also relates to methods for producing the inventive compounds and to the use of said compounds in antibacterial agents.

Description

- 1 -

Substituted 2-oxo-alkanoic acid-f 2- (indol-3-yl) ethyl] amides

The invention relates to new substituted 2-oxoalkanoic acid [2- (indol-3-yl) ethyl] amides, processes for their preparation and antibacterial agents containing them.

From US Pat. No. 5,569,668, certain 2-oxo-alkanoic acid [2- (1H-indol-3-yl) ethyl] amides and their antifungal and antibacterial properties, in particular against staphylococci, have become known. Particularly noteworthy is a compound, which is a natural product formed by the bacterium Xenorhabdus nematophilus, with the name nematophin. The action and properties of nematophin and certain derivatives have also become known from Bioorganic & Medicinal Chemistry Letters, 7 (1997) 1349-1352.

The ever increasing number of multi-resistant bacterial pathogens makes the search for new antibacterial substances an urgent task (Chemistry & Industry 1997, 131; Drug Discovery Today, 1997, 47). The antibacterial effect of nematophin and its known derivatives is not entirely satisfactory.

The present invention relates to

1. Compounds of the general formula (I)

H O

(I), in which R ^{1 represents} optionally branched Cj-C ₈ alkyl or C ₄ -C ₈ cycloalkyl,

R ^{2 is} independently of R ^{3 is} hydrogen, -CC alkyl, C _j -C ₄ alkoxy, C _j -C thioalkyl, phenyl or halogen,

R ^{3 represents} hydrogen, -CC alkyl or halogen and

R ⁴ for optionally branched C _j -Cg alkyl, C ₄ -Cg cycloalkyl, optionally one to three times by C] -C ₃ alkyl, C _| -C ₃ alkoxy,

Cj-C ₃ -thioalkyl, halogen, nitro or amino-substituted phenyl or optionally mono- to trisubstituted by Cj-C ₃ -alkyl, Ct-C ₃ -alkoxy, -C-C ₃ -thioalkyl, halogen, nitro or amino-substituted benzyl .

The compounds of the general formula (I) can be present in the form of their racemates or as enantiomerically pure compounds and in the form of their pharmaceutically usable hydrates and acid addition salts.

Process for the preparation of the compounds of formula (I)

H O

(I), in which

R ^{1 represents} optionally branched Ci-Cg-alkyl or C ₄ -C ₈ cycloalkyl, - 3 -

R ² independently of R ^{3 represents} hydrogen, Cj-C alkyl, C _r C alkoxy, C _j -C ₄ thioalkyl, phenyl or halogen,

R ^{3 represents} hydrogen, C _] -C ₄ alkyl or halogen and

R ⁴ for optionally branched Ci-Cg-alkyl, C -C ₆ cycloalkyl, optionally one to three times by Ct-C ₃ alkyl, C _j -C ₃ alkoxy,

C ₁ -C ₃ -thioalkyl, halogen, nitro or amino-substituted phenyl or optionally mono- to trisubstituted by C _] -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, C] -C ₃ -thioalkyl, halogen, nitro or amino

Benzyl stands,

characterized in that substituted indoles of the formula (II)

R ^, Nh (II),

^{^} N

'R

in which

R ² , R ³ , R ^{4 have} the meaning given above,

with α-ketocarboxylic acid derivatives of the formula (III)

OO li ιι _Λ

Y- -C— C - R (HI), in which

Y represents OH or halogen and

R ^{1 has} the meaning given above, if appropriate in the presence of an acid binding agent and if appropriate in the presence of a diluent.

The compounds of the general formula (I) according to the invention surprisingly have a significantly higher antibacterial action than the known representatives of this type of structure. They are therefore suitable as antibacterial agents for human and veterinary medicine.

Compounds of the formula (I) in which

R ^{1 represents} optionally branched C 1 -C ₄ -alkyl or C ₄ -C ₆ cycloalkyl,

R ² independently of R ^{3 represents} hydrogen, C _r C ₂ alkyl, C _r C ₂ alkoxy, C _r C ₂ thioalkyl, phenyl, fluorine, chlorine or bromine,

R ^{3 represents} hydrogen, C _j -C ₂ alkyl, fluorine, chlorine or bromine and

R ⁴ for optionally branched C _j -C ₄ alkyl, C ₄ -C ₆ cycloalkyl, optionally mono- to triple by -CC ₂ alkyl, -C-C ₂ alkoxy, fluorine, chlorine, bromine, nitro or amino substituted phenyl or optionally mono- to trisubstituted by C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, fluorine, chlorine, bromine, nitro or amino,

and their pharmaceutically usable hydrates and acid addition salts.

Compounds of the formula (I) in which

R 'represents optionally branched C 1 -C ₆ -alkyl 1 or C ₄ -C ₆ -cycloalky 1,

R ² independently of R ³ for hydrogen, -C ₂ alkyl, -C ₂ alkoxy, fluorine or

Chlorine stands, R ^{3 represents} hydrogen, -CC ₂ alkyl, fluorine or chlorine and

R ⁴ for optionally branched C _j -C ₄ alkyl, C ₄ -Cg cycloalkyl, optionally once or twice by Cj-C ₂ alkyl, -C-C ₂ alkoxy, fluorine, chlorine,

Nitro or amino substituted phenyl or optionally mono- or disubstituted by C _j -C ₂ alkyl, C _j -C ₂ alkoxy, fluorine, chlorine, nitro or amino,

and their pharmaceutically usable hydrates and acid addition salts.

Compounds of the formula (I) in which

R ^{1 represents} branched alkyl having up to 4 carbon atoms,

R ² and R ^{3 represent} hydrogen,

R ⁴ for C _! -C ₄ - alkyl, phenyl or benzyl.

The process according to the invention for the preparation of the compounds of the formula (I) by reacting the compounds of the formula (II) with α-ketocarboxylic acid derivatives of the formula (III) where Y is chlorine can be represented by the following reaction scheme:

H

NH, O I O N

CC ₄ H ₉ )

Cl

N O i N CH i CH

(II) (III) (I) The compounds of the formula (II) are known (for example J. Med. Chem. 37 (1994) 4307-4316) or can be prepared by known methods. The following may be mentioned as examples of compounds (II):

1-methyl-3- (2-aminoethyl) indole,

1-ethyl-3- (2-aminoethyl) indole, l-propyl-3- (2-aminoethyl) indole, l-isopropyl-3- (2-aminoethyl) indole, l-cyclopentyl-3- (2nd aminoethyl) indole, 1-phenyl-3- (2-aminoethyl) indole,

1-benzyl-3- (2-aminoethyl) indole, l- (4-chlorobenzyl) -3- (2-aminoethyl) indole, l- (2,6-dichlorobenzyl) -3- (2-aminoethyl) - indole.

The compounds of formula (III) are also known and in some cases. commercially available. Compounds of formula (III) where Y is halogen, e.g. Chlorine, can be obtained from the compounds of formula (III) with Y equal to OH by known methods by reaction with halogenating agents such as e.g. be prepared with thionyl chloride or oxalyl chloride. Examples of compounds (III) where Y is OH are:

Pyruvic acid,

2-oxo-butyric acid,

2-oxo-valeric acid, 2-oxo-4-methyl-valeric acid,

2-oxo-3-methylvaleric acid,

Cyclobutyl-glyoxylic acid,

Cyclopentyl-glyoxylic acid,

Cyclohexyl-glyoxylic acid. - 7 -

If compounds of the formula (III) where Y is chlorine are used as starting compounds, the compounds of the formula (I) are prepared in an inert solvent in the presence of an acid scavenger. Halogenated hydrocarbons, e.g. Methylene chloride, chloroform, carbon tetrachloride, aliphatic or aromatic

Hydrocarbons, e.g. Toluene, polar inert solvents such as e.g. Dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or sulfolane can be used. Mixtures of these solvents can also be used.

Conventional acid binding agents such as e.g. Alkali or alkaline earth carbonates, trimethylamine, triethylamine, tributylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or pyridine can be used .

The acid scavengers used are generally used in an amount of 80 to

200 mol%, based on the molar amount of compound (III) where Y is chlorine, is used. It is preferred to work with an amount of 110 to 150 mol%.

It is also possible to carry out the reaction in a large excess of pyridine, which thus serves simultaneously as a solvent and acid scavenger.

The compounds of the formula (II) and (III) are generally used in an approximately equimolar ratio.

The reaction temperatures can be varied between -20 and 80 ° C with this procedure. It is preferred to work between -10 ° C and 25 ° C.

The reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar. If compounds of the formula (III) where Y is OH are used as starting compounds, the reaction is carried out in an inert solvent in the presence of an auxiliary which is customary for the formation of amide bonds. The solvents mentioned above, such as methylene chloride, chloroform, dimethylformamide or N-methylpyrrolidone, can be used as solvents. Mixtures of these solvents can also be used.

For example, N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC) or dicyclohexylcarbodiimide (DCC) are used as auxiliaries.

Hydroxybenzotriazole in the presence of an organic base such as triethylamine, tributylamine or N-methylmorpholine, for example, can be used as an auxiliary to form the amide bond. Starting compounds of the formula (II) and (III) are used in an approximately equimolar ratio to one another. The auxiliaries are used in approximately equimolar amounts based on the compound of the formula (III).

The reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar.

After the reaction has taken place, the compounds of formula (I) obtained are purified by conventional organic chemistry methods, e.g. by crystallization or chromatography.

The acid addition salts of the compounds according to the invention are prepared in the customary manner, for example by dissolving them in a sufficient amount of aqueous acid and precipitating the salt with a water-miscible organic solution. - 9 -

medium such as methanol, ethanol, acetone, acetonitrile. Equivalent amounts of the compound and acid according to the invention can also be dissolved in water and then evaporated to dryness or the precipitated salt can be suctioned off.

The compounds according to the invention have a strong antibiotic action and are distinguished by a very good action against gram-positive germs, especially staphylococci.

These valuable properties enable them to be used as chemotherapeutic agents in medicine and veterinary medicine and as substances for the preservation of inorganic and organic materials, in particular of all kinds of organic materials, e.g. Polymers, lubricants, paints, fibers, leather, paper and wood, food and water.

With the aid of the compounds according to the invention, gram-positive bacteria, in particular staphylococci, and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.

The compounds according to the invention also show surprising increases in activity against bacteria which are classified as less sensitive to other antibacterial agents, in particular resistant Staphylococcus aureus.

The compounds 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.

The compounds are also suitable for combating protozoonoses and

Helmets. - 10 -

The compounds according to the invention can be used in various pharmaceutical preparations. Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules, suppositories, injection and orally administrable solutions, suspensions and emulsions, as well as pastes, ointments,

Called gels, creams, lotions, powders and sprays.

The active ingredients are preferably suitable for combating bacterial diseases which occur in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development as well as against resistant and normally sensitive strains. By combating bacterial diseases, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active ingredients enables more economical and easier animal husbandry.

The livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, pigeons, bird species for home or zoo keeping. It also includes

Farm and ornamental fish.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

In general, it has proven to be advantageous to administer amounts of about 0.5 to about 50 mg, preferably 1 to 20 mg, of active ingredient per kg of body weight per day in order to achieve effective results.

The active ingredients can also be administered together with the animal's feed or drinking water. - 11 -

Feed and food contain 0.01 to 100 ppm, preferably 0.5 to 50 ppm of the active ingredient in combination with a suitable edible material.

Such feed and food can be used for medicinal purposes as well as for prophylactic purposes.

Such a feed or foodstuff is produced by mixing a concentrate or a premix containing 0.5 to 30%, preferably 1 to 20% by weight, of an active ingredient in a mixture with an edible organic or inorganic carrier with conventional feedstuffs. Edible carriers are e.g. Corn meal or corn and soybean meal or mineral salts, which preferably contain a small amount of an edible dust control oil, e.g. Corn oil or soybean oil. The premix obtained in this way can then be added to the complete feed before it is fed to the animals.

The minimum inhibitory concentrations (MIC) of the compounds according to the invention were determined by serial dilution on Iso-Sensitest Agar (Oxoid). A series of agar plates were prepared for each test substance, which contained decreasing concentrations of the active ingredient at twice the dilution. The

Agar plates were inoculated with a multipoint inoculator (Denley). Overnight cultures of the pathogens were used for inoculation, which were previously diluted so that each inoculation point contained approximately 10 ⁴ colony-forming particles. The inoculated agar plates were incubated at 37 ° C and the germ growth was read after about 20 hours. The MIC value (μg / ml) indicates the lowest active substance concentration at which no growth could be seen with the naked eye.

The table below shows the MIC values of some of the compounds according to the invention. The following compounds A and B known from US Pat. No. 5,569,608 are listed as reference compounds. - 12th

Comparative Compound A

H O i

Nematophin

Comparative Compound B

Hi O

Table: MIC values (μg / ml)

Compare: connections 5i according to the invention

Species strain A B 1 2 3 4 5 6 o

Staph. aureus ATCC 6538 0.25 0.125 0.015 0.03 0.03 0.125 0.03 0.125

ATCC 25923 0.125 0.25 0.015 0.03 0.03 0.06 0.06 0.125

ATCC 29213 0.125 0.25 0.015 0.03 0.03 0.25 0.06 0.125

Staph. interm. ATCC 29663 8 2 2 2 4 2 1 8

Staph. hyicus 9621 * 1 0.25 0.06 0.03 1 0.06 0.06 1

9622 * 0.5 0.03 0.06 0.03 0.5 0.25 0.015 1

9637 * 0.25 0.25 0.015 0.03 0.03 0.125 0.06 0.125

9641 * 0.25 0.25 0.015 0.03 0.03 0.125 0.06 0.125 -

* current clinical isolates

O

H pB -β v ©

© o

14

Manufacture of active ingredients

example 1

To a solution of 1 g of l-methyltryptamine in 5 ml of pyridine at 0 ° C under

Ice cooling 0.9 g of 2-oxo-3-methyl-valeric acid chloride added dropwise. You let go

Come to room temperature and stir overnight. The reaction mixture is then mixed with water and extracted three times with ether. The organic phase is washed in succession with saturated ammonium chloride solution, 5% sodium hydroxide solution,

Shaken water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue obtained is chromatographed on silica gel (methylene chloride / methanol 99: 1). 0.31 g of oily is obtained

Product.

Η NMR (400 MHz, CDC1 ₃ ): δ = 0.88 (t, 3H), 1.09 (d, 3H), 1.35-1.45 (m, 1H), 1.57-

1.68 (m, 1H), 1.95-2.05 (m, 1H), 2.93-3.03 (m, 2H), 3.55-3.63 (m, 2H), 3, 75 (s, 3H),

5.53 (s, br, 1H), 6.87 (s, 1H), 7.12 (m, 1H), 7.25 (m, 1H), 7.32 (m, 1H), 7.6 (m, 1H) ppm.

MS / EI (-70 eV): m / e = 286 (M ⁺ , 5%), 157 (32%), 144 (100%).

Example 2

- 15 -

1.34 g of 1-hydroxy-1H-benzotriazole hydrate (HOBT) and 1.68 g of N 'are added to a solution of 0.91 g of 4-methyl-2-oxo-valeric acid in 40 ml of DMF at -30 ° C. - (3-Dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC) given. The mixture is stirred for half an hour and then a solution of 1.22 g of 1-methyl-tryptamine in 5 ml of DMF is added. Then so much triethylamine is added that a pH

Value of approx. 9 is set. The mixture is stirred at 0 ° C. for 1 hour, then allowed to come to room temperature and stirred overnight at room temperature. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The solution is shaken out successively with water, aqueous Na ₂ CO 3 solution and saturated aqueous sodium chloride solution, dried over

Sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (methylene chloride / methanol 99: 1). 1.34 g of a viscous oil are obtained. Η NMR (400 MHz, CDC1 ₃ ): δ = 0.94 (d, J = 6.6 Hz; 6H), 2.1-2.2 (m; 1H), 2.79 (d, J = 6.8 Hz; 2H), 3.0 (m; 2H), 3.58 - 3.63 (m; 2H), 3.76 (s; 3H), 6.89 (s; 1H), 7, 05 (m, br; 1H), 7.1 (m; 1H), 7.23 (m; 1H), 7.3 (m; 1H), 7.58 (m; 1H) ppm.

Example 3

Analogously to the procedure from Example 2, 0.53 g of the title compound is prepared as an oil from 0.91 g of 3-methyl-2-oxovaleric acid and 1.43 g of 1-isopropyl-tryptamine. Η NMR (400 MHz, CDC1 ₃ ): δ = 0.88 (t, 3H), 1.1 (d, 3H), 1.35-1.45 (m, 1H), 1.52 (d, 6H), 1.67-1.78 (m, 1H), 3.02 (m, 2H), 3.47-3.55 (m, 1H), 3.63 (m, 2H), 4.6 -4.7 (m, 1H), 7.03 (s, br, 1H), 7.07 (s, 1H), 7.12 (m, 1H), 7.22 (m, 1H), 7, 37 (m, 1H),

7.59 (m, lH) ppm. 16

Example 4

Analogously to the procedure from Example 2, 0.5 g of product in the form of a thick oil is prepared from 0.91 g of 4-methyl-2-oxovaleric acid and 1.43 g of 1-isopropyl-tryptamine.

»H NMR (400 MHz, CDC1 ₃ ): δ = 0.94 (d, 6H), 1.52 (d, 6H), 2.1-2.2 (m, 1H), 2.8 (d ,

2H), 3.0 (m, 2H), 3.62 (m, 2H), 4.6-4.7 (m, 1H), 7.03 (s, br, 1H), 7.07 (s , 1H), 7.12

(m, 1H), 7.22 (m, 1H), 7.37 (m, 1H), 7.58 (m, 1H) ppm.

Example 5

Analogously to the procedure from Example 2, 0.53 g of product is prepared from 0.65 g of 4-methyl-2-oxovaleric acid and 1.2 g of 1-phenyl-tryptamine.

Η NMR (400 MHz, CDC1 ₃ ): δ = 0.94 (d, J = 6.6 Hz; 6H), 2.1-2.2 (m; 1H), 2.80 (d, J = 7 Hz; 2H), 3.04-3.1 (m; 2H), 3.65-3.72 (m, 2H), 7.12 (m, br; 1H), 7.17-7.28 (m; 3H), 7.32-7.38 (m; 1H), 7.47-7.55 (m; 4H), 7.58 (m; 1H), 7.67 (m; 1H) ppm . - 17th

Example 6

Analogously to the procedure from Example 2, 1.43 g of the oily product are obtained from 0.91 g of 3-methyl-2-oxovaleric acid and 1.75 g of 1-benzyl-tryptamine.

^! H-NMR (400 MHz, CDC1 ₃ ): δ = 0.86 (t, 3H), 1.08 (d, 3H), 1.33-1.43 (m, IH), 1.65-

1.75 (m, IH), 3.01 (m, 2H), 3.45-3.55 (m, IH), 3.63 (m, 2H), 5.29 (s, 2H), 6 , 97 (s,

IH), 7.05 (s, br, IH), 7.12 (m, 3H), 7.18 (m, IH), 7.23-7.35 (m, 4H), 7.62 (m , IH) ppm.

Example 7

Analogously to the procedure from Example 2, 1.08 g of product are obtained from 0.91 g of 4-methyl-2-oxovaleric acid and 1.75 g of 1-benzyl tryptamine.

Melting point: 82-3 ° C.

^! H-NMR (400 MHz, CDC1 ₃ ): δ = 0.93 (d, 6H), 2.1-2.2 (m, IH), 2.78 (d, 2H), 3.0 (m,

2H), 3.62 (m, 2H), 5.29 (s, 2H), 6.96 (s, IH), 7.05 (s, br, IH), 7.12 (m, 3H), 7.2 (m,

IH), 7.25-7.35 (m, 4H), 7.6 (m, IH) ppm.

Claims

- 1 !

claims

1. Compounds of the general formula (I)

H O

I.

R N

R ¹ O (I),

RN ^'

in which

R ^{1 represents} optionally branched C 1 -C ₄ -alkyl or C ₄ -C ₈ -cycloalkyl,

R ² independently of R ^{3 represents} hydrogen, Cj-C ₄ -alkyl, Cj-C ₄ -alkoxy, C _] -C ₄ -thioalkyl, phenyl or halogen,

R ^{3 represents} hydrogen, -CC ₄ - alkyl or halogen and

R ⁴ for optionally branched C _] -C ₆ alkyl, C ₄ -C ₆ cycloalkyl, optionally one to three times by Cj-C ₃ alkyl, -C-C ₃ alkoxy, C _j -C ₃ thioalkyl, halogen , Nitro or amino substituted phenyl or optionally mono- to trisubstituted by C _] -C ₃ alkyl, C _j -C ₃ alkoxy, C _r C ₃ thioalkyl, halogen, nitro or amino substituted benzyl,

in the form of their racemates or enantiomerically pure compounds and in the form of their pharmaceutically usable hydrates and acid addition salts. - 19 -

2. Process for the preparation of compounds of the general formula (I)

/ \ ϊ N ° R '

(I), O i ₄

R in which

R ^{1 represents} optionally branched Cj-C ₈ alkyl or C -C ₈ cycloalkyl,

R ² independently of R ^{3 represents} hydrogen, C _r C alkyl, C _r C alkoxy, C _j -C ₄ thioalkyl, phenyl or halogen,

R ^{3 represents} hydrogen, Cj-C alkyl or halogen and

R ⁴ for optionally branched C _j -C ₆ alkyl, C ₄ -Cg cycloalkyl, optionally one to three times by Cj-C ₃ alkyl, -C-C ₃ alkoxy, C _r C ₃ thioalkyl, halogen, nitro or amino-substituted phenyl or optionally mono- to trisubstituted by C _j -C ₃ alkyl, C ₁ -C ₃ alkoxy, C _j ^ thioalkyl, halogen, nitro or amino,

characterized in that substituted indoles of the formula (II)

R, NH ₀

(II), ^ "N ^'

in which - 20 -

R ² , R ³ , R ^{4 have} the meaning given above

with α-ketocarboxylic acid derivatives of the formula (III)

O O

II II. (HI),

Y C C - R in which

Y represents OH or halogen,

R ^{1 has} the meaning given above,

if appropriate in the presence of an acid binding agent and if appropriate in the presence of a diluent.

Compounds of formula (I) according to claim 1, in which

R ¹ represents optionally branched C _j -CG alkyl or C ₄ -CG-cycloalkyl;

R ^{2 is} independently of R ³ for hydrogen, -C ₂ - alkyl, C _r C - alkoxy,

-C-C ₂ thioalkyl, phenyl, fluorine, chlorine or bromine,

R ^{3 represents} hydrogen, C ₁ -C ₂ -alkyl, fluorine or bromine and

R ⁴ for optionally branched Cj-C ₄ alkyl, C -C ₆ cycloalkyl, optionally mono- to trisubstituted by -CC ₂ alkyl, Cj-C ₂ alkoxy, fluorine, chlorine, bromine, nitro or amino-substituted phenyl or optionally benzyl which is mono- to trisubstituted by C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, fluorine, chlorine, bromine, nitro or amino, 21

and their pharmaceutically usable hydrates and acid addition salts.

4. Compounds of formula (I) according to claim 1, in which

R ^{1 represents} optionally branched C _r C ₆ alkyl or C ₄ -C ₆ cycloalkyl,

R ² independently of R ^{3 represents} hydrogen, C ₁ -C ₂ alkyl, C _j -G ^ alkoxy, fluorine, chlorine or bromine,

R ^{3 represents} hydrogen, C _j -C ₂ alkyl, fluorine or chlorine and

R ⁴ for optionally branched C 1 -C ₄ -alkyl, C ₄ -C ₆ cycloalkyl, optionally one or two times by C ₁ -C ₂ alkyl, C _j -C ₂ alkoxy,

Fluorine, chlorine, nitro or amino-substituted phenyl or optionally mono- or disubstituted by CC ₂ alkyl, C ₁ -C ₂ alkoxy, fluorine, chlorine, nitro or amino substituted benzyl,

and their pharmaceutically usable hydrates and acid addition salts.

5. Medicament-containing compounds of formula (I) according to claim 1.

6. Use of compounds of formula (I) according to claim 1 for the manufacture of medicaments.

7. Use of compounds of formula (I) according to claim 1 in antibacterial agents.