WO2000029396A1 - Novel substituted phenyloxazolidone derivatives - Google Patents

Novel substituted phenyloxazolidone derivatives Download PDF

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WO2000029396A1
WO2000029396A1 PCT/EP1999/008469 EP9908469W WO0029396A1 WO 2000029396 A1 WO2000029396 A1 WO 2000029396A1 EP 9908469 W EP9908469 W EP 9908469W WO 0029396 A1 WO0029396 A1 WO 0029396A1
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alkyl
hydrogen
nr
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PCT/EP1999/008469
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German (de)
French (fr)
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Stephan Bartel
Siegfried Raddatz
Michael Härter
Ulrich Rosentreter
Hanno Wild
Rainer Endermann
Hein-Peter Kroll
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Bayer Aktiengesellschaft
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to novel substituted phenyloxazolidone derivatives, to a method for producing them, to pharmaceutical compositions containing them and to their use for producing medicaments, especially for producing antibacterial medicaments for treating human beings and animals.

Description

New substituted derivatives Phenyloxazolidon

The present invention relates to novel substituted Phenyloxazolidon-derivatives, processes for their preparation, to pharmaceutical comprehensive cooperation ratios and their use for the production of medicaments, especially for the preparation of antibacterial medicaments for treating humans and animals.

Antibacterial oxazolidone derivatives which have stand on the nitrogen of oxazolidone a substituted phenyl, are known in the art (see, WO 96/23788, WO 93/09103, WO 93/23384, WO 95/14684, WO 94 / 13649, WO 95/07271, WO 97/09328, WO 97/21708, WO 97/30981, EP-A-0127902, EP-A-0184170, EP-A-0316594, EP-A- 0,311,090,

EP-A-0352781 and WO 97/30995). These 3-position is substituted by substituted phenyl groups have oxazolidones in the 5-position z. as a

Carbonylaminomethylsubstituenten, which may carry further substituents on the carbonyl carbon. The inventors of the present invention set themselves the task of finding new phenyl-oxazolidone derivatives having antibacterial activity, and they succeeded to find antibacterial an exceptionally strong new thiocarbonylaminomethyl-substituted oxazolidones with substituted phenyl radicals at the 3-position of the oxazolidone effectiveness have.

Accordingly, the present invention relates to compounds of the general formula (I)

Figure imgf000004_0001
embedded image in which

R 1 is -OR 4 wherein R 4 is (C, -C 8) -alkyl or (C 3 -C 8) cycloalkyl, or

-NR 5 R 6 wherein R 5 and R 6 are identical or different and denote hydrogen, phenyl, pyridyl or (C, -C 8) -alkyl which is optionally substituted on N-linked morpholine, mean

R 2 is hydrogen, (C, -C 4) alkyl, hydroxy or halogen,

R 3 is a saturated, unsaturated and / or aromatic, optionally fused and / or substituted, carbomono-, bi- or tri-cyclic group or a saturated, unsaturated and / or aromatic, optionally fused and / or substituted, heteromono- heterobi- or heterotricyclic group, or

O

R 3 - C- R 7 wherein R 7 is hydrogen, (C, -C 4) alkyl or (C 3 -C 8) -cycloalkyl,

or - C - R 7 i st> wherein R 7 is as defined above, and R 8 is -NR 7 R 9, wherein R 7 'independently as R 7 defined above and R 9 is hydrogen, (C, -C 4) alkyl or

(C 3 -C 8) cycloalkyl, or -OR 7 'wherein R 7 is as defined above, or halogen,

(C 2 -C 5) alkynyl,

Figure imgf000005_0001
5 wherein R 7 is as defined above,

Wherein R 7 and R are as defined above, and R "is hydrogen

Figure imgf000005_0002
or (C, -C 4) alkyl;

Wherein R 7, R 9 and R u are as defined above,

Figure imgf000005_0003

Figure imgf000005_0004
Wherein R 9 is as defined above and R 12 and R 13 are independently hydrogen or (C 1 -C 4) alkyl or together form a (C 2 - C 3) form alkanediyl group,

Figure imgf000005_0005
Wherein R 7 and R 9 are as defined above, and R 15 and R 16 are independently hydrogen, (C, -C 4) alkyl or (C 3 -C 8) cyclo-alkyl, or R 3
Figure imgf000006_0001
wherein R "is as defined above, R '7 and R 18 are independently hydrogen, (C, -C 4) alkyl, -NO 2 or -CN, or

R 2 and R 3 together form a group of the formula

'Form, where m is an integer of 1 to 3,

Figure imgf000006_0002

X is -CH 2 -, -O-, -S- or -NR ", wherein R 11 is as defined above, and

R 19 and R 20 are both hydrogen, hydrogen and hydroxyl, hydrogen, and -N (R, 8) 2 or together are = O, = NOH, = NOR 21 wherein R 21 (C r

O

II 22

C 4) alkyl, = N- O- C- R j wor i n R 22 is hydrogen, (C, - C 4) alkyl, (C 2 -C 4) alkenyl, (C 3 -C 4) cycloalkyl, or -OR 21, wherein

R 21 is as defined above, or

- N NN CH 3,

and pharmaceutically acceptable salts thereof.

The inventive compounds can exist in stereoisomeric forms which are either like image and mirror image (enantiomers) or not like image and mirror image (diastereomers) exist. The invention relates both to the enantiomers or diastereomers or their respective mixtures. can shape the Racem- be separated in a known manner into the stereoisomerically uniform components, like the diastereomers. The following reaction scheme illustrates the respective realizations for enantiomerically pure and racemic forms of Oxazolidongerüstes:

Figure imgf000007_0001

(A) (racemic) <B) (enantiomer)

Physiologically acceptable salts of the compounds of the invention can be acids salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic. Especially preferred are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid,

Propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Suitable salts salts may further be mentioned with customary bases, such as alkali metal salts (eg sodium or potassium salts), alkaline earth (for example,

Calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines of such as diethylamine, triethylamine, amine Ethyldiisopropyl-, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methyl-piperidine.

(C r C 8) alkyl in the present invention represents straight-chain or branched alkyl having 1 to 8 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl and their branched isomeric forms. From this definition, the corresponding alkyl groups derived analogously with less coal lenstoffatomen such as (C r C4) alkyl off. In general it holds that (C r C 4) alkyl is preferred. Furthermore, (4 C 2 -C) alkenyl are derived from this definition, the respective meanings of the alkyl moiety in the functionalized groups, such as (C 2 -C 5) alkynyl (for example ethynyl, propynyl etc.), (eg, vinyl, propenyl etc.), (C r C4) acyl (eg formyl, acetyl, propionyl, butyryl etc.), (C r C4) alkoxy (such as methoxy,

Ethoxy, propoxy, butoxy etc.), (Ci-C ^ alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, n-hexoxycarbonyl, etc.) etc.

(C 3 -C 8) cycloalkyl represents a cyclic hydrocarbon radical having 3 to 8

Carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl may be mentioned. cyclopropyl, cyclopentane and cyclohexane are preferred.

Aryl in general represents an aromatic radical having 6 to 10 carbon atoms.

Preferred aryl radicals are phenyl and naphthyl.

Halogen in the context of the invention represents fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

A saturated, unsaturated and / or aromatic, optionally fused and / or substituted, carbomono-, bi- or tri-cyclic group for R 3 includes Carbomono-, bi- or tricyclic groups, wherein when it is bi-or tricyclic radicals the cycles can be present aneinanderkondensiert, may be connected to each other via a bond or two bonds can be connected to each other (spirocyclic compounds), and these cycles if more than two are present in the residue, saturated independently, unsaturated and / or aromatic can , This group can be further substituted or unsubstituted. Such groups are known per se in the art and are described for example in the above-described prior art. Analog include saturated, unsaturated and / or aromatic, optionally fused and / or substituted heteromono-, heterobi- or heteromono- heterotricyclic groups for R 3, heterobi- or heterotricyclic groups, at least one hetero atom, preferably 1 to 3 heteroatoms selected from S, N or

O contain one, where the cycles may be condensed, may be joined together by a bond or, may be joined together as in the case of the spiro compounds via two bonds. This definition also includes radicals R 3, in which the same carbocyclic and heterocyclic groups are present. The individual cycles may, when more than two are present, independently of one another be saturated, unsaturated and / or aromatic and may be substituted. Such groups are also known per se from the prior art and are described, for example, by the mentioned in the introduction the prior art. Concrete examples of R 3 are in the following preferred embodiment of the compounds of general formula

(I) described in the

R 3 is selected from the groups of the formulas:

i st> wherein R is selected

Figure imgf000009_0001
is selected from the group of substituents consisting of:

(A) hydrogen

(B) halogen,

(c) -OR 24, (d) -SR 24,

(e) -S (O) n R 24 wherein n is an integer of 1 or 2,

(F) cyano, O

(G) 24 - O- C- R

HO

00

HO

(I) 2 '- N- C- O- R

Figure imgf000010_0001

O - COR 24

(K)

Figure imgf000010_0002

(n) (C, -C 8) alkyl or (C 3 -C 8) cycloalkyl, which may be optionally substituted with one or more substituents, which the above-mentioned substituents from the group

(A) to (m),

(Q) phenyl, which may optionally be substituted with one or more substituents (a) to (n) from the group of substituents mentioned above,

wherein R 24 and R 24 are independently selected from:

(A) hydrogen,

(b) (C, -C 6) alkyl or (C 3 -C 8) cycloalkyl, which may be tuiert optionally substitutable with one or more substituents selected from the group (consisting of fluorine, chlorine, hydroxyl C, -C 4) alkoxy, (C, -C 4) acyl, (C, -C 4) acyloxy, or

Figure imgf000011_0001
and

(c) phenyl which may be optionally substituted with one or more substituents selected from the group advertising the consisting of fluorine, chlorine, (C, -C 4) alkyl, hydroxy, (C, -C 4) -

Alkoxy, (C, -C 4) acyl, (C, -C 4) acyloxy, or

Figure imgf000011_0002
is, or is phenyl or pyridyl, which may be optionally substituted with R 25 and R 26 wherein R 26 is selected from the group of substituents consisting of:

(A) hydrogen,

(B) halogen,

(c) -R 27 and -OR 27 wherein R 27 is hydrogen or (C, -C 4) alkyl,

(d) -NO 2, and

R 25 is selected from the group of substituents consisting of:

(A) hydrogen,

(b) (C, -C 8) alkyl which may be optionally substituted with one or more substituents selected from the group consisting of: halogen; -OH,

Oxo, that is not in α-position, - -S (O) 0 R 28, wherein o is an integer of 0, 1 or 2 and R 28 (C, -C 4) alkyl or (C 3 -C 8 ) cycloalkyl, -NR 29 R 30 wherein R 29 and R 30 are identical or different, and are hydrogen, (C, -C 8) alkyl, (C, -C 8) cycloalkyl, - (CH2) - oR 31 m, where m is an integer of 1, 2 or 3 and R 31 is hydrogen or (C, -C 4) alkyl, (Ob (CH) -. NR 32 R 33

P m, where m is as defined above and p is 0 or 1 and R 32 and R 33 are the same or different and 5 is hydrogen or (C, -C 4) alkyl or together form a (C 4 -C 6) form alkanediyl group or R 29 and R 30 together are - (CH 2) 2 -O- (CH 2) 2 - or - (CH 2) 2 -N (R 31) - (CH 2) 2 -, wherein R 3 'are as above is defined, form, 10 (c) (C 2 -C 5) alkenyl,

(d) (C 3 -C 8) cycloalkyl,

(e) -OR 29, wherein R 29 is as defined above,

(F) cyano,

(g) -S (O) 0 R 34, wherein o is as defined above and R 34

15 - (C, -C 4) -alkyl which is optionally substituted with one or more substituents selected from group R 30 is selected from halogen, hydroxy, cyano, -NR 29 wherein R 29 and R 30 as described above are defined, and

20

Figure imgf000012_0001
wherein R 32 is as defined above, (C 2 -C 4) alkenyl,

-NR 35 R 36 wherein R 35 is hydrogen, (C, -C 4) alkyl,

And (C 3 -C 8) cycloalkyl, R 36 is hydrogen, (C, -

25 C 4) alkyl, alkyl, (C 2 -C 4) alkenyl, (C 3 -C 8) -

Cycloalkyl, -OR 37, wherein R 37 is hydrogen or (C, -C 4) alkyl, or -NR 32 R 33 wherein R 32 and R 33 as defined above, -N 3,

H π, wherein R 38 (C, -C 4) alkyl;

- - C- R 38 that can be optionally substituted with one or more halogen atoms, 5

(h) 5 wherein p ne whole Zam

Figure imgf000013_0001
is 0 or 1 and R 39 and R 40 are independently (C r C 2) alkyl or together form a (C 3 - C 5) form alkanediyl group,

O

10 (i) II, R, wherein R is as defined above,

- S- C- R

(J) tetrazolyl,

(k) -NR 29 R 30 wherein R 29 and R 30 as defined above,

(1) -N (R 29) COR 38 wherein R 29 and R 38 as defined above,

15 (m) -NR 29 S (O) 0 R 38, where R 38 are as defined above 29, o and R,

(n) -CONR 29 R 30, wherein R 29 and R 30 as defined above,

(o) -COR 41 wherein R 41

20 - Hydrogen

(C, -C8) alkyl that may be optionally substituted with one or more halogen atoms,

(C, -C 4) alkyl that optionally substituted with -OR 37,

25 -OC (O) R, wherein R 37 is each as defined above 37, -NR 29 R 30, wherein R 29 and R 30 are as defined above, -S (O) 0 R 28, wherein o and R 28, are as defined above, (C 3 -C 8) cycloalkyl,

R is (C 2 -C 5) alkenyl optionally substituted with -CHO, or -CO 2 37,

(p) -C (= NR 42) R 41 wherein R 41 is as defined above, and R 42

-NR 29 R 30, wherein R 29 and R 30 as defined above,

-OR 29 wherein R 29 is as defined above, or

HO, wherein P R29 is as defined above,

I. II, 29

- N- C- FT

10 (q) -C (R 41) (OR 43) (OR 43 ') wherein R 4' is as defined above, and R 43 and R 43 'may be identical or different and are (C, -C 4) alkyl or together a (C 2 -C 3) - alkanediyl form,

(r) wherein R 29, R 35 and R 4 'as above Defi-

Figure imgf000014_0001

15 are defined, and R 44 R 29 or -NR 29 R 31, wherein R 29 and

R 31 are as defined above,

(s), wherein R 29, R 31 and R 41 as above

Figure imgf000014_0002
are defined,

Figure imgf000014_0003
(u) wherein m, R 29, R 30 and R 31
Figure imgf000015_0001
are as defined above, or

R 3 is a group of the formula:

Wherein q is an integer from 0 to 4,

Figure imgf000015_0002
and R 45 is -COR 46 wherein R 46 (C, -C 6) alkyl that may be substituted with hydroxy, or -C (O) -OR 47, wherein R 47 (C, -C 6) alkyl or

R 3 is a group of the formula

wherein R 47 is as defined above, or

Figure imgf000015_0003

R 3 is a group of the formula:

Figure imgf000015_0004
is wherein Y is S or O, or

R 3 is a group of the formula:

Wherein R 48 is hydrogen, (C, -C 6) alkyl, that

Figure imgf000015_0005
may optionally have one or more substituents selected from OH, CN or halogen, - (CH 2) r - (C 6 -C 10) aryl, wherein r is an integer from 1 to 4, or - (CH 2) r -OR 49, wherein R is as defined above, and R 49 is hydrogen, (C, -C 6) alkyl, - (CH 2) r - (C 6 -C 10) aryl, wherein r is as defined above, or -C (O) R 50, wherein R 50 (C, C6) alkyl, or

R 3 is a group of the formula:

Figure imgf000016_0001

R 3 is a group of the formula:

Figure imgf000016_0002
are selected from hydrogen, -NO 2, and halogen, or

R 3 is a group of the formula:

5 wherein R 55 and R 56 independently of one

Figure imgf000016_0003
each hydrogen, (C, -C 4) alkyl, (C 3 -C 8) cycloalkyl or phenyl or together form a (C, -C 6) alkanediyl form, or

R 3 is a group of the formula:

Figure imgf000017_0001

a group of the formula:

or preferably

Figure imgf000017_0002

R is as defined above,

R 57 is selected from the group of substituents consisting of:

(A) hydrogen,

(b) -NO 2,

(c) -S (O) 0 R 59 wherein o is as defined above and R 59 (C, - C 4) alkyl that optionally may be substituted by one or more substituents selected from the group consisting of, -OH, -CN, -NR 29 R 30, wherein R 29 and R 30 as defined above, and -C (O) OR 37 wherein R 37 is as defined above; (C 2 - C 4) alkenyl or -NR 7 R 60, wherein R 7 is as defined above and R 60 R 22 or -NR 32 R 33, wherein R 22, R 32 and R 33 as defined above, (d) tetrazolyl,

(e) wherein p? R39 and R4 O how

Figure imgf000018_0001
are as defined above,

(F) -SH

O 5 (g) - S - C - R 38 wherein R 38 is as defined above,

(h) -COR 41 wherein R 41 is as defined above,

(i) -CONR 29 R 30, wherein R 29 and R 30 as defined above, (j) -C (= NR 42) R 41 wherein R 41 is as defined above, and R 42 -NR 29 R 10 30 wherein R 29 and R 30 are as defined above,

-OR 29 wherein R 29 is as defined above, or

HO

I II, Q is wherein R is as defined above, - N- C- R 29

(k) wherein R 29, R 3 'and R 41 as defined above

Figure imgf000018_0002
are,

15 (1): wherein R 29, R 31 and R 41 as above

Figure imgf000018_0003
are defined,

(m) wherein m, R 29, R 30 and R 3 '

Figure imgf000018_0004
are as defined above, (n) -CN, (o) -OR 29 wherein R 29 is as defined above,

(P) halogen,

(q) -NR 29 R 30, wherein R 29 and R 30 as defined above,

R 29 0 (r) N- CR 38 'worm R29 and R38 i e w ° ben defined

5 are

(s), wherein o, R 29 and R 38 are as above

Figure imgf000019_0001
are as defined, (t) -C (R 1) (OR 43) (OR 43 '), wherein R 41 is as defined above, and R 43 and R 43' are the same or different from 10 and (C, -C 4 ) alkyl or together form a (C 2 -

C 3) alkanediyl form,

(u) wherein R 29, R 35 and R 41 as defined above

Figure imgf000019_0002
, and R 44 -R 29 or -NR 29 R 31 wherein R 29 and R 31 as defined above, 15 (v) (C, -C 8) alkyl which may be optionally substituted with one or more substituents which are selected from the group consisting of: halogen; -OH, 20 - oxo that is not in α-position,

-S (O) 0 R 28 wherein R 28 and o are as defined above, or

-NR 29 R 30 wherein R 29 and R 30 are as defined above, 25 (w) (C 2 -C 5) alkenyl, and

(x) (C 3 -C 8) cycloalkyl, and R 58 is hydrogen, halogen, OR 37 wherein R 37 is as defined above, (C, -C 3) alkyl, or NO 2, or when R 3

or R 57 and R 58 together

Figure imgf000020_0001
Figure imgf000020_0002
may form a six-membered carbocyclic ring.

Particularly preferred are compounds of general formula (I) wherein

R 1 is -OR 4 wherein R 4 is (C, -C 8) alkyl, or -NHR 5, wherein R 5 is hydrogen or (C, -C 8) alkyl,

R 2 is hydrogen or halogen,

O

II 7

R 3 "CR, wherein R 7 is (C, -C 4) alkyl,

Figure imgf000020_0003
, wherein R 7 is (C r C 4) alkyl, and R 'wherein R 7' 8 -OR 7 is as defined above,

Figure imgf000020_0004
Wherein R 11 is as defined above, R 17 is hydrogen and

R 18 is -CN or -NO 2 or R 17 is -CN or -NO 2 and R '8 is hydrogen,

pyridyl or

Figure imgf000021_0001
is wherein Y is S or O is.

Very particularly preferred compounds of the invention are selected from the group consisting of:

Figure imgf000021_0002

Figure imgf000021_0003

Figure imgf000021_0004

Figure imgf000022_0001

Figure imgf000022_0002

Figure imgf000022_0003

Figure imgf000022_0004
Figure imgf000023_0001

Figure imgf000023_0002

Figure imgf000023_0003

Figure imgf000024_0001

The invention further relates to a process for preparing the compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein

(A) Compounds of formula II)

Figure imgf000024_0002
wherein R 2 and R 3 are as defined above, or their salts with compounds of the general formula (III)

Figure imgf000024_0003

are wherein R 4 is as defined above, to yield compounds of formula (Ia)

Figure imgf000025_0001

wherein R 4 is as defined above, or to obtain a salt thereof.

The preparation of the starting compounds of general formula (II) are known per se, and the preparation of these amine compounds is described, for example, in the mentioned in the introduction the prior art. Likewise, it is the compound of the general formula (III) compounds which are known in the art. Furthermore, compounds of the invention are obtained by the following methods:

(B) compounds of general formula (II)

Figure imgf000025_0002
wherein R 2 and R 3 are as defined above, in inert solvents first with S = CC1 2, and then with compounds of the general formula (III)

H-NR 5 R 6 (III) wherein R 5 and R 6 are as defined above, is reacted to obtain compounds of formula (Ib)

Figure imgf000026_0001

wherein R 2, R 3, R 5 or R 6 as defined above, or

(C) compounds of general formula (II)

Figure imgf000026_0002

wherein R 2 and R 3 are as defined above, in inert solvents with compounds of the formula (IV)

S

ACR 1

wherein A is halogen, preferably chlorine, are reacted to obtain compounds of formula (I), or

(D) compounds of the general formula (II)

Figure imgf000027_0001

wherein R 2 and R 3 are as defined above, are reacted with Ethyldithiocarboxylaten and triethylamine and, if R 1 = NR 5 R 6 with thioisocyanates in inert solvents to

to obtain compounds of formula (I).

The compounds of the invention find use as a medicament.

The invention thus further provides pharmaceutical

Compositions comprising at least one compound of the invention in a mixture with at least one pharmaceutically vertäglichen carrier, as well as the use of the compounds of the invention for the manufacture of a medicament for treating bacterial infections in humans or animals.

As can be seen from the following test results, the compounds of the invention have a high antibacterial activity which is superior to that of the analogous compounds of the prior art, as shown by Comparative Examples 1 and 2, which is extremely surprising.

For this, the MIC values ​​were determined using the microdilution in BH medium. Each test substance was dissolved in the nutrient medium. In the microtiter plate, a concentration series of the test substances was created by serial dilution. For inoculation, overnight cultures of the pathogens were used previously in the nutrient medium 1: were diluted 250th To 100 .mu.l of the diluted active substance-containing,

Nutrient solutions were added 100 .mu.l inoculation. The microtiter plates were incubated at 37 ° C and read after 20 hours or after 3 to 5 days. The MIC value (.mu.g / ml) indicates the lowest active compound concentration at which no growth could be seen.

We found the following results:

MIC values ​​(.mu.g / ml):

Figure imgf000028_0001
Figure imgf000029_0001

The compounds of the invention have a broad antibacterial spectrum, especially against Gram-positive bacteria and some gram-negative bacteria and Mycobacteria, corynebacteria, Haemophilus influenzae and anaerobic bacteria.

These properties make possible their use as chemotherapeutic active compounds in human and veterinary medicine.

The present compounds are active against a broad spectrum of microorganisms. With their help, Gram-positive bacteria, gram negative bacteria and bacteria-like microorganisms such as mycoplasma can combated and the diseases caused by these pathogens prevented, alleviated and / or cured.

Particularly effective compounds of this invention 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 such pathogens. The active ingredient can also be in micro-encapsulated form, if appropriate, in one or more carriers.

The therapeutically active compounds should be present in the abovementioned pharmaceutical compositions preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 wt .-% of the total mixture.

The abovementioned pharmaceutical preparations can addition to inventions compounds according to contain other active pharmaceutical ingredients.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds in total amounts of about 0.5 to about 500, preferably 5 to 100 mg kg body weight per 24 hours, optionally in the form of several to administer individual doses to achieve the desired results. An individual dose preferably contains the active compound or compounds in amounts of from about 1 to about 80, especially 3 to 30 mg / kg, body weight.

The compounds of the invention, for the purpose of expanding the

and achieve spectrum of action to increase an effect, also be combined with other antibiotics.

Examples Example 1

Figure imgf000031_0001

(5S) -3- (3-Fluoro-4-mo holinylphenyl) -5- (methoxy-thionocarbonylaminomethyl) - oxazolidin-2-one

140 mg (0.46 mmol) of (5S) -3- (3-Fluoro-4-morpholinylphenyl) -5-aminomethyl-oxa- zolidin-2-one, 110 mg (0.92 mmol) and 0.2 ml Thionocarbonylmonomethylmonothiomethylester ( 1.15 mmol) of Hunig base are stirred in 5 ml of methanol overnight at room temperature. The mixture is concentrated and purified on silica gel (dichloromethane / methanol gradient). Yield: 60 mg, R F = 0.87 (dichloromethane / methanol 100: 7)

In analogy to Example 1 are from the literature the following amines

Examples receive:

Figure imgf000031_0002

Figure imgf000032_0001
Figure imgf000033_0002

example 10

Figure imgf000033_0001

(5S) -3- (3-Fluoro-4-moφholinylphenyl) -5- (aminothionocarbonylaminomethyl) - oxazolidin-2-one

400 mg (1.35 mmol) of (5S) -3- (3-Fluoro-4-moφholinylphenyl) -5-aminomethyl-oxa- zolidin-2-one in 12 ml of chloroform / water 1: 1 at 0 ° C with 410 mg (4 mmol)

Calcium carbonate and 0.15 ml (2 mmol) of thiophosgene was added. The mixture is stirred overnight at room temperature, the organic phase is separated off and the aqueous phase extracted three times with chloroform. The combined organic phases are dried and concentrated. The intermediate product is taken up in 38 ml of methanol and treated with 19 ml of 2N ammonia in methanol. The mixture is stirred overnight at room temperature and concentrated, filtered off and dried. Yield: 142 mg, R F = 0.19 (dichloromethane / methanol 100: 3)

In analogy to Example 10, the following examples are obtained from the literature amines:

Figure imgf000034_0001

Claims

claims
1. Compounds of general formula (I):
Figure imgf000035_0001
wherein
R 1 is -OR 4 wherein R 4 is (C, -C 8) alkyl or (C 3 -C 8) cycloalkyl, or
-NR 5 R 6 wherein R 5 and R 6 are identical or different and denote hydrogen, phenyl, pyridyl or (C, -C 8) -alkyl which is optionally substituted on N-bound Moφholin, mean
R 2 is hydrogen, (C, -C 4) alkyl, hydroxy or halogen,
R 3 is a saturated, unsaturated and / or aromatic, optionally fused and / or substituted, carbomono-, bi- or tri-cyclic group or a saturated, unsaturated and / or aromatic, optionally fused and / or substituted, heteromono- heterobi- or heterotricyclic group, or
OR 3 - - R 7, wherein R 7 is hydrogen, (C, -C 4) alkyl or (C 3 -C 8) -cycloalkyl, or
Figure imgf000036_0001
wherein R 7 is as defined above, and R 8 is -NR 7 R 9, wherein
R 7 'independently as R 7 defined above and R 9 is hydrogen, (C, - C 4) alkyl or (C 3 -C 8) -cycloalkyl or -OR 7' wherein R 7 'is as defined above, or
R 3 is halogen,
(C 2 -C 5) alkynyl,
Figure imgf000036_0002
R; wor in R 7 as defined above, is,
Figure imgf000036_0003
Wherein R 7 and R 9 are as defined above, and R "
Is hydrogen or (C, -C 4) alkyl;
Figure imgf000036_0004
Wherein R 7, R 9 and R 11 are as defined above,
Figure imgf000037_0001
Wherein R is as defined above and R 12 and R 13 are independently hydrogen or (C, -C 4) alkyl or together form a (C 2 -C 3) form alkanediyl group,
Figure imgf000037_0002
Wherein R and R are as defined above, and R 15 and
R 16 is independently hydrogen, (C, -C 4) alkyl or (C 3 -
C8) cyclo-alkyl, or
R 3
Figure imgf000037_0003
ISTJ ιι wherein R is as defined above, R "and R 18 are independently hydrogen, (C, -C 4) alkyl, -NO 2 or -CN, or
R 2 and R 3 together form a group of the formula
Figure imgf000037_0004
form, wherein m is an integer of 1 to 3, X
-CH 2 -, -O-, -S- or -NR 11 wherein R "is as defined above, and R 19 and R 20 are both hydrogen, hydrogen and hydroxyl, hydrogen, and -N (R, 8) 2 or together are = O, = NOH, = NOR 21 wherein R 21 (C r
O
II
C 4) alkyl, - = N "- O- C ^ - R '*, w" "ori_-n_ R n 2 2 2 2 is hydrogen, (C, C4) alkyl, (C 2 -C 4) - alkenyl, (C 3 -C 4) cycloalkyl or -OR 21, wherein R 21 is as defined above, or
Figure imgf000038_0001
are,
and pharmaceutically acceptable salts thereof.
2. Compounds according to claim 1, wherein
R 3 is selected from the groups of the formulas:
or wherein R 23 is selected
Figure imgf000038_0003
Figure imgf000038_0002
is selected from the group of substituents consisting of:
(A) hydrogen
(b) halogen, (c) -OR 24,
(d) -SR 24,
(e) -S (O) π R 24, wherein n is an integer of 1 or 2;
(F) cyano,
O
(g) __ 0 _c-R24>
Figure imgf000038_0004
Figure imgf000039_0001
-OR 24
00
oo = 1
Figure imgf000039_0002
O
II
(m) - C -R 32
(n) ((CC ,, - CC 88)) AAllkkyyll ooder (C 3 -C 8) cycloalkyl which may be optionally substituted with one or more substituents selected from the group of the above-mentioned substituents (a) to ( m are selected), (q) phenyl, which may optionally be substituted with one or more substituents a) to (n) (from the group of substituents mentioned above,
wherein R 24 and R 24 'are independently selected from:
(A) hydrogen,
(b) (C, -C 6) alkyl or (C 3 -C 8) cycloalkyl, which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, hydroxy, (C -C 4) alkoxy, (C, -C 4) acyl, (C, -C 4) acyloxy, or
Figure imgf000039_0003
and
(c) phenyl which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, (C, -C 4) alkyl, hydroxy, (C, -C 4) - alkoxy (C, -C 4) acyl, (C, -C 4) acyloxy, or
Figure imgf000040_0001
consists, or
Is phenyl or pyridyl, which may be optionally substituted with R 25 and R 26 wherein R 26 is selected from the group of substituents consisting of:
(A) hydrogen,
(B) halogen,
(c) -R 27 and -OR 27 wherein R 27 is hydrogen or (C, -C 4) alkyl,
(d) -NO 2, and
R is selected from the group of substituents consisting of:
(A) hydrogen,
(b) (C, -C 8) alkyl which may be optionally substituted with one or more substituents selected from the group consisting of: halogen; -OH,
Oxo, that is not in α-position, - -S (O) 0 R 28, wherein o is an integer of 0, 1 or 2 and R 28 (C, -C 4) alkyl or (C 3 -C 8 ) cycloalkyl, -NR 29 R 30 wherein R 29 and R 30 are identical or different, and are hydrogen, (C, -C 8) alkyl, (C, -C 8) cycloalkyl, (CH,), - oR 31 m, wherein m is an integer of 1, 2 or 3 and R 31 is hydrogen or (C, -C 4) alkyl, (O) - (CH 2) - NR 32 R 33rd
H ιπ, Wonn m defined as above and p is 0 or 1 and R 32 and R 33 are identical or different and are hydrogen or (C, -C 4) alkyl or together a (C 4 -C 6) form alkanediyl group, or R 29 and R 30 together are - (CH 2) 2 -O- (CH 2) 2 - or - (CH 2) 2 -N (R 31) - (CH 2) 2 -, wherein R 31 is as defined above form, 5 (c) (C 2 -C 5) alkenyl,
(d) (C 3 -C 8) cycloalkyl, (h) -OR 29 wherein R 29 is as defined above, (i) cyano,
(j) -S (O) 0 R 34, wherein o is as defined above and R 34 10 - (C, -C 4) -alkyl which is optionally substituted with one or more substituents selected from group consisting of halogen, hydroxy, cyano, -NR 29 R 30 wherein R 29 and R 30 as defined above, and
15
Figure imgf000041_0001
, where R 32 is as defined above, (C 2 -C 4) alkenyl,
-NR 35 R 36 wherein R 35 is hydrogen, (C, -C 4) alkyl,
And (C 3 -C 8) cycloalkyl, R 36 is hydrogen, (C, -
20 C 4) alkyl, alkyl, (C 2 -C 4) alkenyl, (C 3 -C 8) -
Cycloalkyl, -OR 37, wherein R 37 is hydrogen or (C, -C 4) alkyl, or -NR 32 R 33 wherein R 32 and R 33 as defined above, -N 3,
25 f 8, wherein R 38 (C, -C 4) alkyl;
- N-E-R 38 that optionally with one or more
Halogen atoms may be substituted, (h) wherein p is an integer
Figure imgf000042_0001
is 0 or 1 and R 39 and R 40 are independently (C, -C 2) alkyl or together form a (C 3 - C 5) form alkanediyl group,
O
5 (i) II 38, wherein R 38 is as defined above,
- S - C - R
(J) tetrazolyl,
(k) -NR 29 R 30 wherein R 29 and R 30 as defined above,
(1) -N (R 29) COR 38 wherein R 29 and R 38 as defined above,
10 (m) -NR 29 S (O) 0 R 38, where R 38 are as defined above 29, o and R,
(n) -CONR 9 R 30 wherein R 29 and R 30 as defined above,
(o) -COR 41 wherein R 41
15 - Hydrogen
(C, -C8) alkyl that may be optionally substituted with one or more halogen atoms,
(C, -C 4) alkyl that optionally substituted with -OR 37,
20 -OC (O) R, wherein R 37 is each as defined above 37, -NR 29 R 30, wherein R 29 and R 30 are as defined above, -S (O) 0 R 28, wherein o and R 28, are as defined above,
(C 3 -C 8) cycloalkyl,
25 - (C 2 -C 5) alkenyl optionally substituted with -CHO or -CO 2 R 37,
(p) -C (= NR 42) R 41 wherein R 41 is as defined above, and R 42
-NR 29 R 30, wherein R 29 and R 30 as defined above, -OR, wherein R is as defined above, or
| ii, wherein R 29 is as defined above,
- N- C- R 29
(q) -C (R 4l) (OR 43) (OR 43 '), wherein R 41 is as defined above, and R 43 and R 43' are or may be identical or different and are (C r C4) alkyl or together a (C 2 -C 3) - alkanediyl form,
(r) wherein R 29, R 35 and R 41 as previously defi
Figure imgf000043_0001
ned, and R 44 R 29 or -NR 29 R 31 wherein R 29 and R 31 as defined above,
(s) where R 29, R 31 and R 41 as above
Figure imgf000043_0002
are defined,
Wherein m, R 29, R 30 and R 3
Figure imgf000043_0003
are as defined above, or
a group of the formula:
Wherein q is an integer from 0 to 4,
Figure imgf000043_0004
and R 45 is -COR 46 wherein R 46 (C, -C 6) alkyl that may be sub- stituiert with hydroxy, or -C (O) -OR 47, wherein R 47 (C, -C6) alkyl, or
R 3 is a group of the formula:
wherein R 47 is as defined above, or
Figure imgf000044_0001
R 3 is a group of the formula:
Figure imgf000044_0002
is wherein Y is S or O, or
R 3 is a group of the formula:
Wherein R 48 is hydrogen, (C, -C 6) alkyl, that
Figure imgf000044_0003
may optionally have one or more substituents selected from OH, CN or halogen, - (CH 2) r - (C 6 -C 10) aryl, wherein r is an integer from 1 to 4, or - (CH 2) r -OR 49, wherein R is as defined above, and R 49 is hydrogen, (C, -C 6) alkyl, - (CH 2) r - (C 6 -C 10) aryl, wherein r is as defined above, or -C (O) R 50, wherein R 50 (C, - C 6) alkyl, or
R 3 is a group of the formula:
Figure imgf000044_0004
R 3 is a group of the formula: wherein R 51 to R 54 independently
Figure imgf000045_0001
are selected from hydrogen, -NO 2, and halogen, or
R 3 is a group of the formula:
Wherein R> 55 un .DA R D5 5 6 0 regardless of
Figure imgf000045_0002
each hydrogen, (C, -C 4) alkyl, (C 3 -C 8) cycloalkyl or phenyl or together form a (C, -C 6) alkanediyl form, or
R 3 is a group of the formula:
Figure imgf000045_0003
R 3 is a group of the formula: or preferably
Figure imgf000046_0001
R is as defined above,
R 57 is selected from the group of substituents consisting of:
(A) hydrogen,
(b) -NO 2,
(c) -S (O) 0 R 59 wherein o is as defined above and R 59 (C, - C 4) alkyl that optionally may be substituted by one or more substituents selected from the group consisting of, -OH, -CN, -NR 29 R 30, wherein R 29 and R 30 as defined above, and -C (O) OR 37 wherein R 37 is as defined above; (C 2 - C 4) alkenyl or -NR 7 R oo, wherein R 7 is as defined above and R 60 R 22 or -NR 32 R 33, wherein R 22, R 32 and R 33 as defined above .
(D) tetrazolyl, (e)
n R 39 R 40, wherein p, R 39 and R are as
Figure imgf000046_0002
are as defined above,
(0 SH (g)
O - S - C - R 38 wherein R 38 is as defined above,
(h) -COR 41 wherein R 41 is as defined above,
(i) -CONR 29 R 30, wherein R 29 and R 30 as defined above, (j) -C (= NR 42) R 41 wherein R 41 is as defined above, and R 42 -NR 9 R 30 wherein R 29 and R 30 are as defined above, -OR 29 wherein R 29 is as defined above, or
HO
I is II, q, wherein R is as defined above, - N- C- R 29
10 (k)
Wherein R 29, R 31 and R 41 as above
Figure imgf000047_0001
are as defined
(1)
wherein R 29, R 31 and R 41 as above
Figure imgf000047_0002
15 are defined,
(M)
and R 31
Figure imgf000047_0003
are as defined above, (n) -CN 20 (o) -OR 29 wherein R 29 is as defined above,
(p) halogen, (q) -NR 29 R 30, wherein R 29 and R 30 as defined above, (r)
R 29 O | {J R 38 wherein R 5 are 29 and R 38 as defined above,
5 (s)
Wherein o, R 29 and R 38 are as above
Figure imgf000048_0001
are as defined, (t) -C (R 41) (OR 3) (OR 43 ') wherein R 4' is as defined above, and R 43 and R 43 'are the same or different from 10 and (C, -C 4) alkyl or together form a (C 2 -
C 3) alkanediyl form,
(U)
wherein R 29, R 35 and R 41 as previously defi
Figure imgf000048_0002
ned, and R 44 -R 29 or -NR 29 R 31, wherein R 2 9 15 and R 31 are as defined above,
(v) (C, -C 8) alkyl which may be optionally substituted with one or more substituents selected from the group consisting of: halogen; 20 - OH,
Oxo that not present in α-position -S (O) 0 R 28, wherein o and R 28 are as defined above, or
-NR 29 R 30 wherein R 29 and R 30 as defined above is 25,
(w) (C 2 -C 5) alkenyl, and (x) (C 3 -C 8) cycloalkyl, and
(-C 3 C) alkyl, or NO 2 R 58 is hydrogen, halogen, OR 37 wherein R 37 is as defined above, or when R 3
, R 57 and R 58 together
Figure imgf000049_0001
may form a six-membered carbocyclic ring.
3. Compounds according to claim 1 or 2, wherein
R 1 is -OR 4, wherein R 4 is (C, -C 8) alkyl, or NHR 5 wherein R 5 is hydrogen or (C, -C 8) alkyl
R 2 is hydrogen or halogen,
OR 7 R 3 OB-R, wherein R 7 is (C, -C 4) alkyl,
Figure imgf000049_0002
Wherein R 7 is (C, -C 4) alkyl, and R 'wherein R 7' 8 -OR 7 is as defined above,
Figure imgf000049_0003
Wherein R 11 is as defined above, R 17 is hydrogen and
R 18 is -CN or -NO 2 or R 17 is -CN or -NO 2, and R 18 is hydrogen,
Pyridyl or \ / -, wherein Y is S or O is.
4. Compounds according to claim 1, 2 or 3, selected from the group of compounds consisting of:
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000051_0004
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
Figure imgf000053_0001
A process for the preparation of the compounds of formula (I) according to claim 1 and pharmaceutically acceptable salts thereof, wherein
(A) Compounds of formula II)
Figure imgf000053_0002
wherein R 2 and R 3 are as defined in claim 1, or their salts with compounds of the general formula (III)
Figure imgf000053_0003
wherein R 4 is as defined in claim 1, are converted to compounds of formula (Ia)
Figure imgf000054_0001
wherein R4 is as defined in claim 1, or to obtain a salt thereof, or
(B) compounds of general formula (II)
Figure imgf000054_0002
wherein R "are as defined in claim 1. 3> 2" un "d JR τ, first in inert solvents with S = CC1 2, and then with compounds of the general formula (III)
H-NR 3 R O (III)
are wherein R are as defined in claim 1 and R ° 5 are reacted to obtain compounds of formula (Ib)
Figure imgf000055_0001
wherein R 2, R 3, R are as defined in claim 1 5 or R 6, or
(C) compounds of general formula (II)
Figure imgf000055_0002
wherein R 2 and R 3 are as defined in claim 1, in inert solvents with compounds of the formula (IV)
S ACR 1
wherein A is halogen, preferably chlorine, are reacted to obtain compounds of formula (I), or
(D) compounds of the general formula (II)
Figure imgf000056_0001
wherein R 2 and R are as defined in claim 1 3, are reacted with thioisocyanates 6 in inert solvents with Ethyldithiocarboxylaten and triethylamine and, if R 1 = NR 5 R, to obtain compounds of formula (I).
6. Compounds according to claim 1 for use as a medicament.
7. A pharmaceutical composition comprising a compound of claim 1 in admixture with at least one pharmaceutically acceptable carrier.
8. Use of the compound according to claim 1 for the manufacture of a medicament for treating bacterial infections in humans or animals.
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