WO2000029396A1

WO2000029396A1 - Novel substituted phenyloxazolidone derivatives

Info

Publication number: WO2000029396A1
Application number: PCT/EP1999/008469
Authority: WO
Inventors: Stephan Bartel; Siegfried Raddatz; Michael Härter; Ulrich Rosentreter; Hanno Wild; Rainer Endermann; Hein-Peter Kroll
Original assignee: Bayer Aktiengesellschaft
Priority date: 1998-11-17
Filing date: 1999-11-05
Publication date: 2000-05-25
Also published as: AU1379900A

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 phenyloxazolidone derivatives

The present invention relates to new substituted phenyloxazolidone derivatives, processes for their preparation, pharmaceutical compositions comprising them and their use for the production of medicaments, in particular for the production of antibacterial medicaments for the treatment of humans and animals.

Antibacterial oxazolidone derivatives which have a substituted phenyl group on the nitrogen of the oxazolidone skeleton are known in the prior art (cf. 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-0 127 902, EP-A-0 184 170, EP-A-0 316 594, EP-A- 0 311 090,

EP-A-0 352 781 and WO 97/30995). These substituted in the 3-position by substituted phenyl groups oxazolidones have in the 5-position z. B. one

Carbonylaminomethyl substituents, which can carry further substituents on the carbonyl carbon atom. The inventors of the present invention set themselves the task of finding new phenyl-substituted oxazolidone derivatives with antibacterial activity, and they succeeded in finding new thiocarbonylaminomethyl-substituted oxazolidones with substituted phenyl radicals in the 3-position of the oxazolidone, which have an extraordinarily strong antibacterial Effectiveness.

The present invention therefore relates to compounds of the general formula (I)

woπn

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

-NR ⁵ R ⁶ , in which R ⁵ and R ^{6 are} identical or different and are hydrogen, phenyl, pyridyl or (C, -C ₈ ) alkyl, which is optionally substituted by N-linked morpholine,

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

R ^{3 is} a saturated, unsaturated and / or aromatic, optionally condensed and / or substituted, carbomono-, bi- or tricyclic group or a saturated, unsaturated and / or aromatic, optionally condensed and / or substituted, heteromono-, heterobi- or heterotricyclic Group is, or

O

R ³ - C - R ⁷ , in which 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 -NR ⁷ R ⁹ , wherein R ^{7 'is} independently as R ⁷ defined above and R ^{9 is} hydrogen, (C, -C ₄ ) alkyl or

Is (C ₃ -C ₈ ) cycloalkyl, or is -OR ^{7 '} wherein R ^{7 is} as defined above, or Halogen,

(C ₂ -C ₅ ) alkynyl,

₅ wherein R ^{7 is} as defined above,

wherein R ⁷ and R are as defined above and R "is hydrogen

or (C, -C ₄ ) alkyl,

, wherein R ⁷ , R ⁹ and R ^{u are} as defined above,

, 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 ) alkanediyl group,

, 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 ) cycloalkyl, or R ³

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

'where m is an integer from 1 to 3,

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

R ¹⁹ and R ²⁰ both hydrogen, hydrogen and hydroxy, hydrogen and -N (R ^{, 8} ) ₂ or together = O, = NOH, = NOR ²¹ , where 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 is where

R ^{21 is} as defined above, or

- N— NN— CH ₃ ,

and pharmaceutically acceptable salts thereof.

The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner. The following formula shows the corresponding spellings for enantiomerically pure and racemic forms of the oxazolidone skeleton:

(A) (racemic) < ^B ) (enantiomeric)

Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid,

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

Salts which can furthermore be mentioned are salts with customary bases, such as, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g.

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

In the context of the invention, (C _r C ₈ ) -alkyl stands for straight-chain or branched alkyl having 1 to 8 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl and their branched-chain isomeric forms. The corresponding alkyl groups with fewer carbon atoms, such as (C _r C ₄ ) alkyl, are derived analogously from this definition. In general, (C _r C ₄ ) alkyl is preferred. Furthermore, the corresponding meanings of the alkyl moiety in functionalized groups are derived from this definition, such as (C ₂ -C ₅ ) alkynyl (eg ethynyl, propynyl etc.), (C ₂ -C ₄ ) alkenyl (eg vinyl, propenyl etc.), (C _r C ₄ ) acyl (e.g. formyl, acetyl, propionyl, butyryl etc.), (C _r C ₄ ) alkoxy (such as methoxy,

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

(C ₃ -C ₈ ) Cycloalkyl stands for a cyclic hydrocarbon residue with 3 to 8

Carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cyclopropyl, cyclopentane and cyclohexane rings are preferred.

Aryl generally 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 tricyclic group for R ³ includes carbomono-, bi- or tricyclic groups, if these are bi- or tricyclic radicals which can be fused to one another, linked via a bond or linked via two bonds (spirocyclic compounds), and these cycles, if there are more than two in the remainder, can be independently saturated, unsaturated and / or aromatic . This group can also be substituted or unsubstituted. Such groups are known per se in the prior art and are described, for example, in the prior art described above. Analogously, saturated, unsaturated and / or aromatic, optionally fused and / or substituted heteromono-, heterobi- or heterotricyclic groups for R ³ include heteromono-, heterobi- or heterotricyclic groups which have at least one heteroatom, preferably 1 to 3 heteroatoms selected from S, N or

Contain O, a, where the cycles can be condensed, can be connected to one another by a bond or, as in the case of the spiro compounds, can be connected to one another by two bonds. This definition also includes radicals R ³ in which carbocyclic and heterocyclic groups occur simultaneously. If there are more than two, the individual cycles can be independently saturated, unsaturated and / or aromatic and substituted. Such groups are also known per se from the prior art and are described, for example, by the prior art mentioned in the introduction. Specific examples of R ³ are shown in the following preferred embodiment of the compounds of the general formula

(I) described in the

R ^{3 is} selected from the groups of the formulas:

i ^st > where R is selected

from the group of substituents which consists of:

(a) hydrogen

(b) halogen,

(c) -OR ²⁴ , (d) -SR ²⁴ ,

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

(f) cyano, O

(g) 24, - O— C— R

H O

00

H O

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

O - COR ²⁴

(k)

(n) is (C, -C ₈ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which can optionally be substituted with one or more substituents, which come from the group of the abovementioned substituents

(a) to (m) are selected,

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

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 optionally be 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

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

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, which consists 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 the α-position, - -S (O) ₀ R ²⁸ , where o is an integer of 0, 1 or 2 and R ^{28 is} (C, -C ₄ ) alkyl or (C ₃ -C ₈ ) Is cycloalkyl, -NR ²⁹ R ³⁰ , in which R ²⁹ and R ^{30 are} identical or different, and hydrogen, (C, -C ₈ ) alkyl, (C, -C ₈ ) cycloalkyl, - (CH ₂ ) - 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 5 different and are hydrogen or (C, -C ₄ ) alkyl or together form a (C ₄ -C ₆ ) alkanediyl group , or R ²⁹ and R ³⁰ together - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ - or - (CH ₂ ) ₂ -N (R ³¹ ) - (CH ₂ ) ₂ -, wherein R ³ '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 optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, -NR ²⁹ R ³⁰ , wherein R ²⁹ and R ^{30 are} as above are defined, and

20

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,

Is (C ₃ -C ₈ ) cycloalkyl and 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 are} as defined above, -N ₃ ,

^H π, where R ^{38 is} (C, -C ₄ ) alkyl,

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

(h) _{5 where p ne whole Zam}

is 0 or 1 and R ³⁹ and R ⁴⁰ independently of one another (C _r C ₂ ) alkyl or together form a (C ₃ - C ₅ ) alkanediyl group,

O

10 (i) II, _R , where R is as defined above,

- S— C— R

(j) tetrazolyl,

(k) -NR ²⁹ R ³⁰ , wherein R ²⁹ and R ^{30 are} as defined above,

(1) -N (R ²⁹ ) COR ³⁸ , wherein R ²⁹ and R ^{38 are} as defined above,

15 (m) -NR ^{29 is} S (O) ₀ R ³⁸ , wherein R ²⁹ , o and R ^{38 are} as defined above,

(n) -CONR ²⁹ R ³⁰ , wherein R ²⁹ and R ^{30 are} as defined above,

(o) -COR ⁴¹ , wherein R ⁴¹

20 - hydrogen

(C, -C ₈ ) alkyl, which can optionally be substituted by one or more halogen atoms,

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

25 -OC (O) R ³⁷ , in which R ^{37 is in} each case as defined above, -NR ²⁹ R ³⁰ , in which R ²⁹ and R ³⁰ are as defined above, -S (O) ₀ R ²⁸ , where o and R ^{28 are} as defined above, (C ₃ -C ₈ ) cycloalkyl,

(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 are} as defined above,

-OR ²⁹ , wherein R ^{29 is} as defined above, or

H O is where 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 the same or different and (C, -C ₄ ) alkyl are or together form a (C ₂ -C ₃ ) alkanediyl group,

(r), wherein R ²⁹ , R ³⁵ and R ⁴ 'are as defined above

15 are renated, and R ^{44 is} 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 are} as above

are defined

(u), wherein m, R ²⁹ , R ³⁰ and R ³¹

are as defined above, or

R ^{3 is} a group of the formula:

where q is an integer from 0 to 4,

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

R ^{3 is} a group of the formula

where R ^{47 is} as defined above, or

R ^{3 is} a group of the formula:

is where Y is S or O, or

R ^{3 is} a group of the formula:

, wherein R ^{48 is} hydrogen, (C, -C ₆ ) alkyl, that

can 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 is} -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 is -C (O) R ⁵⁰ , wherein R ^{50 is} (C, C ₆ ) alkyl, or

R ^{3 is} a group of the formula:

R ^{3 is} a group of the formula:

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

R ^{3 is} a group of the formula:

₅ wherein R ⁵⁵ and R ^{56 are} independent of

are each other hydrogen, (C, -C ₄ ) alkyl, (C ₃ -C ₈ ) cycloalkyl or phenyl or together form a (C, -C ₆ ) alkanediyl group, or

R ^{3 is} a group of the formula:

a group of the formula:

or preferably

R is as defined above,

R 57 is selected from the group of substituents, which consists of:

(a) hydrogen,

(b) -NO ₂ ,

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

(e) _{where p? R39 and R4} O _as

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

-OR ²⁹ , wherein R ^{29 is} as defined above, or

H O

I is II, _Q , where R is as defined above, - N - C - R ²⁹

(k) wherein R ²⁹ , R ³ 'and R ^{41 are} as defined above

are,

15 (1) wherein R ²⁹ , R ³¹ and R ^{41 are} as above

are defined

(m), wherein m, R ²⁹ , R ³⁰ and R ³ '

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 are} as defined above,

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

5 are

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

(t) -C (R ¹ ) (OR ⁴³ ) (OR ⁴³ '), wherein R ^{41 is} as defined above, and R ⁴³ and R ⁴³ ' may be the same or different 10 and (C, -C ₄ ) Are alkyl or together form a (C ₂ -

C ₃ ) form alkanediyl group,

(u), wherein R ²⁹ , R ³⁵ and R ^{41 are} as defined above

and R ^{44 is} -R ²⁹ or -NR ²⁹ R ³¹ , wherein R ²⁹ and R ^{31 are} 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 the 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 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

can form a six-membered carbocyclic ring.

Compounds of the general formula (I) in which

R ^{1 is} -OR ⁴ , in which R ^{4 is} (C, -C ₈ ) alkyl, or -NHR ⁵ , in which 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,

, wherein R ^{7 is} (C _r C ₄ ) alkyl and R ^{8 is} -OR ^{7 '} , where R ^{7' is} as defined above,

, wherein R ^{11 is} as defined above, R ^{17 is} hydrogen and

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

Pyridyl or

is where Y is S or O.

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

The invention further relates to a process for the preparation of the compounds of formula (I) and their pharmaceutically acceptable salts, in which

a) compounds of the formula (II)

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

wherein R ^{4 is} as defined above, are reacted to give compounds of the formula (Ia)

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

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

(b) compounds of the general formula (II)

wherein R ² and R ^{3 are} as defined above, are first in inert solvents 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, reacted to obtain compounds of formula (Ib)

wherein R ² , R ³ , R ⁵ or R ^{6 are} as defined above, or

(c) compounds of the general formula (II)

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, reacted to obtain compounds of formula (I), or

(d) compounds of the general formula (II)

wherein R ² and R ^{3 are} as defined above, are reacted with ethyl dithiocarboxylates and triethylamine and in the case R ¹ = -NR ⁵ R ⁶ with thioisocyanates in inert solvents in order to

Obtaining compounds of formula (I).

The compounds of the invention find use as medicaments.

The invention therefore also relates to pharmaceuticals

Compositions comprising at least one compound of the invention in admixture with at least one pharmaceutically acceptable carrier, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of 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 prior art analog compounds, as shown by comparative examples 1 and 2, which is extremely surprising.

For this purpose, the MIC values were determined using the microdilution method in BH medium. Each test substance was dissolved in the nutrient medium. A series of concentrations of the test substances was created in the microtiter plate by serial dilution. Overnight cultures of the pathogens were used for inoculation, which were previously diluted 1: 250 in the nutrient medium. To 100 μl of the diluted active ingredient

Nutrient solutions were given 100 μl inoculation solution. The microtiter plates were incubated at 37 ° C and read after about 20 hours or after 3 to 5 days. The MIC value (μg / ml) indicates the lowest active substance concentration at which no growth was discernible.

The following results were found:

MIC values (μg / ml):

The compounds according to the invention have a broad antibacterial spectrum, especially against gram-positive germs and some gram-negative bacteria, as well as mycobacteria, corynebacteria, Haemophilus influenzae and anaerobic germs.

These properties enable their use as chemotherapeutic agents in human and veterinary medicine.

The compounds according to the invention are active against a broad spectrum of microorganisms. With their help, gram-positive germs, gram-negative bacteria and bacteria-like microorganisms such as mycoplasmas can be combated and the diseases caused by these pathogens can be prevented, improved and / or cured.

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 that are caused by such pathogens. The active ingredient (s) can optionally also be in microencapsulated form in one or more carriers.

The therapeutically active compounds should preferably be present in the pharmaceutical compositions listed above in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95% by weight of the total mixture.

In addition to the compounds according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

In general, both in human and in veterinary medicine, it has proven to be advantageous to use the active compound (s) according to the invention 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 Single doses to be administered to achieve the desired results. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg, body weight.

The compounds of the invention can be used for the purpose of expanding the

Range of effects and in order to achieve an increase in effectiveness, can also be combined with other antibiotics.

Examples Example 1

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

140 mg (0.46 mmol) (5S) -3- (3-fluoro-4-morpholinylphenyl) -5-aminomethyl-oxazolidin-2-one, 110 mg (0.92 mmol) thionocarbonylmonomethylmonothiomethyl ester and 0.2 ml ( 1.15 mmol) of Hunig base are stirred in 5 ml of methanol overnight at room temperature. It is concentrated and purified on silica gel (dichloromethane / methanol gradient). Yield: 60 mg, R _F = 0.87 (dichloromethane / methanol 100: 7)

Analogously to Example 1, the amines known from the literature become the following

Get examples:

Example 10

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

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

Calcium carbonate and 0.15 ml (2 mmol) thiophosgene added. The mixture is stirred overnight at room temperature, the organic phase is separated off and the aqueous phase is extracted three times with chloroform. The combined organic phases are dried and concentrated. The intermediate is taken up in 38 ml of methanol and mixed with 19 ml of 2N ammonia in methanol. The mixture is stirred overnight at room temperature, 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 amines known from the literature:

Claims

claims

1. Compounds of the general formula (I):

wherein

-NR ⁵ R ⁶ , in which R ⁵ and R ^{6 are} identical or different and denote hydrogen, phenyl, pyridyl or (C, -C ₈ ) alkyl, which is optionally substituted by N-linked Moφholin,

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

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

wherein R ^{7 is} as defined above, and R ⁸ -NR ⁷ R ⁹ , wherein

R ^{7 'is} 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 halogen,

(C ₂ -C ₅ ) alkynyl,

R _{; which} is defined in R ⁷ as above,

wherein R ⁷ and R ^{9 are} as defined above, and R "

Is hydrogen or (C, -C ₄ ) alkyl,

wherein R ⁷ , R ⁹ and R ^{11 are} as defined above,

, in which 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 ) alkanediyl group,

, wherein R and R are as defined above, and R ¹⁵ and

R ¹⁶ independently of one another is hydrogen, (C, -C ₄ ) alkyl or (C ₃ -

C ₈ ) are cyclo-alkyl, or

R ³

_{istj wherein R} ιι 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

where m is an integer from 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 hydroxy, hydrogen and -N (R ^{, 8} ) ₂ or together = O, = NOH, = NOR ²¹ , where R ²¹ (C _r

O

II

C ₄ ) is alkyl, - = N "- O— C ^ - R '*, w" „ori_-n_ R _n ² ₂ ² ₂ 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

are,

and pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1, wherein

R ^{3 is} selected from the groups of the formulas:

or is where R ^{23 is} selected

from the group of substituents which consists of:

(a) hydrogen

(b) halogen, (c) -OR ²⁴ ,

(d) -SR ²⁴ ,

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

(f) cyano,

O

(g) __ ₀ _c-R ²⁴ >

-OR ²⁴

00

oo = ¹

O

II

(m) - c- -R ³²

(n) ((CC ,, - CC ₈₈ )) AAllkkyyll or (C ₃ -C ₈ ) cycloalkyl, which can optionally be substituted with one or more substituents, which from the group of the above-mentioned substituents (a) m) are selected, (q) is phenyl which may optionally be substituted by one or more substituents which are selected from the group of the above-mentioned substituents (a) to (n),

wherein R ²⁴ and R ^{24 'are} independently selected from:

(a) hydrogen,

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

exists, or

Is phenyl or pyridyl, which may optionally be substituted by 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, which consists of:

(a) hydrogen,

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

H ^ιπ , wonn m as defined above and p is 0 or 1 and R ³² and R ^{33 are the} same or different and are hydrogen or (C, -C ₄ ) alkyl or together form a (C ₄ -C ₆ ) alkanediyl group, or R ²⁹ and R ³⁰ together - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ - or - (CH ₂ ) ₂ -N (R ³¹ ) - (CH ₂ ) ₂ -, in which 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 optionally substituted with one or more substituents selected from the group consisting of Is halogen, hydroxy, cyano, -NR ²⁹ R ³⁰ , wherein R ²⁹ and R ^{30 are} as defined above, and

15

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,

Is (C ₃ -C ₈ ) cycloalkyl and R ^{36 is} hydrogen, (C, -

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

25 f 8, wherein R ^{38 is} (C, -C ₄ ) alkyl,

- N-Ö-R ³⁸ that optionally with one or more

Halogen atoms can be substituted, (h) _{where p is an integer}

is 0 or 1 and R ³⁹ and R ⁴⁰ independently of one another form (C, -C ₂ ) alkyl or together form a (C ₃ - C ₅ ) 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 are} as defined above,

(1) -N (R ²⁹ ) COR ³⁸ , wherein R ²⁹ and R ^{38 are} as defined above,

10 (m) -NR ^{29 is} S (O) ₀ R ³⁸ , wherein R ²⁹ , o and R ^{38 are} as defined above,

(n) -CONR ⁹ R ³⁰ , wherein R ²⁹ and R ^{30 are} as defined above,

(o) -COR ⁴¹ , wherein R ⁴¹

15 - hydrogen

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

20 -OC (O) R ³⁷ , in which R ^{37 is in} each case as defined above, -NR ²⁹ R ³⁰ , in which R ²⁹ and R ^{30 are} as defined above, -S (O) ₀ R ²⁸ , in which 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 are} as defined above, -OR, where R is as defined above, or

| ii is where 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 ' may be the same or different and (C _r C ₄ ) alkyl or together form a (C ₂ -C ₃ ) alkanediyl group,

(r), wherein R ²⁹ , R ³⁵ and R ^{41 are} as defined above

are renated and R ^{44 is} 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 are} as above

are defined

, wherein m, R ²⁹ , R ³⁰ and R ³

are as defined above, or

a group of the formula:

where q is an integer from 0 to 4,

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

R ^{3 is} a group of the formula:

where R ^{47 is} as defined above, or

R ^{3 is} a group of the formula:

is where Y is S or O, or

R ^{3 is} a group of the formula:

, wherein R ^{48 is} hydrogen, (C, -C ₆ ) alkyl, that

can 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 is} -OR ⁴⁹ , in which r is as defined above, and R ^{49 is} hydrogen, (C, -C ₆ ) alkyl, - (CH ₂ ) _r - (C ₆ -C ₁₀ ) aryl, in which r is as defined above, or -C (O) R ⁵⁰ , wherein R ^{50 is} (C, - C ₆ ) alkyl, or

R ^{3 is} a group of the formula:

R ^{3 is} a group of the formula: wherein R ⁵¹ to R ^{54 are} independent

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

R ^{3 is} a group of the formula:

, where R> 55 and .dA R D5 ⁵ 6 ⁰ independently of

R ^{3 is} a group of the formula:

R ^{3 is} a group of the formula: or preferably

R is as defined above,

R 57 is selected from the group of substituents, which consists of:

(a) hydrogen,

(b) -NO ₂ ,

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

(d) tetrazolyl, (e)

_n R ³⁹ R ⁴⁰ , where p, R ³⁹ and R are like

are defined above,

(0 -SH (G)

O - S - C - R ³⁸ , where 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 are} 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

H O

I is II, _q , where R is as defined above, - N - C - R ²⁹

10 (k)

wherein R ²⁹ , R ³¹ and R ^{41 are} as above

are defined

(1)

wherein R ²⁹ , R ³¹ and R ^{41 are} as above

15 are defined,

(M)

and R ³¹

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 are} as defined above, (r)

R ²⁹ O _| { _{j R} 38 ₅ wherein R ²⁹ and R ^{38 are} as defined above,

5 (s)

, wherein o, R ²⁹ and R ³⁸ as above

are defined, (t) -C (R ⁴¹ ) (OR ³ ) (OR ⁴³ '), wherein R ⁴ ' is as defined above, and R ⁴³ and R ⁴³ 'may be the same or different 10 and (C, -C ₄ ) are alkyl or together form a (C ₂ -

C ₃ ) form alkanediyl group,

(u)

where R ²⁹ , R ³⁵ and R ^{41 are} as defined above

are renated, and R ^{44 is} -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 is not in the 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 are 25 as defined above,

(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

is, R ⁵⁷ and R ⁵⁸ together

can form a six-membered carbocyclic ring.

3. Compounds according to claim 1 or 2, wherein

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

R ^{2 is} hydrogen or halogen,

OR ⁷ R ^{3 Ü — R} , wherein R ^{7 is} (C, -C ₄ ) alkyl,

, wherein R ^{7 is} (C, -C ₄ ) alkyl and R ^{8 is} -OR ^{7 '} , where R ^{7' is} as defined above,

, wherein R ^{11 is} as defined above, R ^{17 is} hydrogen and

R ^{18 is} -CN or -NO ₂ or R ¹⁷ -CN or -NO ₂ and R ^{18 is} hydrogen,

Pyridyl or \ / - is where Y is or O is.

4. Compounds according to claim 1, 2 or 3, which are selected from the group of compounds consisting of:

A process for the preparation of the compounds of formula (I) according to claim 1 and their pharmaceutically acceptable salts, wherein

a) compounds of the formula (II)

wherein R ² and R ^{3 are} as defined in claim 1, or their salts with compounds of the general formula (III)

wherein R ^{4 is} as defined in claim 1, are reacted to give compounds of the formula (Ia)

wherein R4 is as defined in claim 1, or to obtain a salt thereof or

(b) compounds of the general formula (II)

wherein R> 2 "and" JR τ »3 are as defined in claim 1, first in inert solvents with S = CC1 ₂ and then with compounds of the general formula (III)

H-NR ³ R ^Ö (III)

wherein R ⁵ and R ° are as defined in claim 1, are reacted to obtain compounds of formula (Ib)

wherein R ² , R ³ , R ⁵ or R ^{6 are} as defined in claim 1, or

(c) compounds of the general formula (II)

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 the formula (I), or

(d) compounds of the general formula (II)

wherein R ² and R ^{3 are} as defined in claim 1, with ethyldithiocarboxylates and triethylamine and in the case R ¹ = -NR ⁵ R ⁶ with thioisocyanates in inert solvents to give 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 the treatment of bacterial infections in humans or animals.