SK8572000A3 - Benzamine derivatives - Google Patents

Abstract

The invention relates to novel compounds of formula (1) wherein X, Y, W, R<1>, R<2>, R<3> and R<4> have the meaning cited in Claim 1. The inventive compounds are inhibitors of coagulation factor Xa and can be used in prophylaxis and/or therapy for thromboembolic diseases.

Description

A benzamidine derivative, a process for its preparation, its use and a pharmaceutical composition containing it

Technical field

The invention relates to a benzamidine derivative of the formula I,

R ⁴ (I) wherein is

R ^{1 is} -C (= NH) -NH 2, which optionally has one substituent selected from -COA, -CO- [C (R ⁵ ) 2] _m -Ar, -COOA, -OH or is a group

O · y-NH o,

N or

R ² is hydrogen, A, OR ⁵ , N (R ⁵ ) ₂ , NO ₂ , CN, Hal,

NR ⁵ COA, NHCOAr, NHSO 2A, NHSO 2 Ar, COOR ⁵ , CON (R ⁵ ) 2, COHNAr, COR ⁵ , COAr, S (O) _n A or S (O) _n Ar,

R ³ R ⁵ or - [C (R ⁵ ) ₂ ] _m -COOR ⁵ ,

R ³ and X together also -CO-N to form a five membered ring, where R ^{3 is} -C -CO and X is N,

R ⁴ A, cycloalkyl, ~ [C (R ⁵ ) 2] m -Ar, - [C (R ⁵ ) 2] _m -Het or -CR ⁵ = CR ⁵ -Ar,

-R ⁵ is hydrogen, A or benzyl,

X is O, NR ⁵ or CH _2,

Y oxygen atom, NR ⁵ , N [C (R ⁵ ) ₂ ] _m -Ar, ^{N [c (R 5)} 2 ^] m ^Het '

N [C (R ⁵ ) ₂ ] _m -COOR ⁵ , -nn-,

N [C (R) ₂ ] _m -CON (R ⁵ ) 2, N [C (R ⁵ ) 2] _m -CONR ⁵ Ar or N [C (R ⁵ ) ₂ ] _m -CONAr ₂ ,

W bond, -SO ₂ -, -CO-, -C00- or -CONR ⁵ ,

A is an alkyl group having 1 to 20 carbon atoms in which one or two CH ₂ groups are optionally replaced by an oxygen or sulfur atom, -CR ⁵ = CR ⁵ - groups and / or one to seven hydrogen atoms by fluorine atoms,

Ar is a phenyl or naphthyl group unsubstituted or substituted by one, two or three of R ¹ , A, Ar ¹ , OR ⁵ , N (R ⁵ ) 2, NO 2, CN, Hal, NHCOA, NHCOAr ', NHSO2A, NHSO2Ar ', COOR ⁵ , CON (R ⁵ ) 2, CONHAr', COR ⁵ , COAr ', S (O) _n A and S (O) _n Ar,

Ar 1 phenyl or naphthyl unsubstituted or substituted by one, two or three of R ¹ , A, OR ⁵ ,

N (R ⁵ ) 2, NO 2, CN, Hal, NHCOA, COOR ⁵ , CON (R ⁵ ) 2, COR ⁵ , COAr 'and S (O) _n A,

Het unsubstituted or one or more of Hal, A, Ar ', OR ⁵ , COOR ⁵ , CN, N (R ⁵ ) ₂ , NO ₂ , NHCOA, NHCOAr' and oxo substituted single or double ring saturated or unsaturated ring a system containing one, two, three or four identical or different heteroatoms such as nitrogen, oxygen and sulfur;

Hal is fluorine, chlorine, bromine or iodine, m is 0, 1, 2, 3 or 4, n is 0, 1 or 2, and salts thereof.

The invention also relates to optically active forms, racemates, diastereomers, as well as hydrates and solvates of these compounds.

BACKGROUND OF THE INVENTION

Aromatic amidine derivatives having antithrombotic activity are known, for example, from European Patent Specification No. 0 540051 B1. Cyclic guanidines for the treatment of thromboembolic diseases are known, for example, from WO 97/08165. Aromatic heterocyclic compounds having inhibitory activity for factor Xa are known, for example, from WO 96/10022.

SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds having valuable properties, in particular for the manufacture of medicaments.

SUMMARY OF THE INVENTION

It has now surprisingly been found that the aforementioned compounds of formula I, wherein the individual symbols are as defined above, and their salts have good pharmacological properties with good tolerability. In particular, they exhibit Factor Xa inhibitory properties and may therefore be used to treat and protect against thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angioplasty restenosis, and gastric pain during walking or on prevention of these conditions.

The antithrombotic and anticoagulant activity of the compounds of the invention is related to the inhibitory action on activated clotting protease, known as factor Xa, or to the inhibition of other activated serine proteases such as factor VIIa, factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex blood clotting process. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin cleaves fibrinogen into fibrin monomers which by crosslinking contribute elementally to thrombus formation. Thrombin activation may lead to the onset of thromboembolic diseases. However, inhibition of thrombin may inhibit the formation of fibrin involved in thrombus formation. For example, inhibition of thrombin can be measured by the method described by G.F. Cousins et al. (Circulation 94: 1705-1712, 1996).

J

Inhibition of factor Xa may prevent the formation of thrombin. The compounds of formula I and their salts interfere with the inhibition of factor Xa in the blood coagulation process, thereby inhibiting thrombus formation.

In addition, the compounds of formula I may be inhibitors of the clotting factor VIIa, IXa and thrombin of the blood clotting cascade.

Inhibition of factor Xa by the compounds of the invention and measurement of anticoagulant and antithrombotic activity are possible by known methods in vitro and in vivo. A suitable method is described by J. Hauptmann et al. (Thrombosis and Haemostasis 63: 220-223 (1990)).

Measurement of factor Xa inhibition is also possible by the method of T. Hara et al. (Thromb. Haemostas. 1994, 71, 314-319).

The clotting factor VIIA, upon binding to tissue factor, initiates the extrinsic fraction of the clotting cascade and contributes to the activation of factor X to factor Xa. Inhibition of Factor VIIa thus prevents the formation of Factor Xa and consequently the formation of thrombin.

Inhibition of factor VIIa by the compounds of the invention and measurement of anticoagulant and antithrombotic activity can be detected by known in vitro or in vivo methods. A conventional method for measuring factor VIIa inhibition is described, for example, by H.F. Ronning et al. (Thrombosis Research 84: 73-81, 1996).

The compounds of the formula I can be used as medicament active compounds in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina, restenosis after angioplasty and calf pain. muscle while walking.

Accordingly, the present invention provides compounds of formula I and salts thereof. A process for the preparation of a compound of the formula I and salts thereof according to the invention consists of:

(a) is released from its functional derivative by the solvolysis or hydrogenolysis agent by:

(i) the amidino group of the oxadiazole derivative is liberated by hydrogenolysis; (ii) the conventional amino-protecting group is replaced with hydrogen by treatment with a solvolysis or hydrogenolysis agent, or the conventional-protected amino group is liberated, or

b) for the preparation of a compound of formula I wherein R ^{1 is a} group

^{ V \ ° or N = \

CH,

R ³ together with X is -CO-N- to form a five-membered ring,

Y group

^r5 . R ⁵

W is -SO ₂ - or -CO-, and R ² and R ⁴ are as defined above, with a compound of formula II (II) wherein R ^{1 is a} group

ABOUT

R ³ together are X is -CO-N to form a five member ring,

Y group

R ^5, R ⁵ and R ² and R ⁵ are as defined above, reacted with a compound of formula III

R ⁴ -W-L (III) where is

W is -SO2- or -CO-,

L is a chlorine, bromine, iodine or νοϊηύ atom or a reactive functionally modified hydroxyl group; and

R ⁴ is as defined above, or

c) for the preparation of a compound of formula I wherein R ^{1 is} {

or

R ³ together with X is -CO-N- to form a five-membered ring,

Y an oxygen atom,

W bond and R ² and R ⁴ are as defined above, with a compound of formula II

wherein R ^{1 is} / N.

HN-4 O or

R ³ together with X is -CO-N- to form a five-membered ring,

Y is O and R ² is as defined above, is reacted with a compound of formula IV

R ⁴ - W - OH (IV) wherein W represents a bond a

R ⁴ is as defined above, or

d) for the preparation of a compound of formula I wherein R ^{1 is} {

or

R ³ together with X is -CO-N- to form a five-membered ring,

Y group

W binding,

R ⁴ - - [C (R ⁵ ) 2] mAr or - [C (R ⁵ ) 2] _m Het, m zero and R ² is as defined above, with a compound of formula V

(v) wherein R ^{1 is a} group

R ³ together with X is -CO-N- to form a five-membered ring,

L is a chlorine, bromine, iodine or νοϊηύ atom or a reactive functionally modified hydroxyl group; and

R ² is as stated above, is reacted with a compound of formula VI

R ⁴ -W-Y-H (VI) wherein W is a bond,

Y group - N N · \ _f

R ⁴ group - [C (R ⁵ ) 2] mAr or ~ [C (R ⁵ ) 2] _m Het am zero, or

e) for the preparation of a compound of the general formula I, wherein it is

R &^lt; ¹ &gt;

or / .N.

H * 0

N = \

CH,

R ³ together with X is -CO-N- to form a five-membered ring,

Y group

NR ^5, -NN-, -N

/

N \

or

R ⁵

R ⁵

R ⁵

W is -CONH-, and R ² and R ⁴ is as defined above, a compound of formula II

Y '.H

(II) where is

R ¹ group

Í ~~ ^ ^N 'O or?

'' 'CH

R ³ together are X is -CO-N to form a five member ring,

Y group

R 5 and R 5 are as defined above, reacted with a radical of formula VII

R ⁴ - N = C = O (VII) wherein R ⁴ is as defined above, or

f) for the preparation of a compound of formula I wherein R ^{1 is a} group

R ³ together are X is -CO-N to form a five member ring,

Y is -N [C (R ⁵ ) ₂ ] _m -COOR ⁵ ,

W is a -S0 ₂ ~

R ² and R ⁴ are as defined above, a compound of formula II

wherein R ^{1 is a} group

R ³ together are X is -CO-N to form a five member ring,

Y is -N [C (R ⁵ ) 2] _m -COOR ⁵ a

R ² and R 5 is as defined above, reacting the compoun ds of formula VIII

R ⁴ - SO ₂ - L (VIII) where denotes

L is a chlorine, bromine, iodine or νοϊηύ atom or a reactive functionally modified hydroxyl group; and

R ⁴ is as defined above, or

g) for the preparation of a compound of formula I wherein X is NH,

R ³ = H,

R ¹ , R ² , R ⁴ , Y and W are as defined above, the compound of formula (I) is released from its oxazolidinone derivative by a solvolysis or hydrogenolysis agent, or

h) for the preparation of a compound of formula I wherein R ^{1 is} -C (= NH) -NH ₂ , and the other symbols are as defined above, the cyano group is changed to an amidino group; or

(i) in the compound of formula (I), one or more Y, R ¹ , R ² , R ³ and / or R ⁴ groups is changed to one or more other groups Y, R ¹ , R ² , R ³ and / or R ⁴ , whereby

i) the ester group is hydrolyzed to a carboxyl group, ii) the nitro group is reduced, iii) the amino group is acylated and / or

k) the base or acid of formula I is converted to a salt.

When some residues in the compound occur several times, for example the group R ⁵ , these residues are the same or different, i.e., they are independent of one another.

Individual symbols or indices L, W, X, Y, R ¹ , R ² ,

R ³ , R ⁴ , R ^{5 and} m have the meanings indicated in the general formulas I to VIII, unless expressly stated otherwise.

Solvates are addition compounds with, for example, organic inert solvents such as alcohols such as methanol, ethanol or propanol.

In the general formulas, A is a straight or branched chain alkyl group having 1 to 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms such as are preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and also pentyl, 1-, 2- or 314 methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,

1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or

2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1-, 1,2- or 1,2,2-trimethylpropyl, heptyl, octyl nonyl or decyl.

A is furthermore, for example, trifluoromethyl, pentafluoroethyl, allyl or crotyl.

The symbol OR ⁵ is hydroxy, benzyloxy, or OA, the OA is preferably methoxy, ethoxy, propoxy, butoxy or hexyloxy.

Cycloalkyl is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group. Cycloalkyl means, for example, a radical of a bicyclic terpene, such as a 3-menthyl group and very particularly a camphor-10-yl group.

The symbol COR ⁵ represents an acyl group, preferably a formyl, acetyl, propionyl group or a butyryl, pentanoyl or hexanoyl group.

Hal is preferably fluorine, chlorine or bromine, but also iodine.

R @ ² is preferably hydrogen, fluorine, chlorine, bromine or iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylthio, sulfonio, sulfonio, sulfonio, sulfonio, sulfo, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, phenylsulfonyl, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, and also acyl or benzoyl. In particular, R ² is hydrogen.

The symbol R ³ is preferably A, benzyl, a group of the formula CH ₂ COOH or CH ₂ COOA, but especially hydrogen.

The symbol R ⁴ is preferably, e.g., A, cycloalkyl, Ar, CH ₂ Ar, CH ₂ CH ₂ Ar, CH ₂ Het, CH ₂ CH ₂ Het or CH = CH Ar.

R @ ⁵ represents a hydrogen atom, a group A, a benzyl group, in particular a hydrogen atom.

X represents an oxygen atom, an imino group, a NA group or an N-benzyl group, and also CH ₂ .

R ³ together with X is also -CO-N, forming a five-membered ring with the -CH ₂ -CH-O- group.

Y is preferably, for example O, NH, N-methyl, N-ethyl, N-N, _N-CH2-Ar, N-Het, _N-CH2-Het, N-COOA, _N-CH2 -COOA, N-CH ₂ -COOH, N-CH ₂ -COObenzyl, a group

N N—, —N

/ ^R \ of ^R5

IN' '

NCH ₂ -CONH ₂ , NCH ₂ -CONHA, NCH ₂ -CONA _2, NCH ₂ -CONR ⁵ Ar or NCH ₂ -CONAr ₂ .

W is preferably, for example, a bond, -SO ₂ or -CO-, and also -COO- or -CONH-.

Ar is preferably unsubstituted phenyl or naphthyl, preferably monosubstituted, disubstituted or trisubstituted phenyl or naphthyl by A, fluorine, chlorine, bromine or iodine, hydroxyl, methoxy, propoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, ethoxy, pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio group, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulphinyl, phenylsulphonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido , butylsulfonamido, phenylsulfonamido, 4- (methylphenyl) sulfonamido, carboxymethoxy, carboxyethoxy, methoxycarbone onylmethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, acyl and benzoyl.

Ar is therefore preferably, for example a ^-, painting, p-tolyl, o-, painting, p-ethylphenyl, o-, painting, p-propylphenyl, o-, painting p-isopropylphenyl, o-, - or p-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m or p- (N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o ^-, m- or p- (N-ethylamino) phenyl, o-, m- or p (N, N-diethylamino) phenyl, o- , m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o- , m- or p-methylsulfonylphenyl, o-, m- or p- (phenylsulfonylphenamido) phenyl, ο-, m- or p- (methylsulfonamido) phenyl, o-, m- or p-methylthiophenyl, further preferably a group

2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-,

2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-,

2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino 4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or a group 3-nitro-4Ν, Ν-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,52,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2 , 4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4 -bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,

3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar is particularly preferably unsubstituted or monosubstituted, disubstituted or trisubstituted eh phenyl groups from amino, OR ^5, Hal, CN, alkyl having 1 to 10 carbon atoms, trifluoromethyl, CH ₃ SO _{2, OCF3} , acetamido, -C (= NH) -NH ₂ , methoxycarbonyl or ethoxycarbonyl, and in each case one substituent selected from the group consisting of Hal, dimethylamino and (C 1 -C 6) alkoxy substituted naphthyl or unsubstituted biphenyl.

In particular, Ar is, for example, phenyl or naphthyl, furthermore preferably o-, m- or ptolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p -isopropylphenyl, o-, m- or p-t-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m18 or p-nitrophenyl, ο-, m- or p-aminophenyl, o-, malebo p- (N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o -, m- or p-methoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- ( N, N-diethylamino-phenyl, o-, m- or p-acetylphenyl, o-, male- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, male- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, p-methylsulfonylphenyl.

Het is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl,

1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl,

2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-,

3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazole- 1-, 3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-yl -pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4 -, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-,

6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,

5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-,

7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2- , 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl and further preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic groups may be partially or fully hydrogenated.

The symbol Het may also be, for example, 2,3-dihydro-2-, -3-, -4- or 5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2. - or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-3-, -4- or 5-pyrrolyl, 2,5- dihydro-1-, 2-, -3-, -4- or

5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-,

-2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4 or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4 -dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl , 1-,

2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2, 3,4-tetrahydro-l-,

-2-, -3-, -4-, -5-, -6-, -7- or 8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4- , -5-, -6-, -7- or 8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzotl-4] oxazinyl group further preferably a group 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or -6-yl, 2,3 (2) oxomethylenedioxy) phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

The Het group is unsubstituted or has one or more substituents selected from the group consisting of Hal, A,

Ar 1, COOR ⁵ , CN, N (R ⁵ ) ₂ , NO ₂ , Ar-CONH-CH ₂ . The term several means two, three, four or five. Het is particularly preferably unsubstituted or one or more substituents selected from the group consisting of Hal, A, phenyl, OR ⁵ , COOR ⁵ , CN, N (R ⁵ ) ₂ , NO ₂ , NHCOA, NHCOphenyl and / or oxo-substituted thiazole -2-, -4- or -5-yl, thiophen-2- or -5-yl, chroman-6-yl, pyridin-2-, -3- or -4-yl, pyrimidin-2- or -5-yl , benzothiophen-2-yl, 1,3-benzodioxol-4- or -5-yl, 1,4-benzodioxan-5 or -6-yl, 2,1,3-benzothiadiazol-4- or -5-yl.

The compounds of formula I may have one or more chiral centers and may therefore be in different stereoisomeric forms. Formula I includes all these forms.

Accordingly, the invention relates in particular to a compound of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula (I) are the following compounds of formulas (Ia) to (Ii), wherein not specifically indicated are as defined in formula (I), wherein in formula (Ia) R ² is hydrogen, 1b R ³ R ⁵ or - (CH _{2). m} -COOR ⁵ , 1c R ⁴ A, cycloalkyl scale, - (CH ₂ ) _n -Ar, - (CH ₂ ) _m Het or -CH = CH-Ar,

Id Y is O, NR ^5, N _{(CH2) m-Ar,} N (CH _{2) m} Het

N (CH ₂ ) _m -COOR ⁵ , - (N, N).

- N

/ R5 R ^{5 N} \ _. ^or

R ⁵

Ie A

If Ar

Ie A

If Ar

Ig Ar '

Ih Het

Ig Ar '

Ih Het

Ii R ¹

R ^{1 is} a C 1 -C 20 alkyl group in which one or two CH ₂ groups are optionally replaced by -CH = CH- groups and / or one to seven hydrogen atoms by a fluorine atom, a phenyl or naphthyl group unsubstituted or substituted by one, two or three of R ¹ , A, phenyl, OR ⁵ , N (R ⁵ ) 2, NO 2, CN, Hal, NHCOA, NHCOphenyl, NHSO2A, NHS02phenyl, COOR ⁵ , CON (R ⁵ ) 2, CONHphenyl , COR ⁵ , COphenyl, S (O) _n A and S (O) _n Ar, a phenyl group, unsubstituted or one or more of Hal, A, phenyl, OR ⁵ , COOR ⁵ , CN, N (R) ⁵ ) ₂ , NO ₂ , NHCOA, NHCOphenyl and oxo substituted thiazol-2-, -4- or -5-yl, thiophen-2- or -5-yl, chroman-6-yl, pyridin-2-, -3- or -4-yl, pyrimidin-2- or -5-yl, benzithiophen-2-yl, 1,3-benzodioxol-4- or -5-yl, 1,4-benzodioxan-5- or -6-yl, 2, l, 3-benzotiadiazol- 4- or -5-yl, -C (= NH) -NH ₂ optionally having one of -COA, -CO- (CH ₂ ) _m Ar-, COOA, OH or a substituent;

CH

R ² is H,

R ³ R ⁵ or - (CH ₂₎ ⁵ -'COOR _LTL,

R ³ and X together also -CO-N to form a five-membered ring,

R ⁴ A, cycloalkyl, - (CH ₂ ) _n -Ar, - (CH ₂ ) _m Het or -CH = CH-Ar,

R @ ⁵ is hydrogen, A or benzyl,

X is O, NR ⁵ or CH _2,

Y is O, NR ^5, N _{(CH2) m-Ar,} N (CH _{2) m} Het

N (CH ₂ ) _m -COOR ⁵ .

/ R ⁵ R ^{5 N} \ / xm ^Z \ ₅ or NV / ^N \

W bond, -SO ₂ -, -CO-, -C00- or -CONH,

A is an alkyl group having 1 to 20 carbon atoms in which one or two CH ₂ groups are optionally replaced by -CH = CH- groups and / or one to seven hydrogen atoms by fluorine atoms,

Ar is phenyl unsubstituted or substituted by one, two or three of NH ₂ , OR ⁵ , Hal, CN, C 1 -C 10 alkyl, trifluoromethyl, CH ₃ SO ₂ , OCF ₃ , acetamido, - C (= NH) -NH ₂ , methoxycarbonyl and ethoxycarbonyl further denotes naphthyl unsubstituted or substituted by one of Hal, dimethylamino and methoxy or represents unsubstituted biphenyl,

Het unsubstituted or substituted by one or more of Hal, A, phenyl, OR ⁵ , COOR ⁵ , CN, N (R ⁵ ) ₂ , NO ₂ , NHCOA, NHCOphenyl and oxo substituted thiazole 23

2-, -4- or -5-yl, thiophen-2- or -5-yl, chroman-6-yl, pyridin-2-, -3- or -4-yl, pyrimidin-2- or -5- yl, benzithiophen-2-yl, 1,3-benzodioxol-4- or -5-yl, 1,4-benzodioxan-5- or -6-yl, 2,1,3-benzothiadiazol-4- or -5- yl.

The compounds of formula (I) and the starting materials for their preparation are prepared by known methods described in the literature (for example, in standard publications such as Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme Verlag, Stuttgart) under reaction conditions, which are known and suitable for the above reactions. It is also possible to use known variants which are not described here in greater detail.

The starting materials may optionally be formed in situ, i.e. they are not isolated from the reaction mixture, but the reaction mixture is immediately used to prepare compounds of formula I.

The compounds of formula I may be prepared by liberating from their functional derivatives by solvolysis, in particular hydrolyzing or hydrogenolyzing agents.

Preferred starting materials for solvolysis or hydrogenolysis are compounds which otherwise correspond to the above general formula (I), but instead have free amino or hydroxyl groups corresponding to protected amino or hydroxy groups, preferably compounds which, instead of a hydrogen atom which is bonded to a nitrogen atom, have an amino protecting group, especially compounds having an R'-N group instead of the HN group, wherein R 'is an amino protecting group, and / or compounds having a hydroxyl protecting group instead of a hydrogen atom in a hydroxyl group, e.g. -COOH have a -COOR group wherein R is a hydroxyl protecting group.

Preferred starting materials are also oxadiazole derivatives which can be converted to the corresponding amidino compounds.

The introduction of the oxadiazole group is accomplished, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformic acid ester, N, N'carbonyldiimidazole or acetic anhydride.

Several of the same or different amino and / or hydroxyl protecting groups may be present in the molecule of the starting material. If the protecting groups are different from each other, they can in many cases be selectively cleaved.

The term amino protecting group is well known and refers to groups which are suitable for protecting (blocking) the amino group from chemical reactions but which are readily removable when the desired reaction elsewhere in the molecule is carried out. Typically, such groups are unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are not critical. However, groups having 1 to 20, and in particular 1 to 8, carbon atoms are preferred. The term acyl is always understood in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC) and arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, CBZ, Fmoc, benzyl and acetyl.

The term hydroxy protecting group is also generally known and refers to groups which are suitable for protecting (blocking) the hydroxy group from chemical reactions but which are readily removable when the desired reaction elsewhere in the molecule is carried out. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups as well as alkyl groups. Since the hydroxyl protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not critical. However, groups having 1 to 20, and especially 1 to 10, carbon atoms are preferred. Examples of hydroxyl protecting groups are benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

Depending on the protecting group used, the release of the compounds of the formula I from their functional derivatives is successful, for example with strong acids, preferably trifluoroacetic acid (TFA) or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid. or with sulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are, for example, organic carboxylic acids, such as acetic acid; ethers such as tetrahydrofuran or dioxane; amides such as dimethylformamide (DMF); halogenated hydrocarbons such as dichloromethane; and also alcohols such as methanol, ethanol or isopropanol as well as water. Mixtures of these solvents may also be suitable. Trifluoroacetic acid is preferably used in excess without the addition of additional solvents, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 ^e C, preferably 15 to 30 "C (room temperature).

For example, the BOC, OBut, and Mtr groups may be conveniently cleaved with trifluoroacetic acid in dichloromethane or about 3-5% hydrochloric acid in dioxane at 15 to 30 ° C, the FMOC group with a 5 to 50% solution of dimethylamine, diethylamine or piperidine in dimethylformamide at 15 up to 30 ”C.

Hydrogenolytically removable protecting groups (e.g., CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as coal). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group performs well, for example, on 5 to 10% palladium on carbon in methanol or ammonium formate (instead of hydrogen) in the presence of palladium on carbon in a methanol / dimethylformamide system at a temperature of 20 to 20%.

30 ° C.

Compounds of formula (I) wherein

R ¹ group

CH.

R ³ together with X is -CO-N- to form a five-membered ring,

Y a group of formula

W is -S0 ₂ "or -C0a R ² and R ⁴ are as stated above, can preferably be obtained by reacting compounds of formula II are reacted with compounds of formula III.

In the compounds of formula III, L is preferably chlorine, bromine, iodine or νοϊηύ or a reactive modified hydroxyl group, such as an activated ester group, an imidazolide group or a C 1 -C 6 alkylsulfonyloxy group (preferably a methylsulfonyloxy group) or arylsulfonyl group 6 up to 10 carbon atoms (preferably phenylsulfonyloxy or p-tolylsulfonyloxy).

The reaction is generally carried out in an inert solvent in the presence of an acid binding agent, preferably in the presence of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other weak alkali metal or alkaline earth metal salt, preferably potassium, sodium, calcium or cesium. The addition of an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline, or an excess of the amine component of the formula II or the alkylation derivative of the formula III can also be favorable. The reaction time is, depending on the reaction conditions, a few minutes to 14 days, the reaction temperature being about 0 to 150 ° C, typically 20 to 130 ° C.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulphide; organic carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; or mixtures of these solvents.

The starting compounds of the formulas II and III are generally known. If they are new, they can be prepared by known methods.

Compounds of formula I wherein R ^{1 is a} group

R ³ together with X is -CO-N- to form a five-membered ring,

Y is an oxygen atom

W bond and R ² and R ⁴ are as defined above, can preferably be obtained by reacting compounds of formula II wherein Y is O with a compound of formula IV according to the Mitsunobe reaction in the presence of, for example, triphenylphosphine and diethyl azodicarboxylate in an inert solvent.

The starting compounds of the formula II in which Y is oxygen and IV are generally known. If new, they can be prepared by known methods.

Compounds of formula I wherein R ^{1 is a} group

or

R ³ together with X is -CO-N- to form a five-membered ring,

Y a group of formula

W binding

The R ⁴ group - [C (R ⁵ ) 2] mAr or - [C (R ⁵ ) 2] _m Het and R ² is as defined above, can preferably be obtained by reacting compounds of formula V with compounds of formula VI.

In the compounds of formula (V), L is preferably a chlorine, bromine, iodine or reactive modified hydroxyl group such as an ester-activated, imidazolide, C 1 -C 6 alkylsulfonyloxy (preferably methylsulfonyloxy) or C 6 -C 6 arylsulfonyloxy group phenylsulfonyloxy or p-tolylsulfonyloxy).

The reaction of the compound of the formula V with the compound of the formula VI is preferably carried out in an inert solvent and at the temperatures indicated above.

The starting compounds of the formulas V and VI are generally known. If new, they can be prepared by known methods

Compounds of formula I wherein R ^{1 is a} group

or

R ³ together with X is -CO-N- to form a five-membered ring,

Y a group of formula

R ⁵

NR ⁵ , —N

R ⁵ or

W is CONH R ² and R ⁴ are as stated above, can preferably be obtained by reacting compounds of formula II in which

R · ¹ · group

or

N =

CH ₃

R ³ together with Y -CO-N- to form a five-membered ring,

Y a group of formula

R ⁵ R ⁵

W is CONH R ² and R ⁵ are as defined above, are reacted with compounds of formula VII.

The reaction of compounds of formula II wherein W is -CONH- with a compound of formula VII is preferably carried out in an inert solvent and at the temperatures indicated above.

The starting compounds of the formula II in which W is -CONH- and VII are generally known. If new, they can be prepared by known methods.

Compounds of formula I wherein R ^{1 is a} group

C ch ₃

R ³ together with X is -CO-N- to form a five-membered ring,

Y a group of the formula -N [C (R ⁵ ) ₂ ] _m -COOR ⁵ ,

W is -S0 ₂ R 32, and ² and R ⁴ are as defined above, can be obtained by a compound of the formula II in which

R ³ together with Y -CO-N- to form a five-membered ring,

Y a group of the formula -N [C (R ⁵ ) ₂ ] _m "COOR ⁵ , and R ² and R ⁵ are as defined above, are reacted with compounds of formula VIII.

In the compounds of formula VIII, L is preferably a chlorine, bromine, iodine or reactive modified hydroxyl group such as an ester-activated, imidazolide, C 1 -C 6 alkylsulfonyloxy (preferably methylsulfonyloxy) or C 6 -C 10 arylsulfonyloxy group preferably phenylsulfonyloxy or p-tolylsulfonyloxy).

The reaction of a compound of formula II wherein Y is -N [C (R ⁵ ) ₂ ] _m -COOR ⁵ with a compound of formula VIII is preferably carried out in an inert solvent and at the temperatures indicated above.

Compounds of formula I wherein X is NH,

R ^{3 of the} hydrogen atom and R ¹ , R ² , R ⁴ , Y and W are as defined above may be converted from the oxazolidinone derivatives by treatment with a solvolysis or hydrogenolysis agent. This reaction is carried out under the deprotection conditions described above.

Compounds of formula I wherein R ^{1 is} -C (= NH) -NH 2 may be further obtained from the corresponding cyano compounds. The cyano group is converted to the amidino group by reaction with, for example, hydroxylamine and subsequent reduction of N-hydroxyamidine with hydrogen in the presence of a catalyst, for example palladium on carbon.

Ammonia can also be added to the nitrile of formula I (wherein R ^{1 is} CN) to prepare an amidine of formula I (wherein R ^{1 is} -C (= NH) -NH ₂ ).

The addition is preferably carried out in several stages, whereby in a known manner a) the nitrile is reacted with hydrogen sulphide to give a thioamide which is converted by an alkylating agent, for example methyl iodide, into the corresponding S-alkylimidothioester which is reacted with ammonia to give amidine; is changed by treatment with an alcohol such as ethanol in the presence of hydrochloric acid to give the corresponding imidoester which is treated with ammonia; or c) the nitrile is reacted with lithium bis- (trimethylsilyl) amide and the product is then hydrolyzed.

Moreover, the compound of formula I is converted into another compound of formula I by converting one or more radicals Y, R ^1, R ^2, R ³ and / or R ^4, is converted into one or more other radicals Y, R ¹ , R ² , R ³ and / or R ⁴ wherein, for example, the amino group is acylated or the nitro groups are reduced to amino groups (for example, by hydrogenation in the presence of Raney nickel or palladium on carbon in an inert solvent such as methanol or ethanol).

Esters may be saponified, for example, with acetic acid or sodium hydroxide or potassium hydroxide in water, in a mixture of water and tetrahydrofuran or in a mixture of water and dioxane at a temperature of 0 to 100 ° C.

Furthermore, free amino groups can be acylated in a known way, acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, expediently in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 ^e C .

The base of formula (I) can be converted into the appropriate acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and then evaporating the solvent.

Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic acids may be used or sulfuric acids such as formic, acetic, propionic, pivalic, diethyl acetic, malonic, succinic, pimelic, fumaric, maleic lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, ethanesulfonic, methanesulfonic, methanesulfonic, methanesulfonic, methanesulfonic, methanesulfonic, hydroxyethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, naphthalene monosulfonic acid, naphthalenedisulfonic acid and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

On the other hand, the compounds of the formula I can be converted into the corresponding metal salts, in particular the alkali metal or alkaline earth metal salts, or also the corresponding ammonium salts, by treatment with a base (for example with hydroxide or sodium or potassium carbonate). Physiologically acceptable organic bases such as ethanolamine can also be used.

The compounds of the formula I can be chiral on the basis of their molecular structure and can therefore be in various enantiomeric forms. They may therefore be in racemic or optically active form.

Since the pharmaceutical efficacy of the racemates or stereoisomers of the compounds of the invention may vary, it may be desirable to use enantiomers. In such cases, the end product or intermediates may be separated into the enantiomeric compounds by known chemical or physical means, or the individual enantiomers may already be used as starting materials.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent.

Examples of such resolving agents are optically active acids, such as the R- and S-forms of tartaric, diacetyltartaric, dibenzoyltartaric, mandelic, malic, lactic, suitably nitrogen-protected amino acids (e.g. benzoylproline or N-benzolsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic separation of enantiomers by optically active resolving agents (such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or silica gel-fixed chiral derivatized methacrylate polymers) is also preferred. Suitable eluents are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile, for example in a volume ratio of 82: 15: 3.

The compounds of formula I and their physiologically acceptable salts can be used for the production of pharmaceutical compositions, in particular by a non-chemical route. For this purpose, they can be converted into a suitable dosage form with at least one solid or liquid and / or semi-liquid carrier or excipient and optionally in admixture with one or more other active substances.

The invention therefore also relates to compositions, in particular pharmaceutical compositions, comprising at least one compound of the formula I and / or a physiologically acceptable salt thereof.

The compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration and which do not react with compounds of formula I, such as water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, suppositories for rectal use, solutions for parenteral use, in particular oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the resulting lyophilisates used, for example, for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more more other active ingredients such as vitamins.

The compounds of formula I and their physiologically acceptable salts can be used to treat thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and gastric pain in walking or to prevent these conditions.

As a rule, the compounds of the formula I according to the invention are preferably used in doses of approximately 1 to 500 mg, in particular 5 to 100 mg per dosage unit. The daily dose is preferably about 0.02 to 10 mg / kg body weight. The dose for each individual patient depends on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, elimination rate, drug combination, and severity of the disease. . Oral administration is preferred.

The invention is illustrated by the following non-limiting examples. Temperatures are always given in degrees Celsius. In the following examples, the expression conventional processing means:

Optionally, water is added or, depending on the constitution of the final product, the pH is adjusted to 2-10, the reaction mixture is extracted with ethyl acetate or dichloromethane, separated, dried over the organic phase with sodium sulfate, evaporated and purified by silica gel chromatography and / or crystallization. Rf values are on silica gel, eluent is ethyl acetate / methanol 9: 1,

Mass spectrometry (MS): EI (electron impact ionization) M ⁺ FAB (fast atom bombardment) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 100 mg of 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] 5-piperazin-1-ylmethyl-oxazolidin-2-one (A) [obtainable by reaction of 3- [4- ( 5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolium-5-methyl methanesulfonic acid ester with 1-tert-butoxycarbonylpiperazine and sodium bicarbonate in acetonitrile; by cleavage of the BOC protecting group with hydrochloric acid / dioxane followed by treatment with sodium hydroxide solution] and 110 mg of 2,4,6-trichlorobenzenesulfonyl chloride in 10 ml of dichloromethane are reacted with 400 mg of 4-dimethylamino pyridine on polystyrene and stirred for 18 hours at temperature rooms. The reaction mixture was filtered, the solvent removed to give 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,4,6-trichlorophenylsulfonyl)]. piperazin-1-ylmethyl] oxazolidin-2-one, FAB 586/588.

Similarly, it is obtained by reacting A with 4-biphenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-biphenylylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with phenylvinylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-phenylvinylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2- nitrophenylsulfonyl

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-nitrophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2, 5-dimethoxyphenylsulfonyl

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,5-dimethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2- naphthylsulphonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2- chloro-4fluorophenylsulfonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-chloro-4-fluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s (2-acetamido-4-methylthiazole-5-yl) sulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 - ((2-acetamido-4-methylthiazol-5-yl) sulfonyl) piperazin-1- ylmethyl] oxazolidin-2-one, with cyanophenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-cyanophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 5- nitro-2-methylphenylsulfonyl

3- [4- (5-methyl- [1,2,4] oxadxazol-3-yl) phenyl] -5- [4- (5-nitro-2-methylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with benzylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-benzylsulfonylpiperazin-1-ylmethyl) oxazolidin-2-one, with decylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-decylsulfonylpiperazin-1-ylmethyl) oxazolidin-2-one, with 2-trifluoromethylphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -5- [4- (2-trifluoromethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-2-one, with 3-chloro- 4fluorophenylsulfonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-chloro-4-fluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4-chloro-2,5-dimethylphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadxazol-3-yl) phenyl] -5- [4- (4-chlór40

2,5-dimethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2-fluorophenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-fluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3, 4-dibromophenylsulfonyl

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,4-dibromophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3- chlorophenylsulfonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-chlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2, 6-dichlorophenylsulphonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,6-dichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one 3,4-dichlorophenylsulphonyl chloride

3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,4-dichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one with 3,5 -dichlórfenylsulfonylchloridom

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,5-dichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one with 2- naphthylcarboxylic acid

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-naphthylcarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with methylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-methylsulfonyl) piperazin-1-ylmethyl) oxazolidin-2-one, with 2-methylsulfonylphenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-methylsulfonylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2- nitrobenzyl sulfonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-nitrobenzylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s (4 3-Methoxycarbonyl-3-methoxythiophen-2-yl) sulfonyl chloride 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 - ((4-methoxycarbonyl-3-methoxythiophene) 2-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3-trifluoromethylphenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-trifluoromethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4 -trifluórmetoxyfenylsulfonylchloridom

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with ( 1 S) - (camphor-10-yl) sulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 - (((1S) camphor 10-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin- 2-one, with (R) - (camphor-10-yl) sulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 - (((1R) camphor 10-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin- 2-one, with (2,2,5,7,8-pentamethylchroman-6-yl) sulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 - ((2,2,5,7,8-pentamethylchroman-6-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4-isopropylphenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-isopropylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4- t-butylphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-tert-butylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 4-butylphenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-butylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3, 5-dinitro-4-methoxyphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -5- [4- (3,5-di-nitro-4-methoxy-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidine

2-one, with ethylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-ethylsulfonyl) piperazin-1-ylmethyl) oxazolidin-2-one, with nitrophenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-nitrophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2 -trifluórmetoxyfenylsulfonylchloridom

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2,4 -dinitrofenylsulfonylchloridom

3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,4-dinitrophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with isopropylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-isopropylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4-ethylphenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-ethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4- bromo-2-trifluórmetoxyfenylsulfonylchloridom

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-bromo-2-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin

2-one, with 2,3,4-trifluorophenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,3,4-trifluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 3,4-difluórfenylsulfonylchloridom

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,4-difluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 2,2,2-trifluóretylsulfonylchloridom

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,2,2-trifluoroethylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 3-nitro-4-methylphenylsulfonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-nitro-4-methylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 2-nitro-6-chlorophenylsulfonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-nitro-6-chlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 2,5-dimetoxyfenylacetylchloridom

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,5-dimethoxyphenylacetyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3, 4-dichlorobenzoyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,4-dichlorobenzoyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3 -fluórbenzoylchloridom

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-fluorobenzoyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4- trifluórmetoxybenzoylchloridom

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -5- [4- (4-trifluoromethoxy-benzyl) -piperazin-1-ylmethyl] -oxazole idin-2-one, with 3-pyridylcarboxylic acid chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-pyridylcarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with chloride 2 -benzothienylcarboxylic acid

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-benzothienylcarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4- chlorophenylacetyl

3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-chlorophenylacetyl) piperazin-1-ylmethyl] oxazolidin-2-one, with chloride Of 1-naphthylcarboxylic acid

3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (1-naphthylcarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with chloride 1,3-benzodioxol-5-yl) carboxylic acid

3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (1,3-benzo dioxol-5-yl) carbonyl] piperazin-1-ylmethyl Oxazolidin-2-one, with 3-nitrobenzoyl chloride

3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-nitrobenzoyl) piperazin-1-ylmethyl] oxazolidin-2-one, with chloride 4-biphenylylcarboxylic acid

3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-biphenylylcarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with cyclopentylcarboxylic chloride of

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (cyclopentylcarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with [5-chloro] -1- (4-methylphenyl) -1H-pyrazol-4-yl] sulfonyl chloride 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [5 -chloro-1- (4-methylphenyl) -1H-pyrazol-4-yl) sulfonyl] piperazin-1-ylmethyl} oxazolidin-2-one, with 4-chlorophenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-chlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 5, 7,7-trimethyl-2- (1,3,3-trimethylbutyl) oktylsulfonylchloridom

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [5,7,7trimetyl 2- (1,3,3-trimethylbutyl) octylsulfonyl] piperazin-1-ylmethyl} oxazolidin-2-one, with 2-butoxy-5- (1,1-dimethylpropyl) phenylsulfonyl chloride 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] - 5- {4- [2-butoxy-5- (1,1-dimethylpropyl) phenylsulfonyl] piperazin-1-ylmethyl} oxazolidin-2-one, with 2-butoxy-5- (1,1,3,3-tetramethylbutyl) phenylsulfonyl chloride 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [2-butoxy5- (1,1,3,3-tetramethylbutyl) phenylsulphonyl] piperazine-l- ylmethyl} oxazolidin-2-one, with 2-nitro-4-trifluoromethylphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-nitro-4-trifluoromethyl) phenylsulfonyl] piperazin-1-ylmethyl] oxazolidin-2-one , with 4-bromo-2-ethylphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-bromo-2-ethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-2-one, s 4-trifluórmetylfenylsulfonylchloridom

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-trifluoromethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3,4- difluórfenylsulfonylchloridom

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,4-difluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 1-naphthylsulfonyl

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (1-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4-methoxyphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-methoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 4-tolylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-tolylsulfonyl] piperazin-1-ylmethyl] oxazolidin-2-one, with 4-propylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-propylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 6- chloro-2-naphthylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, s 2- (naphth-l-yl) ethylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [2- (naphth-1-yl) ethylsulfonyl] piperazin-1-ylmethyl} oxazolidin-2 -on, with butyl chloroformate

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (isobutyloxycarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one.

Example 2

Solution 100 mg 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] 5- [4- (2,4,6-trichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin The -2-one in 15 ml of methanol is treated with 100 mg of Raneynicl and a drop of acetic acid and hydrogenated for eight hours at room temperature. The catalyst was filtered off and the solvent was removed to give 4- {2-oxo-5- [4- (2,4,6-trichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 543/548.

Similarly, the following benzamidine derivatives are obtained by hydrogenation of the compounds of Example 1:

4- {2-ΟΧΟ-5- [4- (4-biphenylylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 520,

4- {2-ΟΧΟ-5- [4- (2-2-phenylethylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 472,

4- {2-Oxo-5- [4- (2-aminophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 452,

4- {2-oxo-5- [4- (2,5-dimethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 504,

4- {2-Oxo-5- [4- (2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-benzamidine, trifluoroacetate, FAB 494,

4- {2-oxo-5- [4- (2-chloro-4-fluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 496,

4- {2-O-5- [4 - ((2-acetamido-4-methylthiazol-5-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 522,

4- {2-oxo-5- [4- (2-cyanophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 469,

4- {2-oxo-5- [4- (5-amino-2-methylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 473,

4- {2- [5- (4-Benzylsulfonylpiperazin-1-ylmethyl) oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 458,

4- {2-oxo-5- (4-decylsulfonylpiperazin-1-ylmethyl) oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 508,

4- {2-Oxo-5- [4- (2-trifluoromethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 512,

4- {2-oxo-5- [4- (3-chloro-4-fluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 496,

4- {2-Oxo-5- [4- (4-chloro-2,5-dimethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 506,

4- {2-Oxo-5- [4- (4- (2-fluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 462,

4- {2-oxo-5- [4- (3,4-dibromophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 600/602/604,

4- {2-oxo-5- [4- (3-chloro-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 478,

4- {2-oxo-5- [4- (2,6-dichloro-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 512,

4- {2-Oxo-5- [4- (3,4-dichloro-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 512,

4- {2-Oxo-5- [4- (3,5-dichloro-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine acetate FAB 512,

4- {2-Oxo-5- [4- (2-naphthylcarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 458,

4- {2-oxo-5- (4-methylsulfonylpiperazin-1-ylmethyl) oxazolidin-3-yl) benzamidine acetate, FAB 382,

4- {2-oxo-5- [4- (2-methylsulfonylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 522,

4- {2-oxo-5- [4- (2-aminobenzylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 473,

4- {2-oxo-5- [4 - ((4-methoxycarbonyl-3-methoxythiophen-2-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 538,

4- {2-Oxo-5- [4- (3-trifluoromethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine acetate FAB 512,

4- {2-oxo-5- [4- (4-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 528,

4- {2-oxo-5- [4 - (((1S) camphor-10-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 518,

4- {2-oxo-5- [4 - (((1R) Camphor-10-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 518,

4- {2-O-5- [4 - ((2,2,5,7,8-pentamethylchroman-6-yl) sulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate,

FAB 570,

4- {2-oxo-5- [4- (4-isopropylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 486,

4- {2-Oxo-5- [4- (4-tert-butylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate,

4- {2-oxo-5- [4- (4-butylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 500,

4- {2-oxo-5- [4- (3,5-diamino-4-methoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 504,

4- {2-oxo-5- (4-ethylsulfonylpiperazin-1-ylmethyl) oxazolidin-3-yl} benzamidine acetate, FAB 396,

4- {2-oxo-5- [4- (4-nitrophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 459,

4- {2-ΟΧΟ-5- [4- (2-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 528,

4- {2-Oxo-5- [4- (2,4-diaminophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 474,

4- {2-Oxo-5- (4-isopropylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 410,

4- {2-ΟΧΟ-5- [4- (4-ethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 472,

4- {2-Iso-5- [4- (4-bromo-2-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 606/608,

4- {2-oxo-5- [4- (2,3,4-trifluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 498,

4- {2-Oxo-5- [4- (3,4-difluorophenylsulfonyl) piperazin-1-ylmethyl] * oxazolidin-3-yl} benzamidine acetate FAB 480,

4- {2-oxo-5- [4- (2,2,2-trifluoroethylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 450,

4- {2-oxo-5- [4- (3-amino-4-methylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 473,

4- {2-oxo-5- [4- (2-amino-6-chloro-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 585,

4- {2-Oxo-5- [4- (2,5-dimethoxyphenylacetyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 482,

4- {2-oxo-5- [4- (3,4-dichlorobenzoyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 476,

4- {2-Oxo-5- [4- (3-fluorobenzoyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 426,

4- {2-Oxo-5- [4- (4-trifluoromethoxybenzoyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 492,

- {2- ΟΧΟ-5- [4- (3-pyridylcarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 409,

4- {2-ΟΧΟ-5- [4- (2-benzothienylcarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 463,

4- {2-ΟΧΟ-5- [4- (4-chloro-phenylacetyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, acetate, FAB 456,

4- {2-oxo-5- [4- (1-naphthylcarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 458,

4- {2-Oxo-5- [4 - ((1,3-benzodioxol-5-yl) carbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 452,

4- {2-oxo-5- [4- (3-aminobenzoyl) piperazin-1-ylmethyl} oxazolidin-3-yl} benzamidine acetate FAB 423,

4- {2-oxo-5- [4- (4-biphenylylcarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate, FAB 484,

4- {2-oxo-5- [4- (cyclopentylcarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 400,

4- {2-oxo-5- {4- [5-chloro-1- (4-methylphenyl) -1H-pyrazol-4-yl) sulfonyl] piperazin-1-ylmethyl} oxazolidin-3-yl] benzamidine acetate, FAB 558.

4- {2-Oxo-5- [4- (4-chloro-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 478,

4- {2-oxo-5- {4- [5,7,7-trimethyl-2- (1,3,3-trimethylbutyl) octylsulfonyl] piperazin-1-ylmethyl} oxazoplidin-3-ylbenzamidine, trifluoroacetate FAB 620,

4- {2-oxo-5- {4- [2-butoxy-5- (1,1-dimethylpropyl) phenylsulfonyl] piperazin-1-ylmethyl} oxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 586,

4- {2-Oxo-5- {4- [2-butoxy-5- (1,1,3,3-tetramethylbutyl) phenylsulfonyl] piperazin-1-ylmethyl} oxazolidin-3-yl] benzamidine, trifluoroacetate, FAB 628,

4- {2-ΟΧΟ-5- [4- (2-amino-4-trifluoromethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, trifluoroacetate,

4- {2-Oxo-5- [4- (4-bromo-2-ethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine, trifluoroacetate, FAB 550/552,

4- {2-Oxo-5- [4- (4-trifluoromethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 512,

4- {2-oxo-5- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 528,

4- {2-oxo-5- [4- (isobutyloxycarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 404.

Similarly, 3- [3- (5-methyl- [1,2,4] oxadiazole) was obtained by reaction

3-yl) phenyl] -5-piperazin-1-ylmethyloxazolidin-2-one with 6-chloro-2-naphthylsulfonyl chloride followed by hydrogenation of the compound

3- {2-oxo-5- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, m.p.

Similarly, 3- [4- (5-methyl- [1,2,4] oxadiazole) was obtained by reaction

3-yl) phenyl] -5-piperazin-1-ylmethyloxazolidin-2-one with 6-methoxy-2-naphthylsulfonyl chloride followed by hydrogenation of the compound

4- {2-oxo-5- [4- (6-methoxy-2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl] benzamidine.

Similarly, 3- [4- (5-methyl- [1,2,4] oxadiazole) is obtained by reaction

3-yl) phenyl] -5-piperazin-1-ylmethyloxazolidin-2-one with 2-fluorobenzyl chloride followed by hydrogenation of the compound

4- {2-oxo-5- [4- (2-fluoro-benzyl) -piperazin-1-ylmethyl] -oxazolidin-3-yl} -benzamidine.

Example 3

Solution 100 mg of 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl]

5- [4- (2,4,6-Trichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one in 8 ml methanol was mixed with 3 ml 1N sodium hydroxide solution and stirred at 60 ° C for 48 hours . After working up in the usual manner, 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] amino] -1- [4- (2,6-dichloro-4-methoxyphenylsulfonyl) piperazine] - is obtained. 1-yl] propan-2-ol, FAB 556/558.

Similarly obtained with 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,4-difluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylamino] -1- [4- (3-fluoro-4-methoxy-phenylsulfonyl) -piperazin-1-yl] -propan-2- ol with 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (1-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (1-naphthylsulfonyl) piperazin-1-yl] propan-2-ol, with 3- [ 4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-trifluoromethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (4-trifluoromethylphenylsulfonyl) piperazin-1-yl] propan-2-ol, with 3 - [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-biphenylylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylamino] -1- [4- (4-biphenylylsulfonyl) -piperazin-1-yl] -propan-2-ol, with 3- [ 4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-trifluoromethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylamino] -1- [4- (3-trifluoromethyl-phenylsulfonyl) -piperazin-1-yl] -propan-2-ol, with 3 - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2 -about him

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (4-trifluoromethoxyphenylsulfonyl) piperazin-1-yl] propan-2-ol, with 3- [4 - (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-isopropylphenylsulfonyl) piperazin-l-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (4-isopropylphenylsulfonyl) piperazin-1-yl] propan-2-ol, with 3- [4 - (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-butylphenyl) piperazin-l-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (4-butylphenylsulfonyl) piperazin-1-yl] propan-2-ol, with 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-methoxyphenyl) piperazin-l-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (4-methoxyphenylsulfonyl) piperazin-1-yl] propan-2-ol, with 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-tolylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (4-tolylsulfonyl) piperazin-1-yl] propan-2-ol, with 3- [4- (5-Methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-propylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylamino] -1- [4- (4-propyl-phenylsulfonyl) -piperazin-1-yl] -propan-2-ol, with 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylamino] -1- [4- (6-chloro-2-naphthylsulfonyl) -piperazin-1-yl] -propan-2-ol with 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-phenylvinylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2- about him

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (2-phenylvinylsulfonyl) piperazin-1-yl] propan-2-ol, with 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [2- (naphthalen-yl) ethylsulfonyl] piperazin-l-ylmethyl} oxazolidin-2-one

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenylamino] -1- {4- [2- (naphth-1-yl) ethylsulfonyl] piperazin-1-yl} propane- 2-ol,

Similarly, it is obtained from 4- {2-oxo-5- [4- (6-methoxy-2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl] benzamidine

4- {2-hydroxy-3- [4- (6-methoxynaphthalene-2-sulfonyl) piperazin-1-yl] propylamino} benzamidine, diacetate, FAB 498 and 4- {2-OXO-5- [4- (2-fluorobenzyl) ) piperazin-ylmethyl] oxazolidin3-yl} benzamidine

4- {2-hydroxy-3- [4- (2-fluorobenzyl) piperazin-1-yl] propylamino} benzamidine acetate FAB 386.

Example 4

A solution of 60 mg of 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenylamino] -1- [4- (2,6-dichloro-4-methoxyphenylsulfonyl) piperazin-1-yl] propane- 2-ol in 5 ml of methanol was mixed with 50 mg of Raney-nickel and a drop of acetic acid and hydrogenated for eight hours at room temperature. The catalyst was filtered off and the solvent was removed. There was thus obtained 4- {3- [4- (2,6-dichloro-4-methoxyphenylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate, FAB 516/518.

Similarly, the following compounds were obtained by hydrogenation from the propan-2-ol derivatives listed in Example 3:

4- {3- [4- (3-Fluoro-4-methoxyphenylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 466,

4- {3- [4- (1-naphthylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 468,

4- (3- [4- (4-Trifluoromethylphenylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 486,

4- {3- [4- (4-Biphenylylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 494,

4- {3- [4- (3-Trifluoromethyl-phenylsulfonyl) -piperazin-1-yl] -2-hydroxy-propylamino] -benzamidine, acetate, FAB 486,

4- {3- [4- (4-Trifluoromethoxyphenylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 502,

4- {3- [4- (4-Isopropyl-phenylsulfonyl) -piperazin-1-yl] -2-hydroxy-propylamino} -benzamidine, acetate, FAB 460,

4- {3- [4- (4-Butylphenylsulfonyl) piperazin-1-yl] -2-hydroxypropylaminobenzamidine, acetate, FAB 474,

4- {3- [4- (4-Methoxyphenylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 448,

4- {3- [4- (4-Tolylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 432,

4- {3- [4- (4-propylphenylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine acetate FAB 460,

4- {3- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino] benzamidine acetate FAB 502,

4- {3- [4- (2-Phenylvinylsulfonyl) piperazin-1-yl] -2-hydroxypropylamino] benzamidine acetate FAB 446,

4- {3- <4- [2- (naphth-1-yl) ethylsulfonyl] piperazin-1-yl} -2-hydroxypropylamino] benzamidine acetate FAB 496.

Example 5

A solution of {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -2-oxo-oxazolidin-5-yl} -methanesulfonic acid methyl ester, 10 g,

6.73 g of 4-BOC-aminopyperidine and 8.5 g of sodium bicarbonate in 200 ml of acetonitrile are heated under reflux for 40 hours. After usual work-up, 5- (4-BOC-aminopiperidin-1-ylmethyl) -3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] oxazolidin-2-one is obtained.

The BOC group is cleaved by treatment with trifluoroacetic acid in dichloromethane to give 5- (4-aminopiperidin-1-ylmethyl) -3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] oxazolidin- 2-one (B).

Analogously to Example 1, N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazole-) - (3-methoxy-4-methoxycarbonylthiophen-2-yl) sulfonyl chloride] is obtained by reaction of B. 3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} piperidin-4-yl) amide (3-methoxy-4-methoxycarbonylthiophen-2-yl) sulfonic acid of the formula

ABOUT

O with benzolsulfonyl chloride

N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} piperidin-4-yl) benzenesulfonamide, with 3, 4-dimetoxybenzolsulfonylchloridom

3,4-dimethoxy-N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} -piperidine-4-yl benzenesulfonamide, with butylsulfonyl chloride

N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} piperidin-4-yl) butylsulfonamide, with 2, 4,6-trimetylbenzolsulfonylchloridom

2,4,6-N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} -piperidine-4 -yl) benzolsulphonamide, with phenylvinylsulfonyl chloride phenylvinyl-N- (1- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} piperidine -4-yl) sulfonamide, with 2-methylsulfonylbenzenesulfonyl chloride

2-Methylsulfonyl-N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} piperidin-4-yl) benzolsul formamide, with 4-biphenylylsulfonyl chloride

4-Biphenylyl-N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} piperidin-4-yl) sulfonamide, with 5-dimethylamino-1-naphthylsulfonyl chloride

5-dimethylamino-N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} piperidin-4-yl) - 1-naphthylsulfonamide, with 1-naphthylsulfonyl chloride

N- (1- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} -piperidine-4-yl) -1-naphthylsulfonamido.

Hydrogenation, similar to Example 2, yields the following compounds from the above compounds:

r

4- {5- [4 - ((3-methoxy-4-methoxycarbonylthiophen-2-yl) sulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 552,

4- {5- [4- (Benzenesulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolin-3-yl} benzamidine acetate FAB 458,

4- {5- [4- (3,4-Dimethoxybenzenesulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 518,

4- {5- [4- (Butylsulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 438,

4- {5- [4- (2,4,6-Trimethylbenzenesulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate, FAB 500,

4- {5- [4- (Phenylethylsulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 486,

I

4- {5- [4- (2-Methylsulfonylbenzolsulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 536,

4- {5- [4- (4-Biphenylylsulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 533,

4- {5- [4- (5-dimethylamino-1-naphthylsulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate, FAB 551,

4- {5- [4- (1-Naphthylsulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 458.

Example 6

A solution of {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -2-oxo-oxazolidin-5-yl} -methanesulfonic acid methyl ester (10 g),

7.4 g of N, N'-dimethylethylenediamine and 8.5 g of sodium bicarbonate in 400 ml of acetonitrile are heated at reflux for 40 hours. After usual work-up, 5 - {[methyl (2-methylaminoethyl) amino] methyl} -3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] oxazolidin-2-one (C) is obtained. .

Similar to Example 1, it is obtained by reacting C with 2,4,6-trichlorophenylsulfonyl chloride

2,4,6-Trichloro-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidine] -5-ylmethyl} amino) ethyl] benzenesulfonamide of formula

with 2-trifluoromethoxyphenylsulfonyl chloride

2-Trifluoromethoxy-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5- ylmethyl} amino) ethyl] benzolsulfonamide, with 2,4,6-trichlorophenylsulfonyl chloride

2,4,6-trichloro-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin- 5-ylmethyl} amino) ethyl] benzenesulfonamide, with 4-trifluoromethylphenylsulfonyl chloride

4-Trifluoromethyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} amino) ethyl] benzenesulfonamide, with 4-isopropylphenylsulfonyl chloride

4-isopropyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] benzolsulfonamide, with 4-propylphenylsulfonyl chloride

4-propyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} amino) ethyl] benzolsulfonamide, with 4-acetamidophenylsulfonyl chloride

4-acetamido-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] benzenesulfonamide, with 2-naphthylsulfonyl chloride

N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] -2 naphthylsulfonamide, with 3-trifluoromethylphenylsulfonyl chloride

3-trifluoromethyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] benzolsulfonamide, with 4-chloro-3-nitrophenylsulfonyl chloride

4-chloro-3-nitro-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin- 5-ylmethyl} amino) ethyl] benzolsulfonamide; with phenylvinylsulfonyl chloride

N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} amino) ethyl] phenylvinyl sulfonamide, with benzylsulfonyl chloride

4-trifluoromethyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] benzylsulfonamide, with tolylsulfonyl chloride

4-Methyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] benzolsulfonamide, with 4-methoxyphenylsulfonyl chloride

4-methoxy-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] benzolsulfonamide, with 1-naphthylsulfonyl chloride

N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] -1-naphthylsulfonamide, with 4-biphenylylsulfonyl chloride

N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} amino) ethyl] -4 -biphenylylsulfonamide, with 3,4-difluorophenylsulfonyl chloride

3,4-Difluoro-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5] -ylmethyl} amino) ethyl] benzolsulfonamide, with 4-pentylphenylsulfonyl chloride

4-Pentyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) (amino) ethyl] benzolsulfonamide, with 4-butylphenylsulfonyl chloride

4-Butyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) (amino) ethyl] benzolsulfonamide, with 4-methylsulfonylphenylsulfonyl chloride

4-Methylsulfonyl-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5- ylmethyl} amino) ethyl] benzolsulfonamide, with 6-chloro-2-naphthylsulfonyl chloride

6-chloro-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) (amino) ethyl] -2-naphthylsulfonamide.

By hydrogenation, similar to Example 2, the following compounds are obtained from the above compounds:

4- {5- [methyl- {2- [methyl- (2,4,6-trichlorobenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine, trifluoroacetate, FAB 548/550 of formula

4- {5- [methyl- {2- [methyl- (2-trifluoromethoxybenzenesulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 530,

4- {5- [methyl- {2- [methyl- (4-trifluoromethylbenzenesulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 514,

4- {5- [methyl- {2- [methyl- (4-isopropylbenzenesulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 488,

4- {5- [methyl- {2- [methyl- (4-propylbenzenesulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 488,

4- {5- [methyl- {2- [methyl- (4-acetamidobenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine trifluoroacetate, FAB 503,

4- {5- [methyl- {2- [methyl- (2-naphthylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 496,

4- {5- [methyl- {2- [methyl- (3-trifluoromethylbenzenesulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine trifluoroacetate, FAB 514,

4- {5- [methyl- {2- [methyl- (3-amino-4-chlorobenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolin-3-yl} benzamidine acetate FAB 495 .

4- {5- [methyl- {2- [methyl- (phenylethylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine trifluoroacetate, FAB 474,

4- {5- [methyl- {2- [methyl- (benzylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 460,

4- {5- [methyl- {2- [methyl- (4-tolylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 460,

4- {5- [methyl- {2- [methyl- (4-methoxybenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine trifluoroacetate, FAB 476,

4- {5- [methyl- {2- [methyl- (1-naphthylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine trifluoroacetate, FAB 496,

4- {5- [methyl- {2- [methyl- (4-biphenylylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine trifluoroacetate, FAB 522,

4- {5- [methyl- {2- [methyl- (3,4-difluorobenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine trifluoroacetate, FAB 516,

4- <5- [methyl- {2- [methyl- (4-pentylbenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine trifluoroacetate, FAB 516,

4- {5- [methyl- {2- [methyl- (4-butylbenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine, trifluoroacetate, FAB 502,

4- {5- [methyl- {2- [methyl- (4-methylsulfonylbenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine trifluoroacetate, FAB 502,

67 4- {5- [methyl- {2- [methyl- (6-chloro-2-naphthylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl} benzamidine, trifluoroacetate, FAB 530 .

Similar to Examples 3 and 4, 6-chloro-N-methyl-N- [2- (methyl- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl]] was obtained -2-oxooxazolidin-5-ylmethyl} amino) ethyl] 2-naphthylsulfonamide

4- [3 - ({2 - [(6-chloro-2-naphthylsulfonyl) methylamino] ethyl} methylamino) -2-hydroxypropylamino] benzamidine acetate FAB 504 formula

az 7-Methoxy-N-methyl-N- [2- (methyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) (amino) ethyl] 2-naphthylsulfonamide

4- [3 - ({2 - [(7-methoxy-2-naphthylsulfonyl) methylamino] ethyl) methylamino) -2-hydroxypropylamino] benzamidine, acetate, FAB 500.

Similar to Example 3, they are obtained by cleaving the oxazolidinone ring from 4- {5 - [(methyl- {2- [methyl- (4-biphenylylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl) benzamidine from 4- {5 - [(methyl- {2- [methyl- (4-isopropylbenzolsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine and 4- {5 - [(methyl 1- {2- [Methyl- (1-naphthylsulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolidin-3-yl] benzamidine the following compounds:

4- [3- ({2 - [(4-Biphenylylsulfonyl) methylamino] ethyl} methylamino) 2-hydroxypropylamino] benzamidine diacetate, EI 460 (M ⁺ -NH ₂ ),

4- [3 - ({2 - [(4-isopropylbenzenesulfonyl) methylamino] ethyl} methylamino) -2-hydroxypropylamino] benzamidine diacetate, EI 461,

4- [3 - ({2 - [(1-naphthylsulfonyl) methylamino] ethyl} methylamino) 2-hydroxypropylamino] benzamidine diacetate, EI 469.

Example 7

A solution of 10.6 g of {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-yl} methanesulfonic acid methyl ester and 3.17 g of sodium azide in 30 ml of acetonitrile was heated to reflux for 40 hours. After working up in the usual manner, 5-azidomethyl-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -oxazolidin-2-one is obtained.

7.7 g of the azido compound are suspended in ethylene glycol dimethyl ether, 3.6 ml of trimethyl phosphite are added and the mixture is stirred at reflux for 1.5 hours. 4.9 ml of semi-concentrated hydrochloric acid are added and boiling for a further three hours. Conventional work-up gives 5-aminomethyl-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -oxazolidin-2-one hydrochloride.

The obtained compound is suspended in dichloromethane, mixed with a basic ion exchanger and stirred for two hours. Removal of the ion exchanger and solvent gave 5-aminomethyl-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] oxazolidin-2-one (D).

Similarly, it is obtained by reaction of D with 3,4-difluorobenzenesulfonyl chloride

3,4-Difluoro-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] 2-oxooxazolidin-5-ylmethyl} benzolsulfonamide, with 4-methoxybenzolsulfonyl chloride

4-Methoxy-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] 2-oxooxazolidin-5-ylmethyl} benzenesulfonamide, with 4-chloro-3-nitrobenzolsulfonyl chloride

4-chloro-3-nitro-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl]

2-Oxooxazolidin-5-ylmethyl} benzolsulfonamide, with butylsulfonyl chloride

N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] butylsulfonamide, with 3-trifluoromethylbenzenesulfonyl chloride

3-Trifluoroethyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] benzenesulfonamide, with 2-naphthylsulfonyl chloride

N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} -2-naphthylsulfonamido.

Similar to Example 2, the following compounds were obtained by hydrogenation of sulfonamides:

4- {5 - [(3,4-difluorobenzenesulfonylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 411,

4- {5 - [(4-methoxybenzenesulfonylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 405,

4- {5 - [(3-amino-4-chlorobenzenesulfonylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 424,

4- {5 - [(butylsulfonylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 355,

4- {5 - [(3-Trifluoromethylbenzenesulfonylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 443,

4- {5 - [(2-naphthylsulfonylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 425.

Example 8

In analogy to Examples 3 and 4, the following compounds were obtained:

from 3,4-difluoro-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] 2-oxooxazolidin-5-ylmethyl) benzolsulfonamide

4- [3- (3,4-difluorobenzolsulfonylamino) -2-hydroxypropylamino] benzamidine, acetate, FAB 385, from 4-methoxy-N- {3- [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] 2-oxooxa of 1-idin-5-ylmethyl} -benz of 1-sulfonamide

4- [3- (4-Methoxybenzenesulfonylamino) -2-hydroxypropylamino] benzamidine, from 4-chloro-3-nitro-N- {3- [4- (5-methyl [1,2,4] oxadiazole-3- yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} benzenesulfonamide

4- [3- (3-amino-4-chlorobenzolsulfonylamino) -2-hydroxypropylamino] benzamidine, from N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] - 2-oxo-oxazolidin-5-ylmethyl] butylsulfonamide

4- [3- (butylsulfonylamino) -2-hydroxypropylamino] benzamidine acetate FAB 329 from 3-trifluoromethyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl)] phenyl] -2-oxo-oxazolidin-5-ylmethyl} benzenesulfonamide

4- [3- (3-Trifluoromethylbenzenesulfonylamino) -2-hydroxypropylamino] benzamidine acetate, FAB 417, from N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxo-oxazolidin-5-ylmethyl} -2-propylsulphonamide

4- [3- (propylsulfonylamino) -2-hydroxypropylamino] benzamidine, acetate, FAB 391.

Example 9

A solution of 30 g of {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -2-oxooxazolidin-5-yl} -methanesulfonic acid methyl ester and 300 mL of an aqueous solution of methylamine in 300 mL of tetrahydrofuran with heating maintained at 80 ° C for 18 hours.

Working up in the usual manner gives 5-methylamino-methyl-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -oxazolidin-2-one (E)

Similar to Example 1, it is obtained by reacting E ** with butylsulfonyl chloride

N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] butylsulfonamide, with 4-isopropylbenzenesulfonyl chloride

4-Isopropyl-N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -2-oxo-oxazolidin-5-ylmethyl} -benzenesulfonamide, with 3-trifluoromethyl-benzenesulfonyl chloride

3-Trifluoromethyl-N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazole)

3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] benzenesulfonamide, with phenylvinylsulfonyl chloride

N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} phenylvinylsulfonamide, with 2-naphthylsulfonyl chloride

N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} -2-naphthylsulfonamide, with 4-propylbenzenesulfonyl chloride

4-propyl-N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] benzenesulfonamide, with 4-methoxybenzolsulfonyl chloride

4-Methoxy-N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] benzenesulfonamide, with 2,4 , 6-trimetylbenzolsulfonylchloridom

2,4,6-trimethyl-N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] benzenesulfonamide, with benzoyl chloride

N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] benzamide, with 2-naphthylcarboxylic acid chloride N-methyl- N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] -2-naphthylcarboxylic acid, with cyclohexylcarboxylic acid chloride, N-methyl- N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl)]]

· · ···· • · ·· • · · • · • · ·· ··· · · · · · · • ·

N-methyl-N- (3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethyl] benzamide, with 2-naphthylcarboxylic acid chloride N-methyl-N- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) -2-naphthylcarboxylic acid with cyclohexylcarboxylic acid chloride N-methyl- N- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) cyclohexylcarboxylic acids,

with. 4-biphenylylcarboxylic acid chloride H-methyl-N- (3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) -4- bi-phenylylcarboxylic acids, with 4-chlorobenzoyl chloride

4-chloro-N-methyl-H- <3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] benzamide, with 4- (1,1 -dimethylpropylIbenzolsulfonylchloridem

4- (1,1-dimethylpropyl) -N-methyl-N- (3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethyl] benzenesulfonamide, with 3, 4-Difluorobenzenesulfonyl chloride

3,4-Difluoro-N-methyl-N- [3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl-phenyl] -2-oxooxazolidin-5-ylmethyl] -benzenesulfonamide, with 4-tert-butylamine .-butylbenzolsulfonylchloridem

4-tert-Butyl -N-methyl-N- (3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenyl] -2-oxooxazolidin-5-ylmethyl) -benzenesulfonamide, with 1-naphthylsulfonyl chloride

N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2oxooxazolidin-5-ylmethyl} -l-naphthylsulfonamido,

Similar to Example 2, the following compounds were obtained;

5- {5 - [((butylsulfonyl) methylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine, acetate, FAB 369, Formula

ABOUT

ABOUT

5- {5 - [((4-Isopropylbenzenesulfonyl) methylamino] methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 431,

5- {5 - [((3-Trifluoromethylbenzenesulfonyl) methylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 457,

5- {5 - [((phenylethylsulfonyl) methylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine acetate FAB 417,

5- {5 - [((2-naphthylsulfonyl) amino) methyl] -2-oxooxazolidin3-ylJbenzamidín,

5- {5 - [((4-propylbenzenesulfonyl) methylamino) methyl] -2-oxooxazolin-3-yl} benzamidine,

5- {5 - [((4-Methoxybenzenesulfonyl) methylamino) methyl] -2-oxooxazolin-3-yl} benzamidine,

5- {5 - [((2,4,6-trimetylbenzolsulfonyl) methylamino) methyl] -2oxooxazolidin-3-ylJbenzamidín,

5- {5 - [(benzoylmethylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine,

5- {5 - [(2-naftylkarbonylmetylamino) methyl] -2-oxooxazolidin3-yl} benzamidine;

5- {5 - [(cyklohexylkarbonylmetylamino) mety1] -2-oxooxazolidin3-yl} benzamidine;

5- {5 - [(4-Biphenylylcarbonylmethylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine,

5- {5 - [(4-chlorobenzoylmethylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine.

Similarly, 5-butylaminomethyl-3- [4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -2-oxooxazolidin-5-yl} -methanesulfonic acid was obtained from methyl ester. (5-Methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -oxazolidin-2-one (EI).

Similarly, it is obtained by reacting E-1 with 6-chloro-2-naphthylsulfonyl chloride

6-chloro-N-butyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl} -2-naphthylsulfonamide, s 4-biphenylylsulphonyl

N-butyl-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] -4-biphenylylsulfonamide, with 2-naphthylsulfonyl chloride

N-butyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2oxooxazolidin-5-ylmethyl} -2-naphthylsulfonamido.

76 Example 10

Similar to Examples 3 and 4, N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} butylsulfonamide was obtained

4- {3 - [(butane-1-sulfonyl) -methylamino] -2-hydroxypropylamino} benzamidine of the formula

ABOUT

O from 4-isopropyl-N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl-2-oxooxazolidin-5-ylmethyl} -benzenesulfonamide

- {3 - [(isopropylbenzenesulfonyl) methylamino] -2-hydroxypropylamino] benzamidine, acetate, FAB 405, from 3-trifluoromethyl-N-methyl-N- {3- [4- (5-methyl [1] 2,4-Oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl-benzenesulfonamide

4- {3 - [(3-trifluoromethylbenzolsulfonyl) methylamino] -2-hydroxypropylamino] benzamidine, acetate, FAB 431, from N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl-2-oxooxazolidin-5-ylmethyl-phenylvinylsulfonamide

- {3 - [(phenylsulfonyl) methylamino] -2-hydroxypropyl-amino] -benzamidine, from N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl)] - ) phenyl-2-oxooxazolidin-5-ylmethyl-2-naphthylsulfonamide

4- {3 - [(2-naphthylsulfonyl) methylamino] -2-hydroxypropylamino] benzamidine, acetate, FAB 413, from 6-chloro-N-methyl-N- {3- [4- (5-methyl [ 1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} -2-naphthylsulfonamide

4- {3 - [(6-chloro-2-naphthylsulphonyl) methylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 447, from 4-propyl-N-methyl-N- {3- [4- (5-methyl) [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl) benzenesulfonamide

4- {3 - [(4-propylbenzolsulfonyl) methylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 405, from 4-methoxy-N-methyl-N- {3- [4- (5-methyl [1,2] 4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} benzenesulfonamide

4- {3 - [(4-methoxybenzolsulfonyl) methylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 393, from 2,4,6-triraethyl-N-methyl-N- {3- [4- (5-methyl) [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} benzenesulfonamide

4- {3 - [(2,4,6-trimethylbenzolsulfonyl) methylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 405, from 5- {5 - [(5-benzoylmethylamino) methyl] -2-oxooxazolidin-3- yl} benzamidine

4- {3 - [(benzoylmethylamino] -2-hydroxypropylamino} benzamidine, from 5- {5 - [(2-naphthylcarbonylmethylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine

4- {3 - [(2-naphthylcarbonylmethylamino) -2-hydroxypropylamino} benzamidine, from 5- {5 - [(cyclohexylcarbonylmethylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine - {3 - [(cyclohexylcarbonylmethylamino) -2 -hydroxypropylamino} benzamidine, from 5- {5 - [(4-biphenylylcarbonylmethylamino) methyl] -2-oxooxazolidin-3-yl} benzamidine

4- {3 - [(4-Biphenylylcarbonylmethylamino) -2-hydroxypropylamino} benzamidine, from 5- {5 - [(4-chlorobenzoylmethylamino) methyl] -2-oxooxazolidin-3-yl] benzamidine

4- {3 - [(4-chlorobenzoylmethylamino) -2-hydroxypropylamino} benzamidine, from 4- (1,1-dimethylpropyl) -N-methyl-N- {3- [4- (5-methyl [1,2, 4] oxadiazol-3-yl) phenyl-2-oxo-oxazolidin-5-ylmethyl} benzenesulfonamide

4- {3 - [(4- (1,1-dimethylpropylbenzenesulfonyl) methylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 433, from 3,4-difluoro-N-methyl-N- {3- [4- (5-methyl [ 1,2,4] oxadiazol-3-yl) phenyl-2-oxo-oxazolidin-5-ylmethyl} benzenesulfonamide

4- {3 - [(3-fluoro-4-methoxybenzolsulfonyl) methylamino] -2-hydroxypropylamino) benzamidine, acetate, FAB 411, from 4-tert-butyl-N-methyl-N- {3- [4- (5- methyl- [1,2,4] oxadiazol-3-yl) phenyl-2-oxo-oxazolidin-5-ylmethyl} benzenesulfonamide

4- {3 - [(3-tert-butylbenzolsulfonyl) methylamino] -2-hydroxypropylamino} benzamidine acetate, FAB 419, from 4-trifluoromethyl-N-methyl-N- {3- [4- (5-methyl [1, 2,4] oxadiazol-3-yl) phenyl-2-oxo-oxazolidin-5-ylmethyl} benzenesulfonamide

4- {3 - [(4-trifluoromethylbenzolsulfonyl) methylamino] -2-hydroxy propylamino} benzamidine, acetate, FAB 431, from 4-pentyl-N-methyl-N- {3- [4- (5-methyl [1, 2,4] oxadiazol-3-yl) phenyl-2-oxo-oxazolidin-5-ylmethyl} benzenesulfonamide

4- {3 - [(4-pentylbenzolsulfonyl) methylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 433, from N-methyl-N- {3- [4- (5-methyl [1,2,4] oxadiazole-3)] yl) phenyl-2-oxooxazolidin-5-ylmethyl} -1-naphthylsulfonamido

4- {3 - [(1-naphthylsulfonyl) methylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 413, from 6-chloro-N-butyl-N- {3- [4- (5-methyl [1,2] , 4] oxadiazol-3-yl) phenyl-2-oxo-oxazolidin-5-ylmethyl] -2-naphthylsulfonamido

4- {3 - [(6-chloro-2-naphthylsulfonyl) butylamino] -2-hydroxypropylamino} benzamidine, from N-butyl-N- {3- [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} -4-biphenylylsulphonamide hydrochloride salt

4- [3 - [(4-biphenylylsulfonyl) butylamino] -2-hydroxypropylamino} benzamidine, from N-butyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl)] 4- {3 - [(2-naphthylsulfonyl) butylamino] -2-hydroxypropylamino} benzamidine phenyl-2-oxooxazolidin-5-ylmethyl} -2-naphthylsulfonamide, from N-methyl-N- {3- [4- (5- methyl- [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} - (7-methoxy-2-naphthyl) sulfonamide

4- {3 - [(7-methoxy-2-naphthylsulphonyl) methylamino] -2-hydroxypropylamino) benzamidine, acetate, FAB 443, from N-methyl-N- {3- [4- (5-methyl [1,2] , 4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} - (6-methoxy-2-naphthyl) sulfonamide

4- {3 - [(6-methoxy-2-naphthylsulfonyl) methylamino] -2-hydroxypropylamino} benzamidine acetate FAB 443.

Example 11

A solution of 10.9 g of 3- (4-cyanophenyl) -5-hydroxymethyloxazolidin-2-one (F), 5.9 g of 3-cyanophenol, 26.2 g of triphenylphosphine and 13.1 g of diethyl azodicarboxylate in 250 ml of tetrahydrofuran is stirred under a protective environment. gas for four hours. After working up in the usual manner, 3- (4-cyanophenyl) -5 - [(3-cyanophenoxy) methyl] oxazolidin-2-one is obtained.

A solution of 8.5 g of the dicyano compound, 5.5 g of hydroxylammonium chloride and 11.2 g of sodium carbonate in 130 ml of dimethylformamide is stirred for three hours at 60 ° C. Working up in the usual manner gives 3- (4-N-hydroxyamidinophenyl) -5 - [(3-N-hydroxyamidinophenoxy) methyl] oxazolidin-2-one.

Analogously to Example 2, 3- (4-amidinophenyl) -5 - [(3-amidinophenoxy) methyl] oxazolidin-2-one, diacetate, FAB 354, melting at 159-160 ° C, was hydrogenated from this compound.

Similarly, it is obtained by reacting F with 4'-hydroxybiphenyl-4-carbonitrile, reacting with hydroxylammonium chloride and reducing the compound obtained.

3- (4-amidinophenyl) -5 - [(4'-amidino-4-biphenylyloxy) methyl] oxazolidin-2-one, diacetate, melting point 214 DEG-224 DEG C., with 4-cyanophenol, reaction with hydroxylammonium chloride and reduction of the compound obtained

3- (4-amidinophenyl) -5 - [(4-amidinophenoxy) methyl] oxazolidin-2-one, diacetate, m.p. 164 ° C (dec.), With 4-cyano-N- (ethoxycarbonyl) benzolsulfonamide

N- [3- (4-cyanophenyl) -2-oxooxazolidon-5-ylmethyl] -N-ethoxycarbonyl-4-cyanobenzenesulfonamide, diacetate, FAB 489.

Example 12

A solution of 400 mg of {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -2-oxo-oxazolidin-5-yl] -methanesulfonic acid methyl ester,

240 mg of phenylpiperazine and 120 mg of sodium bicarbonate in 10 ml of acetonitrile are heated at 80 DEG C. for 18 hours. The reaction mixture is worked up in the usual manner to give 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5 (4-phenylpiperazin-1-ylmethyl) oxazolidin-2-one .

Hydrogenation similar to Example 2 gave 4- [2- [5- (5-phenylpiperazin-1-ylmethyl) oxazolidin-3-yl] benzamidine, acetate, FAB 380.

Similarly, treatment of A with 5-bromomethylbenzo [2,1,3] thiadiazole affords 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 (benzo [2]). , 1,3] thiadiazol-5-ylmethyl) piperazin-l-ylmethyl] oxazolidin-2-one.

Hydrogenation similar to Example 2 yields 4- {2-oxo-5- [4- (benzo [2,1,3] thiadiazol-5-ylmethyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine , acetate, FAB 512.

Similarly, it is obtained by reacting {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-yl] methanesulfonic acid methyl ester with 2-piperazin-1-yl-pyrimidine

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (pirimidin-2-yl) piperazin-1-ylmethyl] oxazolidin-2-one, with benzylpiperazine

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4-benzylpiperazin-1-ylmethyl] oxazolidin-2-one, s (benzo [2,1, 3] thiadiazol-5-yl) piperazine

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4-benzo [2,1,3] thiadiazol-5-yl) piperazin-l-ylmethyl] oxazolidin-2-one.

Similar to Examples 3 and 4, it is obtained by cleaving the oxazolidinone and oxadiazole ring from 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (pirimidin-2-yl)] piperazin-ylmethyl] oxazolidin-2-one

4- [2-hydroxy-3- (4- (pirimidin-2-ylpiperazin-1-yl) propylamino] benzamidine, acetate, FAB 356, from 3- [4- (5-methyl [1,2,4] ] oxadiazol-3-yl) phenyl] -5- [4-benzyl-l-ylmethyl] oxazolidin-2-one

4- [2-hydroxy-3- (4-benzylpiperazin-1-yl) propylamino] benzamidine acetate, FAB 368, from 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl)] phenyl] -5- [4-benzo [2,1,3] thiadiazol-5-yl) piperazin-l-ylmethyl] oxazolidin-2-one

4- [2-hydroxy-3- (4- [4-benzo [2,1,3] triazol-5-yl] piperazin-1-yl) propylamino] benzamidine, trifluoroacetate, FAB 412, from 3- [4- (5-methyl) [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,5-dimethoxybenzyl) piperazin-1-ylmethyl] oxazolidin-2-one 4- {2-hydroxy-3- [4 - (3,5-dimethoxybenzyl) piperazin-1-yl] propylamino) benzamidine, FAB 428.

Similarly, it is obtained by reacting {3- [3- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-yl] methanesulfonic acid methyl ester with 4-piperazin-1-yl-pyridine 3- [ 3- (5-methyl- [1,24] oxadiazol-3-yl) phenyl] -5- [4- (pyridin-4-yl) piperazin-1-ylmethyl] oxazolidin-2-one and its hydrogenation 3- {2 oxo-5- [4 (pyrxdin-4-yl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine, acetate, FAB 381, mp 152-165 (dec.).

Example 13

A solution of 200 mg of A and 66 mg of butyl isocyanate in 10 ml of dichloromethane is stirred for four hours. Add 400 mg of aminomethyl polystyrol and stir for an additional 12 hours. The polystyrol and solvent were removed and conventional work-up gave 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-butylaminocarbonylpiperazin-1-ylmethyl) oxazole-1-yn-2- on.

Similarly, it is obtained by reaction of A with cyclohexyl isocyanate

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-cyclohexylaminocarbonylpiperazin-1-ylmethyl) oxazolidin-2-one, with 4-methoxyphenyl isocyanate

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [N- (4-methoxyphenyl) aminocarbonyl] piperazin-1-ylmethyl} oxazolidin-2-one, with 4-trifluoromethylphenyl isocyanate

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4-N- (4-trifluoromethylphenyl) aminocarbonyl] piperazin-1-ylmethyl] oxazolidin-2- he, with 4-chlorophenyl isocyanate

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4-N- (4-chlorophenyl) aminocarbonyl] piperazin-1-ylmethyl} oxazolidin-2-one , with 3-ethoxycarbonylphenyl isocyanate

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4-N- (3-ethoxycarbonylphenyl) aminocarbonyl] piperazin-1-ylmethyl) oxazolidin-2-one, s 1-naphthyl isocyanate

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (naphth-1-yl) aminocarbonyl] piperazin-1-ylmethyl} oxazolidin-2-one.

Hydrogenation similar to Example 2 gave 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [N- (4-methoxyphenyl) aminocarbonyl] in-1-y-1-oxomethyl-oxa-2-one pipera pipera,

4- {2-ΟΧΟ-5- {4- [N- (4-methoxyphenyl) aminocarbonyl] piperazin-1-ylmethyl} oxazolidin-3-yl} benzamidine acetate FAB 453,

from 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [N- (4-trifluoromethylphenyl) aminocarbonyl] pipera from in-1- y lmetyl 1} oxa zolidin-2-one,

4- {2-oxo-5- {4- [N- (4-trifluoromethylphenyl) aminocarbonyl] piperazin-1-ylmethyl} oxazolidin-3-yl} benzamidine acetate, FAB 473, from 3- [4- ( 5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- [N- (4-chlorophenyl) aminocarbonyl] piperazin-1-ylmethyl} oxazolidin-2-one,

4- {2-oxo-5- {4- [N- (4-chlorophenyl) aminocarbonyl] piperazin-1-ylmethyl} oxazolidin-3-yl} benzamidine, acetate, FAB 457, from 3- [4- (5-methyl [ 1,2,4] oxadiazol-3-yl) phenyl] -5- (4-butylaminocarbonylpiperazin-1-ylmethyl) oxazolidin-2-one,

4- [2-Oxo-5- (4-butylaminocarbonylpiperazin-1-ylmethyl) oxazolidin-3-yl] benzamidine, acetate, FAB 403, from 3- [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] -5- {4- [N- (3-ethoxycarbonylphenyl) aminocarbonyl] piperazin-1-ylmethyl] oxazolidin-2-one,

4- {2-ΟΧΟ-5- {4- [N- (3-ethoxycarbonylphenyl) aminocarbonyl] piperazin-1-ylmethyl) oxazolidin-3-yl} benzamidine acetate, FAB 495, from 3- [4- (5 - methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- {4- (naphth-1-ylaminocarbonyl) piperazin-1-ylmethyl] oxazolidin-2-one,

4- {2-oxo-5- [4- (naphth-1-ylaminocarbonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamidine acetate FAB 403.

Similar to Examples 3 and 4, 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-butylaminocarbonyl) piperazin-1-ylmethyl) is obtained. oxazolidin-2-one

4- [3- (4-Butylaminocarbonyl) piperazin-1-yl) -2-hydroxypropylamino] benzamidine acetate FAB 377, from 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] 5- (4-Cyclohexylaminocarbonyl) piperazin-1-ylmethyl) oxazolidin-2-one

4- [3- (4-cyclohexylaminocarbonyl) piperazin-1-yl) -2-hydroxypropylamino] benzamidine acetate FAB 403

Example 14

A solution of 1 equivalent of {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl-phenyl] -2-oxo-oxazolidin-5-yl} -methanesulfonic acid methyl ester, 3 equivalents of glycine benzyl ester, methanesulfonate, and 3 equivalents of sodium bicarbonate in acetonitrile and refluxed for 18 hours to give {{3- [4- (5-methyl- [1,2,4] oxadiazol-3-ylphenyl] -2-oxooxazolidin-5-ylmethyl} amino) benzyl ester } acetic acid (G).

Similarly obtained by reacting G with 6-chloronaphth-2-ylsulfonyl chloride {N- [6-chloronaphth-2-ylsulfonyl] -N- {3- [4- (5-methyl [1,2,4] oxadiazole-3-) benzyl ester yl) phenyl] -2-oxooxazolidin-5-ylmethyl} amino} acetic acid. '

Hydrogenation, similar to Example 2, yields

- {N- [6-chloronaphth-2-ylsulfonyl] -N- [3- (4-amidinophenyl) -2-oxooxazolidin-5-ylmethyl] amino} acetic acid, acetate, FAB 517 and {N- [benzyl ester] 6-Chloronaphth-2-ylsulfonyl] -N- [3- (4-amidinophenyl) -2-oxooxazolidin-5-ylmethyl] amino} acetic acid.

Similarly, it is obtained by reacting G with naphth-2-ylsulfonyl chloride followed by hydrogenation of {N- [naphth-2-ylsulfonyl] -N- [3- (4-amidinophenyl) -2-oxooxazolidin-5-ylmethyl] amino} acetic acid, acetate, FAB 483

with 4-methoxybenzolsulfonyl chloride followed by hydrogenation of {N- [4-methoxybenzolsulfonyl] -N- [3- (4-amidinophenyl) -2-oxooxazolidin-5-ylmethyl] amino} acetic acid, acetate, FAB 453, with phenylvinylsulfonyl chloride and followed by hydrogenation of {N- [phenylvinylsulfonyl] -N- [3- (4-amidinophenyl) -2-oxooxazolidin-5-ylmethyl] amino} acetic acid benzyl ester acetate, FAB 549,

87 with 4-biphenylylsulfonyl chloride followed by hydrogenation of {N- [4-biphenylylsulfonyl] -N- [3- (4-amidinophenyl) -2-oxooxazolidin-5-ylmethyl] amino} acetic acid, acetate, FAB 509, s 4-propylbenzenesulfonyl chloride followed by hydrogenation of {N- [4-propylbenzolsulfonyl) -N- [3- (4-amidinophenyl) -2-oxooxazolidin-5-ylmethyl] amino} acetic acid benzyl ester, acetate, FAB 565.

Example 15

A solution of 4-oxiranylmethoxybenzonitrile and BOC-piperazine in methanol was stirred at reflux for four hours. Conventional work-up gives 4- [2-hydroxy-3- (4-BOC-piperazin-1-yl) -propoxy] -benzonitrile benzyl ester. Subsequent reaction with hydroxylamine hydrochloride affords N-hydroxy-4- [2-hydroxy-3- (4-BOC-piperazin-1-yl) propoxy] benzamidine. Subsequent acylation with acetic anhydride affords 2-acetoxy-1- (4-BOC-piperazin-1-yl) -3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenoxy] propane. After cleavage of the BOC group with hydrochloric acid in dioxane, 2-acetoxy-1- [4- (4-propylphenylsulfonyl) piperazin-1-yl] -3- [4- (5-methyl [1]) is obtained by treatment with 4-propylphenylsulfonyl chloride. 2,4] oxadiazol-3-yl) phenoxy] propane.

Similar to Examples 3 and 4, it is obtained

4- {2-hydroxy-3- [4- (4-propylphenylsulfonyl) piperazin-1-yl] propoxy} benzamidine

* in

Similarly, the following compounds are obtained:

3- {2-hydroxy-3- [4- (4-biphenylylcarbonyl) piperazin-1-yl] propoxy} benzamidine acetate FAB 459,

3- {2-hydroxy-3- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-yl] propoxy} benzamidine acetate FAB 503,

3- {2-hydroxy-3- [4- (2-naphthylsulfonyl) piperazin-1-yl] propoxy} benzamidine acetate FAB 469,

3- {2-hydroxy-3- [4- (4-propyl-phenylsulfonyl) -piperazin-1-yl] -propoxy} -benzamidine acetate FAB 461,

3- {2-hydroxy-3- [4- (4-isopropyl-phenylsulfonyl) -piperazin-1-yl] -propoxy} -benzamidine acetate FAB 461,

3- {2-hydroxy-3- [4- (4-methoxy-phenylsulfonyl) -piperazin-1-yl] -propoxy} -benzamidine acetate FAB 449,

3- {2-hydroxy-3- [4- (4-butylphenylsulfonyl) piperazin-1-yl] propoxy} benzamidine acetate FAB 399,

3- {2-hydroxy-3- [4-benzoylpiperazin-1-yl] propoxy} benzamidine, acetate, FAB 383,

3- {2-hydroxy-3- [4- (7-methoxy-2-naphthylsulfonyl) piperazin-1-yl] propoxy} benzamidine acetate FAB 499,

3- {2-hydroxy-3- [4- (3,5-dimethoxybenzyl) piperazin-1-yl] propoxy} benzamidine acetate FAB 429,

3- {2-hydroxy-3- [4- (4-biphenylylsulfonyl) piperazin-1-yl] propoxy} benzamidine diacetate, FAB 495,

- {2-hydroxy-3- [4-naphth-2-ylmethyl] piperazin-1-yl) propoxy} benzamidine diacetate, FAB 419,

3- {2-hydroxy-3- [4- (2-naphthylcarbonyl) piperazin-1-yl] propoxy} benzamidine diacetate, FAB 433,

3- {2-hydroxy-3- [4- (biphenyl-4-ylmethyl) piperazin-1-yl] propoxy} benzamidine, diacetate, FAB 445.

Example 16

10.0 g of 3-oxiranylmethoxybenzonitrile (H) and 7.1 g of 3-cyanophenol together with 173 mg of cesium fluoride are melted at 130 ° C. The usual work-up gives 11.8 g of 1,3-bis- (3-cyanophenoxy) -2-hydroxypropane. Subsequent reaction with hydroxylammonium chloride affords 1,3-bis- [3- (N-hydroxyamidino) phenoxy] -2-hydroxypropane. Hydrogenation similar to Example 2 gave 1,3-bis- (3-amidinophenoxy) -2-hydroxypropane, diacetate, FAB 329

HO

Similarly, 1,3-bis- (4-amidinophenoxy) -2-hydroxypropane, diacetate, FAB 329 and

- (3-amidinophenoxy) -3- (4-amidinophenoxy) -2-hydroxypropane, diacetate, FAB 329.

Similarly, they are obtained by reacting H with the following phenols

4-chlorophenol,

4-methylphenol, phenol,

4-methoxyphenol,

4-cyclohexylphenol followed by reaction with hydroxylammonium chloride and hydrogenation of the following compounds:

1- (3-amidinophenoxy) -2-hydroxy-3- (4-chlorophenoxy) propane,

1- (3-amidinophenoxy) -2-hydroxy-3- (4-methylphenoxy) propane 1- (3-amidinophenoxy) -2-hydroxy-3-phenoxypropane,

1- (3-amidinophenoxy) -2-hydroxy-3- (4-methoxyphenoxy) propane and 1- (3-amidinophenoxy) -2-hydroxy-3- (4-cyclohexylphenoxy) propane.

Example 17

A solution of 1 equivalent of N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl-phenyl) -2-oxooxazolidin-5-ylmethyl)} - (6-chloro-2-naphthyl) sulfonamide (I) [obtainable by reacting 5-aminomethyl-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] oxazolidin-2-one with 6-chloro-2-naphthylsulfonyl chloride], each with 1.1 equivalents of N , N'-dimethylchloroacetamide and cesium carbonate in dimethylformamide were stirred at room temperature for 12 hours. Conventional work-up gives 2 - ((6-chloro-2-naphthylsulfonyl- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl}) amino} -N, N-dimethylacetamide.

Similar to Examples 3 and 4, 2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (6-chloro-2-naphthylsulfonyl) amino] -N, N'-dimethylacetamide was obtained from this compound.

Similarly, they are obtained by reaction of I with compounds of the group consisting of

N, N ' diétylchlóracetamid,

N, N ¹ -dipropylchloroacetamide,

N-phenylchloroacetamide,

Ν, Ν'-Diphenylchloroacetamide and chloroacetic acid ethyl ester followed by cleavage of the oxazolidinone and oxadiazole ring according to the procedure of Examples 3 and 4 of the following compound

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (6-chloro-2-naphthylsulfonyl) amino] -N, N'-diethylacetamide

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (6-chloro-2-naphthylsulfonyl) amino] -N, N'-dipropylacetamide

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (6-chloro-2-naphthylsulfonyl) amino] -N-phenylacetamide

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (6-chloro-2-naphthylsulfonyl) amino] -N, N'-diphenylacetamide and

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (6-chloro-2-naphthylsulphonyl) amino] acetic acid, acetate, FAB 491.

Similarly, it is obtained by reacting N- {3- [4- (5-methyl [1,2,4] oxadiazol-3-ylphenyl] -2-oxooxazolidin-5-ylmethyl)} - (4-isopropylphenyl) sulfonamide with the compound of the group including N, N'-dimethylchloroacetamide,

N, N ¹ -diethylchloroacetamide,

N, N ' dipropylchlóracetamid,

N-phenylchloroacetamide,

N, N'-diphenylchloroacetamide, benzyl bromide, iodobutane,

4-chloromethyl-2-methylthiazole,

4-methoxybenzyl bromide, ethyl chloroacetate, ethyl 4-chlorobutyrate, ethyl 3-chloromethylbenzoate, ethyl 4-chloromethylbenzoate,

3,5-dimethoxybenzyl,

4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl bromide.

3- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl bromide a

2-fluorobenzyl bromide followed by cleavage of the oxazolidinone and oxadiazole ring by the method of Examples 3 and 4 of the following compound

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylsulfonyl) amino] -N, N-dimethylacetamide

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylsulfonyl) amino] -N, N-diethylacetamide

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylsulfonyl) amino] -N, N-dipropyl

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylsulfonyl) amino] -N-phenylacetamide

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylsulfonyl) amino] -N, N'-diphenyl acetamide

4 - {(2-hydroxy) -3 - [(4-isopropylbenzenesulfonyl) benzylamino] propylamino} benzamidine acetate FAB 481,

4 - {(2-hydroxy) -3 - [(4-isopropylbenzenesulfonyl) butylamino] propylamino} benzamidine acetate FAB 447,

4 - {(2-hydroxy) -3 - [(4-isopropylbenzenesulfonyl) - (2-methylthiazol-4-ylmethyl) amino] propylamino} benzamidine acetate, FAB 502,

4 - {(2-hydroxy) -3 - [(4-isopropylbenzenesulfonyl) - (4-methoxybenzyl) amino] propylamino} benzamidine acetate FAB 511,

2- [C 3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylbenzenesulfonyl) amino] acetic acid, acetate, FAB 449,

4 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylbenzenesulfonyl) amino] butyric acid acetate, FAB 477,

3 - {[[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylbenzenesulfonyl) amino] methyl} benzoic acid, diacetate,

FAB 525,

4 - {[[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylbenzenesulfonyl) amino] methyl} benzoic acid, diacetate,

FAB 525,

4 - {(2-hydroxy) -3 - [((4-isopropylbenzenesulfonyl) - (3,5-dimethoxybenzyl) amino] propylamino} benzamidine diacetate, FAB 541,

4 - {(2-hydroxy) -3 - [((4-isopropylbenzenesulfonyl) - (4-amidinobenzyl) amino] propylamino) benzamidine, triacetate, FAB 523,

4 - {(2-hydroxy) -3 - [((4-isopropylbenzenesulfonyl) - (3-amidinobenzyl) amino] propylamino} benzamidine, triacetate, FAB 523,

4 - {(2-hydroxy) -3 - [((4-isopropylbenzenesulfonyl) - (2-fluorobenzyl) amino] propylamino} benzamidine, diacetate, FAB 499.

Similarly, it is obtained by reaction of I with compounds of the group consisting of iodoethane, benzyl bromide,

4-methoxybenzyl,

2-bromomethylnaphthalene.

4-chloromethyl-2-methylthiazole and 4-methoxybenzyl chloride followed by cleavage of the oxazolidinone and oxadiazole rings by the procedure of Examples 3 and 4 of the following compound

4- {3 - [(6-chloro-2-naphthylsulfonyl) ethylamino] -2-hydroxypropylamino} benzamidine

Cl

4- {3 - [(6-chloro-2-naphthylsulfonyl) benzylamino] -2-hydroxypropyl amino} benzamidine,

4- {3 - [(6-chloro-2-naphthylsulfonyl) - (4-methoxybenzyl) amino] -2-hydroxypropylamino} benzamidine,

4- {3 - [(6-chloro-2-naphthylsulfonyl) - (naphth-2-ylmethyl) amino] -2-hydroxypropylamino) benzamidine,

4- {3 - [(6-chloro-2-naphthylsulfonyl) - (2-methylthiazol-4-ylmethyl) amino] -2-hydroxypropylamino) benzamidine, diacetate, FAB 544 and

4- {3 - [(6-chloro-2-naphthylsulfonyl) - (4-methoxybenzyl) amino] -2-hydroxypropylamino} benzamidine, diacetate, FAB 553.

Similarly, it is obtained by reacting N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-ylphenyl] -2-oxooxazolidin-5-ylmethyl)} - (4-methoxyphenyl) sulfonamide with iodobutane followed by cleavage of the oxazolidinone and oxadiazole rings by the method of Examples 3 and 4

4- {3 - [(4-methoxyphenylsulfonyl) butylamino] -2-hydroxypropylamino) benzamidine acetate FAB 435.

Similarly, it is obtained by reacting N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-ylphenyl] -2-oxooxazolidin-5-ylmethyl)} - (2-naphthyl) sulfonamide with iodobutane and iodoethane followed by cleavage of the oxazolidinone and oxadiazole rings by the method of Examples 3 and 4

4- {3 - [(2-naphthylsulfonyl) butylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 455 and

4- {3 - [(2-naphthylsulfonyl) ethylamino] -2-hydroxypropylamino} benzamidine, acetate, FAB 427.

Example 18

Similar to Example 11, the following compounds are obtained from the corresponding cyano derivatives by reaction with hydroxylammonium chloride:

3- (3-N-hydroxyamidinophenyl) -5 - [(4-N-hydroxyamidinophenoxy) methyl] oxazolidin-2-one, m.p. 201-205 ° C,

3- (3-N-hydroxyamidinophenyl) -5 - [(3-N-hydroxyamidinofenoxy) methyl] oxazolidin-2-one;

3- (4-N-hydroxyamidinophenyl) -5 - [(3-N-hydroxyamidinobenzyloxy) methyl] oxazolidin-2-one;

3- (3-N-hydroxyamidinophenyl) -5 - [(3-N-hydroxyamidinobenzyloxy) methyl] oxazolidin-2-one;

Similar to Example 2, the following compounds were obtained by hydrogenation from these compounds:

3- (3-amidinophenyl) -5 - [(4-amidinophenoxy) methyl] oxazolidin-2-one, diacetate, m.p. 150-166 ° C (dec.), FAB 354

3- (3-amidinophenyl) -5 - [(3-amidinophenoxy) methyl] oxazolidin-2-one, diacetate, mp 312-318C,

3- (4-amidinophenyl) -5 - [(3-amidinobenzyloxy) methyl] oxazolidin-2-one, triacetate, m.p. 189 DEG-205 DEG C. (dec.), FAB 368,

3- (3-amidinophenyl) -5 - [(3-amidinobenzyloxy) methyl] oxazolidin-2-one, triacetate, m.p. 204-222 ° C (dec.), FAB 368.

Example 19

Similar to Example 16, it is obtained by reaction of 4-oxiranylethylbenzonitrile and 3-cyanophenol, followed by treatment with hydroxylammonium chloride and hydrogenation of 4- [3-hydroxy-4- (3-aminophenoxy) butyl] benzamidine, diacetate, FAB 327 h ₂ n bh ₂

OH

Example 20

In a nitrogen atmosphere, 10.0 g of 3- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenol is introduced into 50 ml of dimethylformamide, followed by 2.6 g of sodium hydride at 0 ° C. Add 5.1 ml of epibromohydrin and stir for 24 hours at room temperature. Conventional work-up gives 5-methyl-3- (3-oxiranylmethoxyphenyl) [1,2,4] oxadiazole. 8.0 g of the oxiranyl compound are dissolved in 400 ml of methanol and ammonia gas is introduced for six hours. Stir for 16 hours and remove the solvent to give 1-amino-3- [3- (5-methyl- [1,2,4] oxadiazol-3-yl-phenoxy] -propan-2-ol (AB).

500 mg of AB and 434 mg of 4-methoxyphenylsulfonyl chloride are mixed together with 2.0 g of polymeric DMAP (1.6 mmol of dimethylaminopyridine / g resin) in 5 ml of pyridine for 24 hours at room temperature. The resin is filtered off and the filtrate is worked up in the usual manner to give N- {2-hydroxy-3- [3- (5-methyl- [1,2,4] oxadiazol-3-yl) phenoxy] propyl} -4- methoxybenzolsulfonamide.

Hydrogenation according to the method of Example 2 yields

3- [2-hydroxy-3- (4-methoxybenzolsulfonamino) propoxy] benzamidine, acetate, FAB 380

NH

ABOUT

Similarly, they are obtained by reacting AB with a compound selected from the group consisting of

4-isopropylphenylsulfonyl chloride,

2-naphthylsulfonyl chloride,

6-chloro-2-naphthylsulfonyl chloride,

7-methoxy-2-naphthylsulfonyl chloride, followed by hydrogenation of the following compound

3- [2-hydroxy-3- (4-isopropylbenzenesulfonylamino) propoxy] benzamidine, acetate, FAB 392,

- [2-hydroxy-3- (2-naphthylsulfonylamino) propoxy] benzamidine, acetate, FAB 400,

3- [2-hydroxy-3- (6-chloro-2-naphthylsulfonylamino) propoxy] benzamidine, acetate, FAB 434 and

3- [2-hydroxy-3- (7-methoxy-2-naphthylsulfonylamino) propoxy] benzamidine, acetate, FAB 430.

Similarly, they are obtained by reacting 1-amino-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenoxy] propan-2-ol with a compound selected from the group consisting of:

4-Methoxyphenylsulfonyl chloride

4-isopropylphenylsulfonyl chloride,

2-naphthylsulfonyl chloride,

6-Chloro-2-naphthylsulfonyl chloride a

7-Methoxy-2-naphthylsulfonyl chloride followed by hydrogenation of the following compound

4- [2-hydroxy-3- (4-methoxybenzenesulfonylamino) propoxy] benzamidine, acetate, FAB 380,

4- [2-hydroxy-3- (4-isopropylbenzenesulfonylamino) propoxy] benzamidine, acetate, FAB 392,

4- [2-hydroxy-3- (2-naphthylsulfonylamino) propoxy] benzamidine, acetate, FAB 400,

4- [2-hydroxy-3- (6-chloro-2-naphthylsulfonylamino) propoxy] benzamidine acetate FAB 434,

4- [2-hydroxy-3- (7-methoxy-2-naphthylsulfonylamino) propoxy] benzamidine, acetate, FAB 430.

Example 21

Add 10.7 g of sodium methylate (30% in methanol) to 30 ml of methanol, add 4- (5-methyl [1,2,4] oxadiazol-3-yl) aniline under nitrogen and stir the reaction mixture for 10 minutes at 45 ° C. The mixture is suspended in 480 mg of paraformaldehyde, 20 ml of methanol are added and the reaction mixture is stirred for two hours at 60 ° C. 440 mg of sodium borohydride is added and the reaction mixture is stirred for one hour at 60 ° C. Subsequently, 1.44 g of paraformaldehyde, 3.1 g of sodium methylate and 220 mg of sodium borohydride are added to the reaction mixture.

After two hours, hydrolysis is carried out by the addition of 1N sodium hydroxide solution and the mixture is worked up in the usual manner. 1.93 g of N-methyl-4- (5-methyl- [1,2,4] oxadiazol-3-yl) aniline are obtained as crude product.

A solution of 1.35 g of N-methyl-4- (5-methyl [1,2,4] oxadiazol-3-yl) aniline and 10 ml of epichlorohydrin in 5 ml of ethanol and 3.5 ml of water is refluxed for 12 hours. hours. The usual work-up gives 0.4 g of N-methyl-N-oxiranylmethyl-4- (5-methyl- [1,2,4] oxadiazol-3-yl) aniline. A solution of 0.39 g of N-methyl-N-oxiranylmethyl-4- (5-methyl- [1,2,4] oxadiazol-3-yl) aniline and 30 ml of methylamine (33% in ethanol) in 10 ml of ethanol is stirred for 15 hours at 65 ° C. Conventional work-up gives 0.44 g of 1-methyl100 amino-3- (methyl- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] amino} propan-2-ol (BC). ).

Stir 100 mg of BC and 87 mg of 4-isopropylphenylsulfonyl chloride together with 300 mg of polymeric DMAP (1.6 mmol of dimethylaminopyridine / g resin) in 5 mL of dichloromethane for 16 hours at room temperature. The resin was filtered off and the filtrate was worked up in the usual manner to give 109 mg of N- (2-hydroxy-3- (methyl [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl) amino] (propyl) -4-isopropyl-N-methylbenzenesulfonamide.

Hydrogenation according to the method of Example 2 yields

4- ({2-hydroxy-3 - [(4-isopropylbenzenesulfonyl) -N-methylamino] propyl} -N-methylamino) benzamidine acetate, FAB 419

NH

Similarly, it is obtained by reaction of BC with 2-naphthylsulfonyl chloride and subsequent hydrogenation

4- ({2-hydroxy-3 - [(naphth-2-ylsulfonyl) -N-methylamino] propyl} -N-methylamino) benzamidine diacetate, FAB 427.

The following examples illustrate pharmaceutical compositions:

Example A. Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water

101 is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and filled into vials, lyophilized under sterile conditions, and the vials sealed. Each vial contains 5 mg of active ingredient.

Example B. Suppositories

A mixture of 20 g of an active compound of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C. Solution

A solution of 1 g of an active compound of the formula I, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of dihydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH of the solution was adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D. Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E. Tablets

Tablets are compressed in a conventional manner from a mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate such that each tablet contains 10 mg of the active ingredient.

102

Example F. Dragees

Analogously to Example E, tablets are compressed and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G. Capsules

In a known manner, 2 kg of active ingredient of the formula I are filled into hard gelatine capsules such that each capsule contains 20 mg of active ingredient.

Example H. Ampoules

A solution of 1 kg of an active compound of the formula I in 60 l of double-distilled water is sterile filtered and filled into ampoules, lyophilized under sterile conditions and the ampoules sealed. Each ampoule contains 10 mg of active ingredient.

Industrial usability

The benzamidine derivative and its pharmaceutically acceptable salts are useful as coagulation factor Xa inhibitors for the manufacture of pharmaceutical compositions.

Claims (3)

PATENT CLAIMS /) '«ΑίΤ? -2J03 First Benzamidine derivative of the general formula 1 W. (I) where is R ^{1 is} -C (= NH) -NH 2, which optionally has one substituent selected from -COA, -CO- [C (R ⁵ ) 2] _m -Ar, -COOA, -OH or is a group HN-4 ^or N = < O CH ₃ R ² is hydrogen, A, OR ⁵ , N (R ⁵ ) ₂ , NO ₂ , CN, Hal, NR ⁵ COA, NHCOAr, NHSO 2A, NHSO 2 Ar, COOR ⁵ , CON (R ⁵ ) 2, COHNAr, COR ⁵ , COAr, S (O) _n A or S (O) _n Ar, R ³ R ⁵ or - [C (R ⁵ ) ₂ ] _m -COOR ⁵ , R ³ and X together also -CO-N to form a five membered ring, where R ^{3 is} -C -CO and X is N, R ⁴ A, cycloalkyl, - [C (R ⁵ ) 2] m -Ar, - [C (R ⁵ ) 2] _m -Het or -CR ⁵ = CR ⁵ -Ar, R @ ⁵ is hydrogen, A or benzyl, 104 O, NR ⁵ or CH ₂ , O, NR ⁵ , N [C (R ⁵ ) 2] m -Ar, N [C (R ⁵ ) 2] _m -Het, N [C (R ⁵ ) ₂ ] _m -COOR ⁵ , -NN 1 '; R ⁵ \ / R ⁵ N [C ^(R5) J m-CON (R ⁵⁾ second N [C (R ⁵⁾ 2] m Ar-CONR ⁵ None ^(R5) J _m-2 Conara, a bond, _-SO2-, -CO-, -COO- or -CONR ⁵ A is an alkyl group having 1 to 20 carbon atoms in which one or two CH ₂ groups are optionally replaced by an oxygen or sulfur atom, -CR ⁵ = CR ⁵ - groups and / or one to seven hydrogen atoms by fluorine atoms, Ar is a phenyl or naphthyl group unsubstituted or substituted by one, two or three of R ¹ , A, Ar ¹ , OR ⁵ , N (R ⁵ ) 2, NO 2, CN, Hal, NHCOA, NHCOAr ', NHSO2A, NHSO2Ar ', COOR ⁵ , CON (R ⁵ ) 2, CONHAr', COR ⁵ , COAr ', S (O) _n A and S (O) _n Ar Ar 1 phenyl or naphthyl unsubstituted or substituted by one, two or three of R ¹ , A, OR ⁵ , N (R ⁵ ) ₂ , NO ₂ , CN, Hal, NHCOA, COOR ⁵ , CON (R ⁵ ) 2, COR ⁵ , CO Ar ¹ and S (O) n A, Het unsubstituted or one or more groups selected from the group consisting of Hal, A, Ar ', OR ⁵ , COOR ⁵ , CN, N (R ⁵ ) ₂ , NO ₂ , NHCOA, NHCOAr' and oxo substituted single or double ring saturated or unsaturated a ring system containing one, two, three or four identical or different heteroatoms such as nitrogen, oxygen and sulfur, Hal is fluorine, chlorine, bromine or iodine, m is 0, 1, 2, 3 or 4, n is 0, 1 or 2, and salts thereof. The benzamidine derivative according to claim 1 of the general formula I selected from the file comprising (a) 4- {3- [4- (2,6-dichloro-4-methoxybenzenesulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine; (b) 4- {3 - [(4-isopropylbenzenesulfonyl) methylamino] -2-hydroxypropylamino} benzamidine; c) 4- {3- [4- (1-naphthylbenzenesulfonyl) piperazin-1-yl] -2-hydroxypropylamino} benzamidine; d) 3- (4-amidinophenyl) -5 - [(3-amidinophenoxy) methyl] oxazolidin-2-one and its salts. A process for the preparation of a benzamidine derivative according to claim 1, wherein the individual symbols are as defined in claim 1 and salts thereof, characterized in that: (a) is liberated from its functional derivative by a solvolysis or hydrogenolysis agent such that: (i) the amidino group of the oxadiazole derivative is released by hydrogenolysis; 106 (11) the conventional amino protecting group is replaced by hydrogen treatment with the treatment with a solvolysis or hydrogenolysis reagent, or is released with a conventional protecting group; or b) for the preparation of a compound of formula I wherein R ^{1 is a} group