CZ20002126A3 - Benzamidine derivative, process of its preparation, its use and pharmaceutical preparation containing thereof - Google Patents

Abstract

The benzamidine derivative of formula (I) wherein R @ 1 is - C (= NH) -NH 2, which optionally has 1 substituent from the - COA, -CO- [C (R 5) 2] m -Ar, -COOA, -OH, or groups (a), R 2 H, A, OR 5, N (R 5) 2, NO 2, CN, Hal, NR 5 COA, NHCOAr, NHSO2A, NHSO2Ar, COOR5, CON (R5) 2, COHNAr, COR5, COAr, S (O) n or S (O) nAr, R3 R5 or CO [C (R 5) 2] m -COOR 5, R 3 and X together also form -CO-N to form The 5-ring, wherein R 3 is -C = O and X N, R 4A, cycloalkyl, - CO- [C (R 5) 2] mHet, or -CR 5 = CR 5 -Ar, R 5 H, A or benzyl, X is O, NR 5 or CH 2, Y is O, NR 5, -CO [C (R 5) 2] m -Ar, -CO- [C (R 5) 2] m -Het, -CO- [C (R 5) 2] m -COOR 5, groups (b), - N [C (R 5) 2] m-CON (R 5) 2, -N [C (R 5) 2] m-CONR 5Ar or - N [C (R 5) 2] m-CONAr 2, W bond, -SO 2 -, -CO-, -COO- or - CONR 5, A 2 C 20 alkyl wherein 1 or 2 CH 2 are optionally replaced by O or S, -CR 5 = CR 5 - and / or 1-7 H F atoms, whose physiologically acceptable salts are suitable as inhibitors of coagulation factor Xa for production pharmaceutical compositions for treatment and protection against

Description

Technical field

The invention relates to a benzamidine derivative of the formula I, ‘1

R ¹

where it means

R ¹ is -C (= NH) -NH 2, which optionally has one substituent selected from the group consisting of -COA, -CO-tC (R ⁵ > 2m-Ar, -COOA, -OH, or is a group

or

O

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

NR ^S COA, NHCOAr, NHSO2A, NHSO2Ar, COOR ⁵ , C0N (R ⁵ ) 2,

COHNAr, COR ⁵ , COAr, S (O) _n A or S (O) _n Ar,

R ³ R ⁵ or - [C (R ⁵ ) 21m-COOR ⁵ ,

R ³ and X together are also -CO-N to form a five-membered ring, where R ³ is -C =O and X is N,

R ⁴

R ⁵

A, cycloalkyl, - [CCR ⁵ ] 21m-Ar, - [CCR ⁵ ] 3] _m -Het or -CR ⁵ = CR ⁵ -Ar, hydrogen, A or benzyl, oxygen, NR ⁵ or CH 2, O, NR ⁵ , N [CCR ⁵ ] 2 µ-Ar,

NCRC ⁵ ) 21 »-Het,

N [C (R ⁵ ) ₂ ] _m -COOR ⁵ , - N N_,

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

N [C (R ⁵ ) ₂ ] _m -CONA ₂ ,

W is a bond, -SO 2 -, -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 a phenyl or naphthyl group unsubstituted or substituted by one, two or three of R ¹ , A, Ar ', OR ⁵ , N (R ⁵ ) 2, NO ₂ , CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSOsAr ',

COOR ⁵ , CON (R ⁵ ) 2, CONHAr ', COR ⁵ , COAr', SCO nA and S <0) _n Ar,

Ar 'a phenyl or naphthyl group unsubstituted or substituted by one, two or three groups selected from the group consisting of R ¹ , A, OR ⁵ , N (R ⁵ ) 2;

NO ₂ , cn, Hal, NHCOA, COOR ⁵ , CON (R ⁵ ) 2, COR ⁵ , CO A 'and S (O) _n A,

Het is unsubstituted or one or more groups from the group consisting of Hal, A, Ar ', OR ^5, COOR ^5, CN, N ^(R) _2, NO2, NHCOA, NHCOAr' and oxo substituted jednokruhý or dvoukruhý saturated or unsaturated 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 invention of diastereomers also relates to optically active forms, the racemate. as well as hydrates and solvates of these compounds.

BACKGROUND OF THE BACKGROUND

Aromatic amidine derivatives having antithrombotic activity are known, for example, from European Patent Specification EP 0 540051 B1. Cyclic guanidines for the treatment of thromboembolic diseases are known, for example, from WO 97/08165. Aromatic heterocyclic compounds having factor Xa inhibitory activity are known, for example, from WO 96/10022.

SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds with 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 can therefore be used for the treatment and protection of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, angiopiastic restenosis and calf muscle pain while walking or preventing these conditions.

The antithrombotic and anticoagulant activity of the compounds of the invention is related to inhibition of activated clotting protease, known as factor Xa, or to 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. Activation of thrombin 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).

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 as described by T. Hara et al. (Thromb. Haemostas. 1994, 71, 314-319).

The clotting factor VIIA, upon binding to the tissue factor, initiates the extrinsic fraction of the clot formation and contributes to the activation of factor X to factor Xa. Inhibition of Factor VIIIa 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 methods known in the art, in vitro or in vivo. 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 medicaments in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy. angina pectoris, angiopiastic restenosis and gastric pain when walking.

Accordingly, the present invention provides compounds of formula I and salts thereof. According to the invention, a process for the preparation of a compound of the formula I and its salts is characterized in that

(a) is released from its functional derivative by solvolyzing or hydrogenolyzing agents by:

(i) the amidino group from the oxadiazole derivative is liberated by hydrogenolysis; (i) the conventional amino-protecting group is replaced with hydrogen by treatment with a solvolyzing or hydrogenolysing 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

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

Y group

W is -SO 3 - or -CO-, and R ² and R ⁴ are as defined above, with a compound of formula II

R ^z

(Π) where means

R @ ¹ is ^K @ 1, °

HN—

O or

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

Y group

and R ² and ^R m j it above a compound of the hereinbefore defined formula III is reacted with

R ⁴ - W - L (III) where is

X is -SO 3 - or -CO-,

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

R ⁴ is as defined above, or

c) for the preparation of R ^{1, a} group of a compound of the general formula

I where

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

Y oxygen atom,

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

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

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

R ⁴ -W-OH (IV) wherein is

W binding a

R ⁴ is as defined above, or

d) for the preparation of a compound of formula I wherein R ¹ is N.

y o

HN— (0 or

• · ·

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

Y group

W binding,

R ⁴ is - [C ^(R) 23mAr or - [C (R ⁵⁾ 2 m Het 1, and R ² has the abovementioned meanings, with a compound of formula wherein R ¹ represents a radical

O fvj

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

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

R ² has the above meaning, is reacted with a compound of formula VI

R ⁴ -W-Y-H (VI) wherein is

K mate,

Υ group

R ⁴ is - [C (R ⁵⁾ ?,] _m or FTR - 1 C (R ⁵⁾ 2 1 am raHet zero, or for straight and right of the R ¹ group of the compound of formula I wherein

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

Y group

W is -CONH-, and R ² and R ⁴ is as defined above, a compound of II V2orce

• "• · · · wherein R ¹ represents a radical

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

Y group

R ² and R> is as defined above, is reacted with a compound 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 with X -CO-N to form a five membered ring,

Y -NtC ^(R5) 21 m -COOR ^5,

W is -SO 2 - and

R ² and R ⁴ are as defined above, with a compound of formula II wherein R ^{1 is a} group

O CH ₃

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

Y is -N [C ^(R) COOR 21 m * ° and

R ² and R ⁵ has the abovementioned meaning, is reacted with a compound of formula VIII

R ⁴ - SO ₂ - L (VIII) where is

L is a chlorine, bromine, iodine atom or a free or 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 is hydrogen and

R ¹ , R ² , R ⁴ , Y and W are as defined above, a compound of formula (I) is released from its oxazolidinone derivative by a solvolyzing or hydrogenolyzing 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 converted to an amidino group; or

(i) in the compound of formula (I), one or more of the groups Y, R ¹ , R ² , R ³ and / or R ⁴ is converted into one or several other groups of Y, R ¹ , R ² , R ³ and / or R ⁴ , wherein:

(i) the ester group is hydrolyzed to a carboxyl group; (i) 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 each other.

The individual symbols or indices L, W, X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^{5 and} m have the meanings indicated for the formulas I to VIII, unless expressly stated otherwise.

Solvates are understood to be 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 3-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, 11,2- or 1,2,2-tri-methylpropyl, heptyl, octyl nonyl or a decyl group.

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

0R symbol ^s denotes OH, OA or benzyloxy, wherein OA is preferably methoxy, ethoxy, propoxy, butyloxy or hexyloxyskupi nu.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. By cycloalkyl is meant, for example, the remainder of a bicyclic terpene, such as the 3-methyl group and very particularly the 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 preferably represents hydrogen, fluorine, chlorine, bromine, or iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methyl amino, dimethylamino, ethy1aminoskupinu, diethylene one amino, acetamido, sulfonamido, methylsulphinyl Onam and doskup methyl, phenylsulfonamido, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, ethoxy. Particularly R ² is hydrogen.

R @ ³ is preferably A, benzyl, CH2COOH or CH3COOA, in particular hydrogen.

R @ ⁴ is preferably, for example, A, cycloalkyl, Ar, CHzAr, CH ₃ CH ₂ Ar, CH ₃ Het CIfeCHsHet or CH = CHAr.

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

The symbol X represents an oxygen atom. imino, NA or N-benzyl, and also CH2.

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

Y is preferably, for example an oxygen atom, NH, N-methyl, N-ethyl, N-Ar, N-CH2-Ar, N-Het, N-CH2-Het, N-COOA, N-CH ₃ -COOA , N-CH2-COOH, N-CH2-COObenzyl, a group

NCH ₂ -CONH ₂ , NCH ₂ -CONHA, NCH ₂ -CONA _2, NCH ₂ -CONR ⁵ Ar or NCH 2 -CONA ₃ .

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

Ar is preferably unsubstituted phenyl or naphthyl, further preferably a monosubstituted, disubstituted or trisubstituted phenyl or naphthyl group selected from the group consisting of A, fluorine, chlorine, bromine or iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio group, methyl sulfinyl, ethy1sulfiny1ovou, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyry1aminoskupinu, methylsulfonic Onam and ethylsulfonamido, propylsulfonam and dosyl, butylsulfonamido, phenylsulfonamido,

4- (methylphenyl) sulfonamido, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxy, benzyloxy, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl;

Thus, Ar is preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, β- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-ni trophenyl, o-, m- or p-aminophenyl, o-, p- 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 ρ- (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- (phenylsul17)

phonamido) phenyl, ο-, m- or p- (methylsulfonamido) phenyl Ονου, ο-, 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 3-nitro-4-Ν, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 23,6-, 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 by a radical of the group consisting of amino, OR ^5, Hal, CN, alkyl having 1 to 10 carbon atoms, a trifluoromethyl group, CH3SO3, OCF3, acetamido, - C (= NH) -NH 2, methoxycarbonyl or ethoxycarbonyl, further represents a substituted naphthyl group or an unsubstituted biphenyl group with one substituent selected from the group consisting of Hal, dimethylamino and (C 1 -C 6) alkoxy.

Ar in particular represents, for example, phenyl or naphthyl, furthermore preferably, for example, o-, m- or ptolyl, O-, m- or p-ethylphenyl, O-, m- or p-propylphenyl, o-, m- or p tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, or p-nitrophenyl, o-, m- or p-aainophenyl, o-isopropylphenyl, -, 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- (Ν, 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.

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 a 1,2,3-triazole group - 1-, -4- or -5-yl, 1,2,4-triazol-1-, 3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole-4- or -5 -yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2 , 3-thiadiazol-4- or -5-yl, 3- or 4-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-isoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl,

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

2,1,3-benzoxadiazol-5-yl.

The heterocyclic groups may be partially or fully hydrogenated.

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-1-, -2-, -3-, -4-, -5-, -6-, -7- or 8-quinolyl 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or 8-isoquinolyl,

A 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo [1,4] oxazinyl group further preferably a 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl group; , 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 a 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl group.

Het 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-COH-CH 2. The term several means two, three, four or five. Het is 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 A / or oxo substituted thiazole- 2-, -4- or -5-yl, thiophen-2- or -5-yl, chroman-6-yl, pyidin-2-, -3- or -4-yl, pyrimidine-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.

The invention therefore 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 (Ia), wherein not specifically indicated are as defined in formula (I), wherein R ² is hydrogen.

Ib R ³

R ⁵ or - (CH 2) m -COOR ⁵ ,

Ic R ⁴ A, cycloalkyl supine, - (CH 2) n -Ar, - (CHzlmHet or -CH = CH-Ar,

Id Y is oxygen, NR ^5, N (CH) m-Ar, -N (CH2> m Het

N (CH ₂ ) _m -COOR ⁵ , -NN ₁₅ ^or Y + ú

 • • •

I f Ar

I f Ar lg Ar *

Ih Het lg Ar

Ih Het li R ¹ li R ¹ 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 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, NHSO2phenyl, COOR 4, CO (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, benithiophen-2-yl,

1,3-benzodioxol-4- or -5-yl, 1,4-benzodioxan-5- or -6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, -C (= NH) -NH 2 which optionally has one substituent selected from the group consisting of -COA, -CO- (CH ₂ ) mAr-, COOA, OH or is a group

CH

- 22 R ²

R ³

R ³ a

R ⁴

R ⁵

X

Y a hydrogen atom,

R ⁵ or - (CH 2) m -COOR ⁵ , together with -CO-N to form a five-membered ring,

A is cycloalkyl, - (CH2) n Ar ^_, - (CH 2) m Het or -CH = CH-Ar, H, A or benzyl, O, NR ⁵ or CH 2, O, NR ⁵ N (CH 3) m -Ar, -N (CH 2) m Het

N (CH ₂ ) _m -COOR ⁵ ,

R ⁵

or \

N /

Ar

Het a bond, -SO2-, -CO-, -C00- or -CONH, an alkyl group having 1 to 20 carbon atoms, in which one or two CH2 groups are optionally replaced by -CH = CH- groups and / or one to one seven hydrogen, F, phenyl unsubstituted or substituted by one, two or three groups selected from NH2, oR ^5, Hal, CN, alkyl having 1 to 10 carbon atoms, a trifluoromethyl group, CH3SO3, OCF3, acetamido, - C (= NH) -NH2, methoxycarbonyl and ethoxycarbonyl further denotes naphthyl unsubstituted or substituted by one of Hal, dimethylamino and methoxy, or unsubstituted biphenyl, unsubstituted or one or more groups from Hal, And, phenyl, OR ^5, COOR ^5, CN, N (R ⁵⁾ 2, NO _{2 R} NHCO NHCOfeny23 • * • ·

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, 2,1,3-benzothiadiazol-4- or -5-yl.

The compounds of formula (I) and the starting materials for their preparation are prepared by methods known per se, as 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 variants which are known per se, not described here in greater detail.

The starting materials can optionally be formed in situ, i.e. they are not isolated from the reaction mixture, but are immediately used for the preparation of the compounds of formula I.

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

Preferred solvolysis or hydrogenolysis starting materials are those compounds which otherwise correspond to the above general formula (I), but instead have free amino or hydroxy groups, instead of free 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 group

Wherein R represents 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 moiety is successful, for example, by reacting the cyano compounds with hydroxylamine and reacting 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 generally known and refers to groups which are suitable for protecting (to block) 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 especially 1 to 8, carbon atoms are preferred. The term acyl is always meant in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl and, in particular, aryloxycarbonyl 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 methoxycarbonyloxy, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC) and aryl sulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, CBZ, Fmoc, bensyl and acetyl.

The term hydroxy protecting group is also generally known and refers to groups which are suitable for protecting (to block) 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. Preferred are, however, groups having 1 to 20, and especially 1 to 10, carbon atoms. 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 general formula I from its 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, strong organic carboxylic acids such as trichloroacetic acid. or 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 organic such as, for example, acetic acid: ethers, such as dioxane; amides such as dimethylformamide carboxylic acid tetrahydrofuran or (DMF); halogenated hydrocarbons, dichloromethane; as well as 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 temperature for the cleavage is expediently about 0 to about 50 ° 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 at about 3-5% hydrochloric acid in dioxane at 15-30 ° C, FMOC with a 5 to 50% solution of dimethylaraine, diethylamine or piperidine in dimethylformamide at 15 ° C. to 30 ° C.

Hydrogenolytically removable protecting groups (e.g. CB2 or benzyl) may be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, conveniently 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 10 MPa. Hydrogenolysis of the CB2 group is successful, for example, on 5 to 10% palladium on carbon in methanol or with ammonium formate (instead of hydrogen) in the presence of palladium on carbon in a methanol / dimethylformamide system at a temperature of 20-30 ° C.

Compounds of formula (I) wherein

R ¹ group {

or

CH

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

Y a group of formula

W -SO ₂ - or -CO ² and R ² and R ⁴ are as defined above, can preferably be obtained by reacting compounds of formula II with compounds of formula III.

In the compounds of formula III, L is preferably chlorine, bromine, iodine or a free or reactive modified hydroxyl group such as an activated ester group, an imidazolide group or a (C 1 -C 6) alkylsulfonyl (preferably methylsulfonyloxy) or arylsulfonyloxy (6) group. 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 an alkylating derivative of the formula III can also be advantageous. The reaction time is, depending on the reaction conditions, several minutes to 14 β

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, petroether, 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 (ethyl glycol or ethylglycol), 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 methods known per se.

Compounds of formula (IR ⁾ wherein the group is

R ³ together with X -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 be advantageously obtained by reacting compounds of formula II wherein Y is O with a compound of formula IV according to the Misunob 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 they are new, they can be prepared by methods known per se.

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

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

Y a group of formula - (Z

W binding

The R ⁴ group - [C (R ⁵ ) 21mAr 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 chlorine, bromine, iodine or a reactive modified hydroxyl group such as an ester-activated, imidazolide, C 1 -C 6 alkylsulfonyloxy (preferably methylsulfonyloxy) or C 6 -C 10 arylsulfonyloxy ( preferably a phenylsulfonyloxy group or a p30.............................. 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 they are new, they can be prepared by methods known per se.

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

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

Y a group of formula

R ⁵ r5

W -CONH and R ² and R ⁴ are as defined above, can be advantageously obtained by providing compounds of formula II wherein R ¹ is {

or ch ₃ e · 99 <· «·

C · i ·

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

Y a group of formula

R ⁵

R ⁵ or

X -CONH R ² and ^R are as defined above, compounds of formula VII.

let me react

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 they are new, they can be prepared by methods known per se.

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

7j ^! or

N ^:

CH,

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

Y a group of the formula - NiC (R ⁵ ) 21κ * COOR ⁵ ,

The W group -SO ² and R ² and R ⁴ are as defined above, can be obtained by providing compounds of formula II. where it means

R ¹

R ³ together with Y is -CO-weight ring

Y a group of the formula -N [C (R ⁵ ) 3] m -COOR ⁵ , and R ² and R ⁵ are as defined above with compounds of formula VIII.

creating five or more members to react

In the compounds of formula (VIII), L is preferably chlorine, bromine, iodine or a reactive modified hydroxyl group such as an ester-activated group, an iraidazolide group, an alkylsulphonyloxy group having 1 to 6 carbon atoms (preferably methylsulfonyloxy group) or an arylsulfonyloxy group having 6 to 10 atoms carbon (preferably phenylsulfonyloxy or ptolylsulfonyloxy).

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,

The R ³ hydrogen atom may be liberated by the group.

and R ^1, Novato or above

R ^2, R ^4, Y and W are as defined above, by treatment of the oxazolidinone derivatives hydrogeno1yzačním agent. This reaction of the described cleavage protective conditions

Compounds of formula (I) wherein -C (= NH) -NH 3 can be further obtained are an R ¹ group from the corresponding samples, for example, with hydrogen carbon.

The cyano group is converted to the amidino group by reaction with hydroxylamine and subsequent reduction with N-hydroxyamides in the presence of a catalyst such as palladium to

For the preparation of an amidine of formula I (where R ¹ is -C (= NH) -NH 2), ammonia can also be added thereto in the triad of formula I (where R ¹ is CN). The addition is preferably carried out in a step-wise manner, in a manner known per se a) reacting the nitrile with hydrogen sulfide to obtain a thioamide which is converted with an alkylating agent, for example methyl iodide, into the corresponding S-alkylimidothioester. the nitrile is converted by treatment with an alcohol such as ethanol in the presence of hydrochloric acid into the corresponding imidoester which is treated with ammonia;

In addition, a compound of formula I can be converted to another compound of formula I by converting one or more Y, R ¹ , R ² , R ³ and / or R ⁴ groups to one or more other Y groups, R ^1, R ^2, R ³ and / or R ^4th 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 can 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, it is possible to acylate the free amino groups in a manner known per se with an acid chloride or anhydride or to alkylate unsubstituted or substituted alkyl halides, suitably in an inert solvent such as dichloromethane or tetrahydrofuran and / or in the presence of a base such as triethylamine; O

pyridine at -60 to +30 C.

The base of the formula (I) can be converted into an acid by, for example, reaction of the corresponding nitric, halogenated or hydrobromic acid addition salt with an acid, a gentle amount of the base and an acid in an inert solvent such as ethanol and subsequent evaporation of the solvent. Particularly suitable acids for this reaction are those which give physiologically acceptable salts. Inorganic acids such as sulfuric acid, hydrogen acids such as hydrochloric phosphoric acids such as orthophosphoric acid may be used. sulphonic acid and ogranic acids, in particular aliphatic, alicyclic, araphatic, aromatic or heterocyclic mono- or polyhydric carboxylic, sulfonic or sulfuric acids such as formic, acetic, propionic, pivalic, diethyl acetic, malonic, succinic, pimelic acids , fumaric, maleic, lactic, tartar, cider, citric, gluconic, ascorbic, nicotine, isonium, methanesulfonic, ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonate, p-toluenesulfonic, naphthalenonosulfonate and naphthalenonosulfonate. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify 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 reaction 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 formula I may be chiral by virtue of their molecular structure and may therefore be in different 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 final product or intermediates may be separated into the enantiomeric compounds by known chemical or physical means, or the individual enantiomers may 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-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 the formula I and their physiologically acceptable salts can be used for the preparation 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 ingredients.

1átkami

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.

These 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 the 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 your li on. 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, suspensions, emulsions or implants, for topical use Use ointments, creams or powders. The compounds according to the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the preparation of injection preparations. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizing agents and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, coloring buffer, flavoring agents and / or one more or, for example, vi. several other active substances, there and now,

The compounds of formula (I) and their physiologically acceptable salts can be used for the treatment of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angio-plastic restenosis and gastric pain during walking or walking. prevention of these conditions.

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

The invention is illustrated by the following examples. Temperatures are always given in degrees Celsius. In the following examples, the expression "customary processing" means;

If necessary, water is added or, depending on the constitution of the final product, the pH is adjusted to 2 to 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 Rf are on silica gel, eluent is ethyl acetate / methanol 9 = 1,

Mass spectrometry (MS): EI (electron impact-ionization) M ⁺

FAB (Fast Attack Bombing) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Solution 100 mg 3-14- (5-methyl-11,2,4) oxadiazol-3-yl-phenyl]

5-Piperazin-1-ylmethyloxazolidin-2-one (A) [obtainable by reaction of 3-14- (5-methyl-11,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazol-38- · din- 5-methyl methanesulonic acid ester with 1-tert-butoxycarbonylpiperazine and sodium hydrogen carbonate 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 is reacted with 400 mg of 4-dimethylaminopyridine on polystyrene and stirred for 18 hours at room temperature. The reaction mixture was filtered, the solvent was removed to give 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2,4,6-trifluorophenyl)]. enyl sulfonyl) piperazin-1-ylmethyl] oxazolin-2-one, FAB 586/588.

Similarly, it is obtained by reaction with 4-biphenylsulfonyl chloride

3- [4- (5-Methyl-1,2,43-oxadiazol-3-yl) -phenyl] -5- [4- (4-biphenylsulfonyl) -piperazin-1-ylmethyl] -oxazol-2-one , with phenylvinylsulfonyl chloride

3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl] -5- [4- (2-phenylvinyl sulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 2-nitrophenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -5- [4- (2'-trophenylsulfonyl) -piperazin-1-ylmethyl] oxazolin-2-one he, with 2,5-dimethoxyphenylsulfonyl chloride

3- [4- (5-Methyl-1,2,41-oxadiazol-3-yl) -phenyl] -5- [4- (2,5-methoxy-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-2-one with 2-naphthylsulfonyl chloride

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

3- [4- (5-Methyl-1,2,41-oxadiazol-3-yl) -phenyl] -5- [4- (2-chloro-4-fluoro-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolin-2-one; acetamido-4-methylthiazol-5-yl) sulfonyl chloride

3-14- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 - ((2-acetamido-4-methylthiazol-5-yl) sulfonyl) piperazine 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] oxazolin-2-one, with 5- nitro-2-methylphenylsulfonyl chloride

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

3- [4- (5-methyl (1,2,4) oxadiazol-3-yl) phenyl] -5- (4-benzylsulphonylpiperazin-1-ylmethyl) oxazolin-2-one, with decylsulphonyl chloride

3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl] -5- (4-decylsulfonylpiperazin-1-ylmethyl) oxazolidin-2-one, with 2-trifluoromethylphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl] -phenyl] -5- [4- (2-trifluoromethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-2-one, with 3-chloro-4-fluorophenylsulfonyl chloride

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- [1,2,41-oxadiazol-3-yl) -phenyl] -5- [4- (4-chloro-40).

2,5-Dimethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolin-2-one, with 2-fluorophenylsulfonyl chloride

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

3- [4- (5-methyl- [1,2,41-oxazazol-3-yl) -phenyl] -5- [4- (3,4-dibromophenylsulfonyl) -piperazin-1-ylmethyl] -oxazolin-2-one -one, with 3-chlorophenylsulfonyl chloride

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

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

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,4-dichlorophenylsulfonyl) piperazin-1-ylmethylloxazolin-2-one, with 3, 5-dichlorophenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3,5-chlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolin-2-one he, with 2-naphthylcarboxylic acid chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-naphthylcarbonyl) piperazin-1-ylmethyl] oxazolin-2-one he, 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; 2-on.

with 2-nitrobenzylsulphonyl chloride

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

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -5- [4- (3-trifluoromethyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolin-2-one , with 4-trifluoromethoxyphenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-2-one, se (1S) - (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 (1R) - (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; 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) piperazine- 1-ylmethyl-1-oxazolidin-2-one with 4-isopropylphenylsulfonyl chloride

* ·

3-14- (5-methyl-1,2,4) oxadiazol-3-yl) phenyl] -5-14- (4-isopropylphenylsulfonyl) piperazin-1-ylmethyl-1-oxazolidin-2-one, with 4-tert-butylphenylsulfonyl chloride

3-14- (5-methyl-1,11,2,43-oxadiazol-3-yl) phenyl-5-14- (4-tert-butylphenylsulfonyl) piperazin-1-ylmethyl-1-oxazolin-2-one, with 4-butylphenylsulfonyl chloride

3-14- (5-methyl 11,2,4] oxadiazol-3-yl) phenyl-5-14- (4-butyphenylsulfonyl) piperazin-1-ylmethyl-3-oxazolidin-2-one with 3,5-din tri-4-methoxyphenylsulfonyl chloride

3-14- (5-methyl-11,2,43-oxadiazol-3-yl) phenyl-5-14- (3,5-di-nitro-4-methoxyphenylsulfonyl) piperazin-1-ylmethyl-1-oxazolin-2-one, s ethylsulfonyl chloride

3- 14- (5-methyl-1,11,2,43-oxadiazol-3-yl) -phenyl-5- (4-ethylsulfonyl) piperazin-1-ylmethyl) oxazolidin-2-one, with nitrophenylsulfonyl chloride

3-14- (5-methyl 11,2,4] oxadiazol-3-yl) phenyl3-5-14- (4-nitrophenylsulfonyl) piperazin-1-ylmethyl-3-oxazolidin-2-one, with 2-trifluoromethoxyphenylsulfonyl chloride

3-14- (5-methyl-1,11,4,4-oxadiazol-3-yl) phenyl-5-14- (2-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl 1-oxazolin-2-one, with 2,4-dinitrophenylsulfonyl chloride

3- 14- (5-methyl-11,2,4] oxadiazol-3-yl) phenyl-3-5-14- (2,4-dinitrophenylsulfonyl) piperazin-1-ylmethyl-1-oxazolidin-2-one.

isopropylsulfonyl chloride

3-14- (5-methyl 11,2,4] oxadiazol-3-yl) phenyl-5- (4-isopropyl-43'-sulfonyl) 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-trifluoromethoxyphenylsulfonylchloride

3- (4- (5-methyl (1,2,4) oxadiazol-3-yl) phenyl) -5- (4- (4-bromo-2-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethylloxazolin-2-one) with 2 3,4,4-trifluorophenylsulphonyl chloride

3- (4- (5-methyl (1,2,41-oxadiazol-3-yl) phenyl) -5- (4- (2,3,4-trifluorophenylsulfonyl) piperazin-1-ylmethyl) oxazolin-2-one, with 3 4-difluorophenylsulfonylchloride

3- (4- (5-methyl (1,2,41-oxadiazol-3-yl) phenyl) -5- (4- (3,4-difluorophenylsulfonyl) piperazin-1-ylmethyl) oxazolidin-2-one, with 2,2, 2-trifluoroethylsulfonyl chloride

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

3- (4- (5-methyl (1,2,41-oxadiazol-3-yl) phenyl) -5- (4- (3-nitro-4-methylphenylsulfonyl) piperazin-1-ylmethyl) oxazolin-2-one, with 2 -ni tro-6-chlorophenylsulfonyl chloride

3- (4- (5-methyl (1,2,4) oxadiazol-3-yl) phenyl) -5- (4- (2-nitro-6-chlorophenylsulfonyl) piperazin-1-ylmethyl) oxazole di-2-one, with 2,5-dimethoxyphenylacetyl chloride

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

L *

9 9 with 9-dichlorobenzoyl chloride

3- [4- (5-methyl [1,2,43-oxadiazol-3-yl) phenyl] -5- [4- (3,4-dichlorobenzoyl) piperazin-1-ylmethyl] oxazolidin-2-one, with 3- fluorobenzoyl chloride

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

3- [4- (5-methyl- [1,2,43-oxadiazol-3-yl) -phenyl] -5- [4- (4-trifluoromethoxy-benzoyl) -piperazin-1-ylmethyl] -oxazolin-2-one, with 3- pyridylcarboxylic acids

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

with 2-benzothienylcarboxylic acid chloride

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

3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl] -5- [4- (4-chlorophenylacetyl) piperazin-1-ylmethyl] oxazolidin-2-one, with chloride 1-Naphthylcarboxylic acid

3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl] -5- [4- (1-naphthylcarbonyl) piperazin-1-ylmethyl] oxazolin-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-benzodioxol-5-yl) carbonyl] piperazin-1-one ylmethyl 1-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] oxazolin-2-one; »« · ^J · • »chloride acid 4-bifeny1ylkarboxylové

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

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (cyclopentylcarbonyl) piperazin-1-ylmethyl] oxazolin-2-one; [5-chloro-1- (4-methylphenyl) -1H-pyrazol-4-yl] sulfonyl chloride 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] - 5-14- [5-chloro-1- (4-methylphenyl) -1H-pyrazol-4-yl) sulfonylpiperazin-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] oxazolin-2-one; 7,7-tri-methyl-2- (1,3,3-tri-methylbutyl) octylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4- [5,7,7tri-methyl-2- (1,3,3-tri-methyl-butyl) ) octylsulfonyl] piperazin-1-ylmethyl} oxazolidin-2-one, with 2-butoxy-5- (1,1-dimethylpropyl) phenylsulfonyl chloride 3- [4- (5-methyl [1,2,41] oxadiazol-3) -y1) phenyl] -5- (4- [2-butoxy-5- (1,1-dimethylpropyl) phenylsulfonyl] piperazin-1-ylmethyl) oxazolin-2-one, with 2-butoxy-5- (1,1 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4- [2-butoxy-5- (1, 3-tetramethylbutyl) phenylsulfonyl) chloride 1,3,3-Tetramethylbutyl) phenylsulfonyl] piperazin-1-ylmethyl-1-oxazolidin-2-one with 2-nitro-4-trifluoromethyl-phenylsulfonyl chloride

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (2-nitro) 46.

* 9 9 9 9 9 9 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99

4-Trifluoromethyl) phenylsulfonylpiperazin-1-ylmethyl] oxazolidin-2-one, with 4-bromo-2-ethylphenylsulfonyl chloride

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

with 4-trifluoromethylphenylsulfonyl chloride

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (4-trifluoromethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolin-2-one, se 3,4-difluorophenylsulfonyl chloride

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

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- [1,4-tolylsulfonyl] -piperazin-1-ylmethyl-oxazolin-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] -oxazolidine- 2-on, •

2- (naphth-1-yl) ethylsulfonyl chloride

3-14- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl-5- (4-12- (naphth-1-yl) ethylsulfonylpiperazin-1-ylmethyl) oxazolin-2-one.

with butyl chloroformate

3-14- (5-methyl-11,2,4] oxadiazol-3-yl) phenyl (5-14-chlorobutyloxycarbonyl) piperazin-1-ylmethyloxazolin-2-one.

Example 2

100 mg solution of 3- [4- (5-methyl-11,2,41-oxadiazol-3-yl) -phenyl]

5-14- (2,4,6-Trichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolin-2-one in 15 ml of methanol is treated with 100 mg of Raney nickel and a drop of acetic acid and hydrogenated for eight hours at a temperature of rooms. The catalyst was filtered off and the solvent was removed to give 4- (2-oxo-5-14 (2,4,6-trichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidine

3-yl) benzamidine acetate, FAB 543/548.

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

4- (2-oxo-5- [4- (4-biphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 520,

4- (2-oxo-5- [4- (2-2-phenylethylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 472,

4- (2-oxo-5-14- (2-aminophenylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-yl) benzamide, trifluoroacetate, FAB 452,

4- (2-oxo-5- [4- (2,5-dimethoxyphenylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 504,

4- [2-oxo-5- [4- (2-naphthylsulfonyl) piperazin-1-ylmethyl] oxazolidin-benzamidide, trifluoroacetate, FAB 494,

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

4- {2-oxo-5- [4 - ((2-acetamido-4-methylthiazol-5-yl) sulfonylpiperazin-1-ylmethylloxazolidin-3-yl] benzamidine, trifluoroacetate, FAB 522,

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

4- {2-oxo-5- [4- (5-amino-2-methyl-phenylsulfonyl) -piperazin-1-ylmethyl-loxazol-3-yl] -benzamide, trifluoroacetate, FAB 473,

4- {2-oxo-5- (4-benzylsulfonylpiperazin-1-ylmethyl) oxazolidine -,

3-ybenzamidene, trifluoroacetate, FAB 458,

4- {2-oxo-5- (4-decylsulfonylpiperazin-1-ylmethyl) oxazoline din-,

3-Ylbenzamidine, trifluoroacetate, FAB 508,

4- (2-oxo-5- [4- (2-trifluoromethylphenylsulfonyl) piperazin-1-ylmethylloxazolidin-3-yl] benzamidine, trifluoroacetate, FAB 512,

4- {2-oxo-5- [4- (3-chloro-4-fluorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-ylbenzamidine, 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-b-1- [4- (3-chlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-ylbenzamidine, 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-dichlorophenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl] benzamidine, trifluoroacetate, FAB 512,

4- (2-oxo-5- [4- (3,5-dichlorophenylsulfonyl) 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) oxazolidine

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-ylmethylloxazolidin-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 53S.

4- [2-oxo-5- [4- (3-trifluoromethylphenylsulfonyl) piperazin-1-ylmethylloxazolidin-3-yl] benzamidine acetate, FAB 512,

4- {2-oxo-5- [4- (4-trifluoromethoxy-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazol-indin-3-yl-benzamine, acetate, FAB 528,

4- {2-oxo-5- [4 - (((1S) camphor-10-yl) sulfonyl) piperazin-1-ylmethyl)

50!

oxazolidin-3-yl-benzamidide, acetate, FAB 518,

4- (2-oxo-5- [4 - (((1R) camphor-10-yl) sulfonyl) piperazin-1-ylmethyl) 3 oxazolidin-3-ylbenzamidine acetate FAB 518,

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

FAB 570,

4- [2-oxo-5- [4- (4-isopropylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-ylbenzamidine acetate, FAB 486,

4- (2-oxo-5- [4- (4-tert-butylphenylsulfonylpiperazin-1-ylmethyl) oxazolidin-3-yl] benzamidine acetate,

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

4- (2-oxo-5- [4- (3,5-diamino-4-methoxyphenylsulfonyl) piperazin-1-ylmethylloxazolidin-3-ylbenzamidine, acetate, FAB 504,

4- (2-oxo-5- (4-ethylsulfonylpiperazin-1-ylmethyl) oxazolidine

3-ylbenzamidium, acetate, FAB 396,

4- (2-oxo-5- [4- (4-nitrophenylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-ylbenzamidine, acetate, FAB 459,

4- [2-oxo-5- [4- (2-trifluoromethoxyphenylsulphonylpiperazin-1-ylmethyl) oxazol-3-yl] -benzamidine, trifluoroacetate, FAB 528,

4- (2-oxo-5- [4- (2,4-diaminophenylsulfonylpiperazin-1-ylmethyl) oxazolidin-3-ylbenzamidine, acetate, FAB 474).

4- (2-oxo-5- (4-isopropylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-ylbenzamidine, acetate, FAB 410;

• 5 « ¹ • ¹ • ¹

4- [2-oxo-5- [4- (4-ethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 472,

4- [2-oxo-5- [4- (4-bromo-2-trifluoromethoxyphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-ylbenzamidine, acetate, FAB 606/608,

4- (2-oxo-5- (4- (2,3,4-trifluorophenylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-yl) benzamido-acetate, FAB 498.

4- (2-oxo-5- [4- (3,4-difluorophenylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-yl-benzamidine, acetate, FAB 480,

- (2-oxo-5- (4- (2,2,2-trifluoroethylsulfonyl) piperazin-1-ylmethyl) oxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 450 ,

4- (2-oxo-5- [4- (3-amino-4-methylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl} benzamide, 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-ylbenzamidine, acetate, FAB 482.

- (2-oxo-5- [4- (3,4-dichlorobenzoylpiperazin-1-ylmethyl) oxazolidin-3-yl) benzamidide, 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-ylbenzamidine, acetate, FAB 492,

4- (2-oxo-5- [4- (3-pyridylcarbonyl) piperazin-1-ylmethylloxazolidin-3-ylbenzamidine, acetate, FAB 409).

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

4- (2-oxo-5- [4- (4-chloro-phenylacetyl) -piperazin-1-ylmethyl-oxazolidin-3-yl-benzamidine, acetate, FAB 456).

4- (2-oxo-5- [4- (1-naphthylcarbonyl) piperazin-1-ylmethylloxazolin-3-yl] benzamidine acetate, FAB 458,

4- (2-oxo-5- [4 - ((1,3-benzodioxol-5-yl) carbonylpiperazin-1-ylmethyl) oxazolidin-3-yl] benzamidine acetate, FAB 452,

4- (2-oxo-5- [4- (3-aminobenzoyl) piperazin-1-ylmethyl) oxazolin-3-yl] benzamidine acetate FAB 423,

4- (2-oxo-5- [4- (4-biphenylcarbonyl) 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) -4-pyrazol-4-yl) sulfonyl] piperazin-1-ylmethylloxazolin-3-yl) benzamidine acetate, FAB 558,

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

4- (2-oxo-5- [4- [5,7,7-trimethyl-2- (1,3,3-trimethylbutyl) octyl sulfonyl] -piperazin-1-ylmethyl) oxazopyridin-3-ylbenzamido , trifluoroacetate FAB 620,

4- (2-oxo-5- (4- [2-butoxy-5- (1,1-dimethylpropyl) phenylsulfonyl) piperazin-1-ylmethylloxazolin-3-yl) benzamidine, tri-fluoroacetate 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,

- (2-Oxo-5- [4- (2-amino-4-trifluoromethylphenylsulfonyl) piperazine);

1-ylmethyl] oxazolidin-3-yl] benzamidine, trifluoroacetate,

4- (2-oxo-5- [4- (4-bromo-2-ethylphenylsulfonyl) piperazin-1-ylmethyl] oxazolidin-3-yl] benzamide, 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,

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

Similarly, by reacting 3- [3- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5-piperazin-1-ylmethyl-oxazolidin-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] benzamide, m.p. 118 ° C,

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

3-yl) phenyl-5-piperazinyl-1-ylmethyl-oxazolidin-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-3-oxazolidin-3-yl] -benzamidine.

Similarly, it is obtained by reacting 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5-piperazin-1-ylmethyl-oxazolidin-2-one with 2-fluoro. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

4- [2-oxo-5- [4- (2-fluorobenzyl)] for per ml of 1-methyl-3-oxazo [1,4] 3-ylbenzamidine.

Example 3

100 mg solution of 3-14- (5-methyl-11,2,41-oxadiazol-3-yl) -phenyl-14- (2,4,6-trichlorophenylsulfonyl) -piperazin-1-yl-methyl-1-yl The lidin-2-one in 8 ml of methanol is mixed with 3 ml of 1N sodium hydroxide solution and stirred for 48 hours at 60 DEG C. After working up in the usual manner, 3-14% of sodium hydroxide is obtained. 5-methyl-11,2,41-oxadiazol-3-yl) phenyl-amino] -1-14- (2,6-dichloro-4-methoxy-phenylsulfonyl-piperazin-1-yl-propan-2-ol, FAB 556/553).

Similarly, 314- (5-methyl-11,2,41-oxadiazol-3-yl) -phenyl] -5- (4, 4-fluorophenylsulfonyl) -piperazin-1-ylmethyl-1-oxazoline-2-one is obtained. -in him

3-14- (5-methyl-111,2.41 oxadiazol-3-yl) phenylsilyl] -1- [4- (3-fluoro-4-methoxyphenylsulfonyl) piperazin-1-yl] ] propane Z with 3-14- (5-methyl 11,2,41-oxadiazol-3-yl) phenyl-14-14 (1 na: 1-sulfonyl) -piperazin-1-ylmethyl-1-oxazolin-2-yl- about him

3-14- (5-methyl 11,2,41-oxadiazol-3-yl) phenylamino] -1- [4- (1-naphthylsulfonyl) piperazin-1-yl] propan-2-ol with 3- [4- (5-methyl) 11 1,2,41-oxadiazol-3-yl) phenyl 1 - 5 - 4 - C 4 - 44, -. methylphenylsulfonyl) piperazin-1-ylmethyloxazolidin-2-one

3-14- (5-methyl 11.2.4] oxadiazol-3-yl) phenylamino] -1- (1,4-trifluoromethylphenylsulfonyl) piperazin-1-yl 1-propane - 2; o 1) 3-14- (5-methyl-11,2,4) oxadiazol-3-yl) phenyl-3,5-14- (4-phenylphenyl) sulfonyl) -piperazin-1-ylmethyl-1-oxazolinone -2-on

14- (5-methyl-11.2.4] oxadiazol-3-yl) phenylamino] -1- (4- (4-biphenylsulfonyl) piperazin-1-yl) propan-2-ol.

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4- (3-trifluoromethylphenylsulfonyl) piperazin-1-yl] methyl 1 oxazolidin-2-oneia

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenylamino] -1- (4- (3-trifluoromethylphenylsulfonyl) piperazin-1-yl) propan-2-ol, 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-trifluoromethoxy-phenylsulfonyl) -piperazin-1-yl) -propan-2-ol; 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4- (4-isopropylphenylsulfonyl) piperazin-1-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-butylphenylsulfonyl) piperazin-1-ylmethyl) oxazolidin-2-one

3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenylamino] -1- [4- (4-butyl-phenylsulfonyl) -piperazin-1-yl] -propan-2-ol, with 3- [4 - (5-methyl- [1,2,41-oxadiazol-3-yl) -phenyl] -5- (4- (4-methoxy-phenylsulfonyl) -piperazin-1-ylmethyl) -oxazolidin-2-one

3- [4- (5-methyl (1,2,41-oxadiazol-3-yl) -phenylamino] -1- (4- (4-methoxy-phenylsulfonyl) -piperazin-1-yl) -propan-2-ol, with 3- [ 4- (5-methyl- [1,2,41-oxazazol-3-yl) -phenyl] -5- [4- (4-tolylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-2-one

3- [4- (5-methyl- [1,2,41-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) oxazolin-2-one

- [4- (5-Methyl [1,2,41-oxadiazol-3-yl) -phenylamino] -1- (4- (4 □ * Ξ>)

propylphenylsulfonyl 1) piperazin-1-yl] propan-2-ol.

3- [4- (5-methyl- [1,2,43] oxadiazol-3-yl) -phenyl-5- [4- (6-chloro-2-naphthylsulfonyl) -piperazin-1-ylmethyl] -oxazolidin-2-one about him

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylamino] -1- [4- (6-chloro-2-naphthylsulfonyl) -piperazin-1-yl] -propan-2-ol; 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -5- [4- (2-phenyl-phenylsulfonyl) -piperazin-1-ylmethyl] -oxazolin-2-one -about him

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylamino] -1- [4- (2-phenynylsulfonyl) -piperazin-1-yl] -propan-2- o1, 3- [4- (5-methyl- [1,2,43-oxadiazol-3-yl) -phenyl] -5- [4- (2- (naphth-1-yl) -ethylsulfonyl] -piperazin-1-ylmethyl) -oxazole-di n-2 -on

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-ylbenzamidine

4- {2-Hydroxy-3- [4- (6-methoxy-naphthalen-2-sulfonyl) -piperazin-1-ylpropylamino] -benzamide, diacetate, FAB 498 and from 4- {2-oxo-5- [4- ( 2-Fluorobenzyl-1-piperazin-1-ylmethyl-oxazol-3-yl-1-benzamidine

4- {2-hydroxy-3- [4- (2-fluorobenzyl) piperazin-1-yl] propylamino] benzamidide, 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-methoxy-phenylsulfonyl) -propan-1-yl] propane The 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. 4- (3- [4- (2,6-dichloro-4-methoxyphenylsulfonyl) piperazin-1-yl) -2-hydroxypropylaminobenzamine, acetate, FAB 516/518 is obtained.

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

4- (3- [4- (3-fluoro-4-methoxyphenylsulfonylpiperazin-1-yl-2-hydroxypropyl) amino) benzamide, acetate, FAB 466,

4- (3- [4- (1-naphthylsulfonyl) piperazin-1-yl) -2-hydroxypropylaminolbenzamide, acetate, FAB 468,

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

4- {3- [4- (4-Biphenylylsulfonyl) piperazin-1-yl] -2-hydroxypropyl amino-benzamidide, acetate, FAB 494,

4- (3-14- (3-Trifluoromethylphenylsulfonyl) piperazin-1-yl-2-hydroxypropyl-aminol-benzamidine acetate, FAB 486,

4- (3-14- (4-Trifluoromethoxyphenylsulfonyl) piperazin-1-yl-2-hydroxypropylamino) benzamide, acetate, FAB 502.

4- (3-14- (4-isopropylphenylsulfonyl) piperazin-1-yl) -2-hydroxypropyl amino-benzamide, acetate, FAB 460,

4- (3-14- (4-Butylphenylsulfonyl) piperazin-1-yl-2-hydroxypropyl) benzamide, acetate, FAB 474,

4- (3-14- (4-methoxyphenylsulfonylpiperazin-1-yl) -2-hydroxypropylaminoaminobenzamidine, acetate, FAB 448,

4- (3- (4- (4-Bolylsulfonyl) piperazin-1-yl) -2-hydroxypropylamino) benzamidide, acetate, FAB 432,

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

4- (3- (4- (6-chloro-2-naphthylsulfonyl) piperazin-1-yl) -2-hydroxypropyl amino) benzamine acetate, FAB 502,

4- (3- (4- (2-phenylvinylsulfonyl) piperazin-1-yl) -2-hydroxypropylaminolbenzamidine, acetate, FAB 446).

4- (3- (4- (2- (naphth-1-yl) ethylsulfonylpiperazin-1-yl) -2-hydroxypropylamino) benzamide), acetate, FAB 496.

Example 5

Solution of 10 g of (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-yl) methanesulfonic acid methyl ester, 6.73 g of 4-BOC-aminopyperidine and 8.5 g of sodium bicarbonate in 200 ml of acetonitrile are heated at reflux for 40 hours. After common work-up, 5- (4-BOC-amino-piperidin-1-ylmethyl) -3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenyl] -oxazolidin-2-one is obtained. -he.

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] oxazole din-2-one (B).

Similar to Example 1, (3-methoxy-4-methoxycarbonylthiophen-2-yl) sulfonyl chloride was obtained by reaction "B" with N- (1- (3- (4- (5-methyl [1,2,4)]) oxadiazol-3-yl) phenyl] -2-oxooxazolin-5-ylmethylpiperidin-4-yl) amide (3-methoxy-4-metho59).

xycarbonylthiophen-2-ylsulfonic acid of formula

with benzolsulfonyl chloride

N- (1- <3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolin-5-ylmethylpiperidin-4-yl) benzenesulfonam id, with 3,4-dimethoxybenzenesulfonyl chloride

3,4-Dihoxy-N- (1- <3- [4- (5-methyl- [1,2,43] oxadiazol-3-ylphenyl) -2-oxooxazolidin-5-ylmethylpiperidin-4-yl) benzenesulfonamide id, with butylsulfonyl chloride

II- (1- <3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethylpiperidin-4-yl) butylsulfonamide, with 2,4,6-trimethylbenzolsulfonyl chloride

2,4,6-Trimethyl-N- (1- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) piperidine-4 -yl 1-benzenesulfonamide, with phenylvinylsulfonyl chloride phenyl-N- (1- (3- [4- (5-methyl [1,2,43-oxadiazol-3-yl] phenyl) -2-oxooxazolidin-5-ylmethyl) -piperidine peridin-4-yl) sulfonamide, with 2-methylsulfonylbenzole sulfonyl chloride

2-Methylsulfonyl-N- (1- [3- (4-i-5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolin-5-ylmethyl-piperidin-4-yl-benzenesulfonamide .

Λ ♦ «

oU♦ with 4-biphenylsulphonyl chloride

4-Biphenyl-N- (1- (3-14- (5-methyl-1,1,2,41-oxadiazol-3-yl) phenyl) 2-oxooxazolidin-5-ylmethyl) piperidin-4-yl) sulfonamide id with 5-dimethylamino-1-naphthylsulfonyl chloride

5-dimethylamino-N- (1- (3- [4- (5-methyl-1,2,21-oxadiazol-3-yl) -phenyl) -2-oxooxazololidin-5-ylmethyl-piperidin-4-yl) -1-naphthylsulfonamide, with 1-naphthylsulfonyl chloride

N- (1- (3-14- (5-methyl-1,1,2,4) oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethyl) piperidin-4-yl) -1-naphthylsulfonamide.

Hydrogenation, similar to Example 2, yields the following compounds 4-15-14 - ((3-methoxy-4-methoxycarbonylthiophen-2-yl) sulfonylamino) piperidin-1-ylmethyl-2-oxooxazolidine- 3-yl) benzamidine. ace melt, FAB 552,

4- (5-14- (benzol sulfonylamino) piperidin-1-ylmethyl] -2-oxooxazololidin-3-ylbenzamidine, acetate, FAB 458,

4- (5-14- (3,4-dimethoxybenzolsulfonylamino) piperidin-1-ylmethyl) -2-oxooxazolidin-3-ylbenzamidine acetate FAB 518,

4- (5-14- (butylsulfonylamino) piperidin-1-ylmethyl) -2-oxooxazolidin-3-ylbenzamidine, acetate, FAB 438,

4- (5-14- (2,4,6-Trimethylbenzenesulfonylamino) piperidin-1-ylmethyl] -2-oxooxazolidin-3-ylbenzamidine acetate, FAB 500,

4- (5-14- (phenylethylsulfonylamino) piperidin-1-ylmethyl) -2-oxooxazolidin-3-ylbenzamidine acetate FAB 486,

4- (5- [4- (2-Methylsulfonylbenzol sulfonylamino) 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-oxooxazolin-3-yl) benzamidine, acetate, FAB 458.

Example 1

Solution of 10 g of 3- [4- (5-methyl- [1,2,43-oxadiazol-3-yl) -phenyl] -2-oxooxazolidin-5-yl) -methanesulfonic acid methyl ester, 7.4 g of 11,11'-di methylethylenediamine and 8.5 g of sodium bicarbonate in 400 ml of acetonitrile are heated at reflux for 40 hours. After customary work-up, 5 - {[methyl- (2-methylaminoethyl) amino] methyl] -3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] is obtained. Oxazolidin-2-one (C).

O

Similarly to Example 1, reaction C was obtained with 2,4,6-trichlorophenylsulfonyl chloride

2,4,6-Tri-chloro-N-methyl-N- [2- (methyl-1,3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) (amino) ethylbenzylsulfonamide of formula

with 2-trifluoromethoxyphenyl sulfonyl chloride

2-Trifluoromethoxy-N-methyl-N- [2- (methyl-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazol-5-yimethyl) amino) ethyl] benzolsulfonamide, with 2,4,6-tri chlorophenylsulfonyl chloride

2,4,6-Trichloro-N-methyl-N- [2- (methyl- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl)) phenyl] -2-oxooxazolin-5-one 4-trifluoromethylphenylsulphonyl chloride with 4-trifluoromethylphenylsulphonyl 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 [1,2,41-oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl] amino no) ethyl 1-benzol sulfonamide, 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-yimethyllamino) ethyl] 1-benzenesulfonamide, with 4-acetamidophenylsulfonyl chloride

4-Acetamido-N-methyl-N- [2- (methyl- (3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) -phenyl) -2-oxooxazolidin-5-ylmethyl-amino) -ethyl] -benzenesulfonyl onam id, with 2-naphthylsulfonyl chloride »·»

Ν-Methyl-(- (2- (methyl- (3- [4- (5-methyl-1,2,2) oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethylamino) ethyl 1-2-naphthylsulfonide, with 3-trifluoromethylphenylsulfonyl chloride

3-Trifluoromethyl-N-methyl-N - (2- (methyl - (3- (4- (5-methyl (1,2,41-oxadiazol-3-yl) phenyl) -2-oxooxazol-5-ylmethyl)) amino) ethyl] benzolsulfonamide, with 4-chloro-3-nitrophenylsulfonyl chloride

4-chloro-3-nitro-N-methyl-N- (2- (methyl- (3- (4- (5-methyl (1,2,41-oxadiazol-3-yl)) phenyl) -2-oxooxazolidine) -5-ymethylmethylaminoethylbenzol sulfonamide, with phenylvinyl sulfonyl chloride

N-methyl-N- [2- (methyl- (3- [4- (5-methyl (1,2,4) oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethyllamino) ethyl] phenylphenylsulfonamide, s benzyl sulfonyl chloride

4-Trifluoromethyl-N-methyl-N- [2- (methyl- (3- (4- (5-methyl (1,2,41-oxadiazol-3-yl)) phenyl) -2-oxooxazolin-5-ylmethyl) amino) ethyl 1-benzylsulfonamide, with tolylsulfonyl chloride

4-methyl-N-methyl-N- (2- (methyl- (3- (4- (5-methyl (1,2,41-oxadiazol-3-yl)) phenyl) -2-oxooxazolin-5-one)) methylmethylamino-ethyl) benzole sulfonamide, with 4-methoxyphenylsulfonyl chloride

4-Methoxy-N-methyl-N- (2- (methyl- (3- (4- (5-methyl (1,2,41-oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethyl-amino)) ethyl) benzenesulfonamide, se 1-naphthylsulfonyl chloride

N-methyl-[- [2- (methyl-13- (4- (5-methyl-1,2,4) oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) amino) ethyl -1-naphthylsulfonamide, with 4-biphenylsulfonyl chloride

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

3,4-Difluoro-N-methyl-N- (2- (methyl- (3- (4- (5-methyl (1,2,41-oxadiazol-3-yl)) phenyl) -2-oxooxazolidin-5-ylmethyl) amine) ethylbenzolsulfonamide, with 4-pentylphenylsulfonyl chloride

4-Pentyl-N-methyl-N- [2- (methyl- (3- (4- (5-methyl-1,2,41-oxadiazol-3-yl) -phenyl) -2-oxooxazolidin-5-ylmethyl-amino) -ethyl) -benzenesulfonamide, with 4-butylphenylsulfonyl chloride

4-Butyl-N-methyl-N- (2- (methyl- (3- (4- (5-methyl- (1,2,41-oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethyllamino) ethyl) benzyl sulfonamide), with 4-methylsulfonylphenylsulfonyl chloride

4-Methylsulfonyl-N-methyl-N- (2- (methyl- (3- (4- (5-methyl- [1,2,41-oxadiazol-3-yl) phenyl) -2-oxooxazolidin-5-ylmethyl) amino) ethylbenzenesulfonamide, with 6-chloro-2-naphthylsulfonyl chloride

6-chloro-N-methyl-N- (2- (methyl- (3- (4- (5-methyl-1,2,4) hexadiazol-3-yl) phenyl) -2-oxooxazol-5-ylmethyl) amino) Ethyl] -2-naphthylsulfonamide.

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

4- [5- [methyl- {2- [methyl- (2,4,6-tri chlorobenzolsulfonyl) amino] ethyl) amino] methyl 1-2-oxooxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 548/550 formulas

4- [5- [methyl-1,2- [methyl- (2-trifluoromethoxybenzenesulfonyl) amino] ethyl) amino) methyl] -2-oxooxazolidin-3-yl) benzamidine. acetate, FAB 530,

4- (5-1methyl- {2- [methyl- (4-trifluoromethylbenzenesulfonyl) amino] ethyl} amino) methyl] -2-oxooxazolin-3-ylbenzamidine acetate FAB 514,

4- {5- [methyl-2- [methyl- (4-isopropylbenzol sulfonyl) amino] ethyl) amino) methyl] -2-oxooxazololidin-3-yl) benzamidine acetate, FAB 488,

4- (5-Methyl-2- [methyl- (4-propylbenzenesulfonyl) amino] ethyl) amino) methyl 1-2-oxooxazololidin-3-yl) benzamide, acetate, FAB 488 ,

4- (5- [methyl- (2-1methyl- (4-acetamoyl-benzenesulfonyl-lamino-ethyl) -amino) -methyl] -2-oxo-oxazolidin-3-yl) -benzamidine, trifluoroacetate, FAB 503,

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

4- (5- [methyl- (2- [methyl- (3-trifluoromethylbenzenesulfonyl) • 6-aminoamino] ethylamino) methyl] -2-oxooxazolin-3-ylbenzamidine, trifluoroacetate, FAB 514,

4- (5- [methyl- (2- [methyl- (3-amino-4-chlorobenzolsulfonyl) amino] ethyl-amino) methyl] -2-oxooxazolidin-3-yl) benzamido, acetate, FAB 495 ,

4- (5- [methyl- (2- [methyl- (phenylethylsulfonyl) amino] ethyl) amino) methyl] -2-oxooxazolin-3-ylbenzamidine, trifluoroacetate, FAB 474 ,

4- [5- [methyl- <2- [methyl- (benzylsulfonyl) amino] ethylamino) methyl] -2-oxooxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 460,

4- (5-1methyl- (2-1-methyl- (4-tolylsulfonyl) amino) ethyl) amino) methyl] -2-oxooxazolidin-3-ylbenzamidine acetate. FAB 460,

4- {5- [methyl- {2- [methyl- (4-methoxybenzenesulfonyl) amino] ethyl) amino) methyl] -2-oxooxazololidin-3-yl) benzamidine, trifluoroacetate, FAB 476,

4- (5-1methyl- (2-1-methyl- (1-naphthylsulphonyl) amino) ethyl-1-amino) methyl] -2-oxooxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 496,

4- (5-1methyl- (2-1-methyl- (4-biphenylsulfonyl) amino-1-ylamino) methyl) -2-oxooxazololidin-3-ylbenzamidine, trifluoroacetate, FAB 522,

4- (5-1-methyl- (2-1methyl- (3,4-difluorobenzenesulfonyl) amino] ethyl-lamino) methyl] -2-oxooxazolidin-3-yl-benzamidine, tri fluoroacetate, FAB 516,

4- (5-methyl- (2-1 methyl- (4-pentylbenzol sulfonyl) amino) 67- (ethyl) amino) methyl 1-2-oxooxalolin-3-ylbenzamidine, tr and fluoroacetate, FAB 516,

4- (5-1-methyl- {2-1methyl- (4-butylbenzenesulfonyl-aminol-ethylamino) -amino-methyl-2-oxooxazolidin-3-ylbenzamidine, trifluoroacetate, FAB 502,

4-15-1 methyl-12-1methyl- (4-methylsulphonylbenzenesulphonylamino-ethyl-amino) methyl 1-2-oxooxazolium di-3-ylbenzamidine, trifluoroacetate, FAB 502,

4-15-1methyl- (2- [methyl- (6-chloro-2-naphthylsulfonyl) arylamino-ethyl-amino) methyl] -2-oxooxazolidin-3-ylbenzamidine. Trifluoroacetate, FAB 530.

Similar to Examples 3 and 4, 6-chloro-N-methyl-N-12- (methyl-13-14- (5-methyl- [1,2,41-oxadiazol-3-yl) phenyl) -2- oxooxazolidin-5-ylmethyl-1-amino) -ethyl-2-naphthylsulfonamide

4-13- (12-1 (6-chloro-2-naphthylsulfonyl) methylamino) ethyl 1 methylamino) -2-hydroxypropylamino) benzamide, acetate,

FAB 504 formula

and from 7-methoxy-N-methyl-N-12- (methyl-13-14- (5-methyl-11,2,41-oxazazol-3-yl) -phenyl-2-oxooxazolidin-5-ylmethyl-amino) -ethyl) -121 naphthyl sulfonamide

4-13 - ((2-1 (7-Methoxy-2-naphthylsulfonyl) methylmethylaminoethylmethylamino) -2-hydroxypropylamino) benzamide, acetate, FAB

500

Similar to Example 3, they are obtained by cleavage of the oxazolidine ring from 4- (5 - [(methyl- (2- (methyl- (4-biphenylsulfonyl) amino) ethyl) amino) methyl 1-2-oxooxazolidin-3- yl] benzamidine of 4- (5 - ((methyl- {2- [methyl- (4-isopropylbenzol sulfonyl) amino] ethyl Jamino) methyl] -2-oxooxazolidin-3-yl) benzamide and of 4- (5- ((methyl- (2- (methyl- (1-naphthylsulfonyl) amino) ethyl) amino) methyl] -2-oxooxazolidin-3-yl) benzamidine of the following compound.

4- (3 - ((2 - ((4-biphenylsulphonyl) methylamino) ethyl) methylamino) 2-hydroxypropylamino] benzamide, diacetate, E1 460 (M ⁺ -NH2).

4- (3 - ((2 - ((4-isopropylbenzol sulfonyl) methylamino) ethylmethylmethylamino) -2-hydroxypropylamino) benzamidide, diacetate, E1 461,

4- (3 - ((2 - ((1-naphthylsulfonyl) methylamino) ethyl) methylamino) 2-hydroxypropylamino] benzamidine diacetate, E1 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 methyl ester g of sodium azide in 30 ml of acetonitrile was heated at reflux for 40 hours to give 5-azidomethyl-3- (4- (5-methyl- [1,2,4] oxadiazol-3-yl)) as usual. phenyloxazoli di n-2-one,

7.7 g are suspended in ethyl ether of methyl ether. 3.6 ml of trimethylphosphite 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 affords 5-aminomethyl-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] oxazolin-2-one hydrochloride.

The obtained compound was 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-E4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] oxazolidin-2-one (D).

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

3,4-Difluoro-η 3 - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] 2-oxooxazolidin-5-ylmethyl) benzenesulfonamide, with 4 -methoxybenzenesulfonyl chloride

4-Methoxy-N- <3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl]]

2-oxooxazolidin-5-ylmethylbenzol sulfonamide, with 4-chloro-3-nitrobenzenesulfonyl chloride

4-chloro-3-nitro-3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazol-5-ylmethyl) benzenesulfonamide, with butylsulfonyl chloride

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

3-Trifluoromethyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-ylphenyl]] 2-oxooxazolidin-5-ylmethylbenzenesulfonamide; naphthylsulfonyl chloride • *

N- (3- [4- (5-methyl (1,2,4) oxadiazol-3-yl) phenyl) -2-oxooxazol-5-ylmethyl) -2-naphthylsulfonamide.

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

4- (5 - ((3,4-difluorobenzenesulfonylamino) methyl 1-2-oxooxazolin-3-yl) benzamidine acetate, FAB 411,

4- (5 - ((4-methoxybenzenesulfonylamino) methyl) -2-oxooxazolin-3-ylbenzamidine, acetate, FAB 405,

4- (5 - ((3-amino-4-chlorobenzenesulfonylamino) methyl 1-2-oxooxazolin-3-yl) benzamide, acetate, FAB 424,

4- (5 - ((butylsulfonylamino) methyl) -2-oxooxazolidin-3-ylbenzamidine acetate, FAB 355,

4- (5 - [(3-trifluoromethylbenzenesulfonylamino) methyl 1-2-oxooxasolidin-3-yl] benzamidine acetate FAB 443,

4- (5 - ((2-naphthylsulfonylamino) methyl) -2-oxooxazolidin-3-yl) benzamidine acetate FAB 425,

Example 8

Analogously 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-oxooxazololin-5-ylmethyl) benzol sulfonamide

4- (3- (3,4-difluorobenzenesulfonylamino) -2-hydroxypropylamino] benzamidine acetate, FAB 385,

• ·

From 4-methoxy-N- (3- (4- (5-methyl-1,2,2,4-oxadiazol-3-yl) -phenyl) 2-oxooxazolidin-5-ylmethyl) -benzenesulfonamide i du

4- (3- (4-methoxybenzenesulfonylamino) -2-hydroxypropylamino) benzamine.

from 4-chloro-3-nitro-N- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) benzenesulfonamide

4- (3- (3-Amino-4-chlorobenzenesulfonylamino) -2-hydroxypropylamino] benzamido, N- (3- (4- (5-methyl (1,2,4) oxadiazole) -) 3-yl) phenyl-2-oxooxazolidin-5-ylmethylbutylsulfonamide

4- (3- (Butylsulfonylamino) -2-hydroxypropylamino) benzaminediate acetate, FAB 329 from 3-trifluoromethyl-N- (3- [4- (5-methyl [1,2,41] oxadiene) azol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl) benzolsulfonamide

4- (3- (3-Trifluoromethylbenzenesulfonylamino) -2-hydroxypropyl amino) benzamidide, acetate, FAB 417, of N- (3- (4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl) -2-propylsulfonamide

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 tetrahydrofuran (300 ml) was heated at 80 DEG C. for 18 hours under heating. After work-up in the usual manner, 5-methylamethylcarbonyl-3- (4- (5-methyl- [1,2,41] oxadiazole-3-) was obtained. yl) phenylloxazolium-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-isopropylbenzole sulfonyl chloride

4-Isopropyl-N-methyl-N-3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenyl] -2-oxooxazolidin-5-ylmethyl-benzol sulfonamide, with 3-trifluoromethyl-benzenesulfonyl chloride

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

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

N-methyl-N- {3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenyl] -2-oxooxazolidin-5-ylmethyl} -phenylvinylsulfonamide, with 2-naphthylsulfonyl chloride

N-methyl-N- [3- (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-Three methylbenzenesulfonyl chloride

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

N-methyl-N- (3- [4- (5-methyl-1,2,41-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-1-phenyl) -2-oxooxazolidin-5-ylmethyl-2-naphthylcarboxylic acid, with cyclohexylcarboxylic acid chloride and N-methyl-N- (3- [ 4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl-1-cyclohexylcarboxylic acid with 4-biphenylcarboxylic acid chloride N-methyl-N- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl-4-biphenylylcarboxylic acid, with 4-chlorobenzoyl chloride

4-chloro-N-methyl-N- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethylbenzamide) with 4- (1, 1-Dimethylpropyl) benzol sulfonyl chloride

4- (1,1-dimethylpropyl) -N-methyl-N- (3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) benzenesulfonamide id, 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-ylmethylbenzenesulfonamide, with 4- tert-butylbenzolsulfonyl chloride

4-tert-Butyl-N-methyl-N- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -2-oxo-oxazolin-5-ylmethyl-benzenesulfonamide) With 4-trifluoromethylbenzol sulfonyl chloride

4-Trifluoromethyl-N-methyl-N-13- [4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethylbenzenesulfonamide, with 4-pentylbenzol chloride

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

N-methyl-N- {3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenyl] -2-oxooxazolidin-5-ylmethyl] -1-naphthylsulfonamide,

Similar to Example 2, the following compounds are obtained ^:

5- <5 - [((butylsulfonyl) methylamino) methyl 1-2-oxooxazolidin-3-yl] benzamidine, acetate, FAB 369, formulas

O

5- (5 - [((4-isopropylbenzol sulfonyl) methylamino) methyl 1-2-oxooxazolidin-3-yl] benzamidine acetate, FAB 431,

5- {5 - [((3-Trifluoromethylbenzenesulfonyl) methylamino) methyl 1-2-oxooxazolidin-3-yl] benzamidine acetate FAB 457,

5- (5 - [((phenylethylsulfonyl) methylamino) methyl 1-2-oxooxazolidin-3-yl) benzamidine acetate, FAB 417,

5- {5 - [((2-naphthylsulfonyl) methylamino) methyl 1-2-oxooxazolidin-3-yl] benzamidine,

5- (5-1 ((4-propylbenzenesulfonyl) methylamino) methyl 1-2-oxooxazolidin-3-yl) benzamidine,

5- (5-1 ((4-methoxybenzenesulfonyl) methylamino) methyl 1-2-oxooxazol-3-ylbenzamidine),

5- (5-1 ((2,4,6-trimethylbenzol sulfonyl) methylamino) methyl) -2-oxooxazolidin-3-ylbenyamidine,

5- (5-1 (benzoylmethylamino) methyl) -2-oxooxazolidin-3-ylbenzamidine,

5- (5-1 (2-naphthylcarbonylmethylamino) methyl 1-2-oxooxazolin-3-ylbenzamidine),

5- (5-1 (cyclohexylcarbonylmethylamino) methyl 1-2-oxooxazolin-3-ylbenzamidine),

5- (5 - [(4-biphenylylcarbonylmethylamino) methyl] -2-oxooxazolidin-3-ylbenzamidine,

5- (5-1 (4-Chlorobenzoylmethylamino) methyl) -2-oxooxazolidin-3-ylbenzamidine.

Similarly, 5-butylamino-methyl-14-14- (5-methyl-1,11,2,4) -methyl-14-14- (5-methyl-1,2,4,4-oxadiazol-3-yl) -phenyl-2-oxooxazolidin-5-ylmethanesulfonic acid methyl ester was obtained. 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- (3-14- (5-methyl-1,2,41-oxadiazol-3-yl) phenyl-2-oxooxazol-5-ylmethyl) -2-naphthylsulfonamide;

with 4-biphenylsulfonyl chloride

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] -2-oxooxazol-4-ylmethyl) -2-naphthylsulfonamide.

Example 10

Similar to Examples 3 and 4, N-methyl-N- (3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazol-5-ylmethyl) butylsulfonam is obtained. i du

4-13-1 (Butane-1-sulfonyl) methylamino] -2-hydroxypropylamino) benzamine of formula

HN

H ₂ N

O

from 4-isopropyl-N-methyl-N- (3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) -phenyl-2-oxooxazol-5-ylmethyl) -benzenesulfonamide]

4- (3 - [(isopropylbenzol sulfonyl) methylamino] -2-hydroxypropylaminolbenzamidine, acetate, FAB 405, from 3-trifluoromethyl-N-methyl-N-β- [4- (5-methyl [1,2] 4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl) benzenesulfonamide

4- (3 - [(3-trifluoromethylbenzol sulfonyl) methylamino-2-hydroxypropylamino) benzamidide, acetate, FAB 431, from N-methyl-N- (3- [4- (5-methyl [1]) 2,4] oxadiazol-3-yl) phenyl-2-oxooxazol-5-ylmethyl) phenyl tinylsulfonamide

4- (3 - [(phenylethylsulfonyl) methylino] -2-hydroxypropyl-

amino) from N-methyl-N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazol-5-ylmethyl} -2- naphthylsulfonamide

4- <3 - [(2-naphthylsulfonyl) methylamino] -2-hydroxypropylamino) benzamidine acetate, FAB 413, of 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-hydroxypropyl amino-benzamine, acetate, FAB 447, of 4-propyl-N-methyl-N-β- [4- (5) methyl [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazol-5-ylmethyl-benzenesulfonamide

4- {3 - [(4-propylbenzolsulfonyl) methylamino] -2-hydroxypropylamino] benzamidine, acetate, FAB 405, from 4-methoxy-N-methyl-N- <3- [4- (5-methyl [1,2,41] oxadiazole) -3-yl) phenyl-2-oxooxazolidin-5-ylmethyl) benzol sulfonamide

4- (3 - [(4-methoxybenzolsulfonyl) methylamino] -2-hydroxypropylamino] benzamidine, acetate, FAB 393, of 2,4,6-trimethyl-N-methyl-N- <3- [4- (5 methyl [1,2,4] oxadiazol-3-yl) phenyl-2-oxooxazol-5-ylmethyl) benzenesulfonamide

4- (3 - [(2,4,6-trimethylbenzol sulfonyl) methylamino] -2-hydroxypropylamino) benzamide, acetate, FAB 405, of 5- {5 - [(5-benzoylmethylamino) methyl 1-2- oxooxazoli din-3-ylbenzamidine

4- {3 - [(benzoylmethylamino) -2-hydroxypropylamino] benzamido,

2e 5- (5 - [(2-Naphthylcarbonylmethylamino) methyl] -2-oxooxazolin-3-ylbenzamidine

4- (3 - [(2-naphthylcarbonylmethylamino) -2-hydroxypropylamino) benzamido di η,

from 5- (5-1 (cyclohexylcarbonylmethylamino) methyl-2-oxooxazolidin-3-ylbenzamidine)

4- (3-1 (cyclohexylcarbonylmethylamino) -2-hydroxypropylamino benzamidine, of 5- (5-1- (4-biphenylylcarbonylmethylamino) methyl) -2-oxooxazololidin-3-ylbenzamidine

4- (3-1 (4-Phenylylcarbonylmethylamino-2-hydroxypropylamino) benzamidine of 5- (5-1 (4-chlorobenzoylmethylamino) methyl) -2-oxooxazololidin-3-ylbenzamidine

4- (3-1 (4-chlorobenzoylmethylamino) -2-hydroxypropylamino) benzamidine of 4- (1,1-dimethylpropyl) -N-methyl-N- (3- [4- (5-methyl11,2,4)] oxa-diazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl-1-benzenesulfonamide

4- (3-1 (4- (1,1-Dimethylpropylbenzenesulfonyl) methylamino] -2-hydroxypropylamino) benzamine, acetate, FAB 433, of 3,4-difluoro-N-methyl-N- (3-14 - (5-methyl-11,2,41-oxadiazol-3-yl) -phenyl-2-oxooxazolidin-5-ylmethyl-benzol sulfonamide

4- (3-1 (3-fluoro-4-methoxybenzolsulfonyl) methylamino] -2-hydroxypropyl aminobenzamine, acetate, FAB 411, of 4-tert-butyl-N-methyl-N- (3-14 - (5-methyl-11,2,4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl-benzol sulfonamide

4- (3-1 (3-tert-butylbenzol sulfonyl) methylamino-2-hydroxypropylaminolbenzamidine, acetate, FAB 419).

from 4-trifluoromethyl-N-methyl-N-β-1,4-β-methyl-11,2,41-oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl-1-benzol sulfonamide

4- (3-1 (4-Trifluoromethylbenzenesulfonyl) methylamino] -2-hydroxypropylaminolbenzamidide, acetate, FAB 431.

«<

»*

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

4- (3-1 (4-pentylbenzolsulfonyl) methylamino] -2-hydroxypropylaminoaminobenzamine diacetate, FAB 433, from N-methyl-N- (3-14- (5-methyltl. 2,4] oxadiazol-3-yl) phenyl-2-oxooxazol-5-ylmethyl) -1-naphthyl sulfonamide

4- (3-1 (1-naphthylsulfonyl) methylamino] -2-hydroxypropylamino) benzamidine acetate, FAB 413, of 6-chloro-N-butyl-N- (3-14- (5-methylll) 2,4,4-azadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl-2-naphthylsulfonamide

4- (3-1 (6-chloro-2-naphthylsulfonyl) butylamino] -2-hydroxypropylamino) benzamidine, from N-butyl-N- (3-14- (5-methyl-11,2,4) oxadiazole- 3-yl) phenyl-2-oxooxazolin-5-ylmethyl-4-biphenylylsulfonamide

4- (3-t (4-biphenylylsulfonyl) butylamino] -2-hydroxypropylamino) benzamidine, from N-butyl-N- (3-14- (5-methyl-11,2,4) oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl) -2-naphthylsulfonamide

4- (3-1 (2-naphthylsulphonyl) butylamino] -2-hydroxypropylamino) benzamidine, from N-methyl-N- (3-I4- (5-methyl-11,2,4) oxadiazole -3 -yl) phenyl-2-oxooxazolidin-5-ylmethyl- (7-methoxy-2-naphthyl) sulfonamide

4- (3-1 (7-methoxy-2-naphthylsulfonyl) methylamino] -2-hydroxypropyl-aminol-benzamidine, acetate, FAB 443, from N-methyl-N- (3-14- (5-methyl)). 2,4] oxadiazol-3-yl) phenyl-2-oxooxazolidin-5-ylmethyl} - (6-methoxy-2-naphthyl) sulfonamide

4- (3-1 (6-Methoxy-2-naphthylsulfonyl) methylamino] -2-hydroxypropyl) -4-benzamido-acetate, FAB 443.

C 9

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) oxazolin-2-one is obtained.

A solution of 8.5 g of the dicyanoic compound, 5.5 g of hydroxyammonium chloride and 11.2 g of sodium carbonate in 130 ml of dimethylformamide is stirred for three hours at 60 DEG C. After working up in the usual manner, 3- (4-N) is obtained. -hydroxyamidinophenyl) -5 - [(3-N-hydroxyamidinophenoxy) methyl] oxazolin-2-one.

Analogously to Example 2, hydrogenation of this compound gave 3- (4-amidinophenyl) -5 - [(3-amidinophenoxy) methyl] oxo.

xazolidin-2-one, diacetate, FAB 354, mp 159-160 C,

Similarly, it is obtained by reaction of F with 4'-hydroxybiphenyl-4-carbonitrile, reaction with hydroxylammonium chloride and reduction of the obtained compound

3- (4-aminophenyl) -5 - [(4'-amidino-4-biphenylyloxy) methyl] and

oxazolidin-2-one, diacetate. 214 DEG-224 DEG C., with 4-cyanophenol, treatment with hydroxylammonium chloride and reduction of the compound obtained

3- (4-amidinophenyl) -5 - [(4-amidinophenoxy) methyl] oxazolinone

2-one, diacetate, mp 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-oxooxazolidin-5-ylmethanesulfonic acid methyl ester 240 mg of phenylpiperazine and 120 mg of sodium bicarbonate in 10 ml of acetonitrile with heating The reaction mixture was worked up in the usual manner to give 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-methylphenyl) -5- enylpiperazin-1-ylmethyloxoxazol-2-one.

Hydrogenation, similar to Example 2, is obtained

4- [2-oxo-5- (4-phenylpiperazin-1-ylmethyl) oxazolidin-3-yl] benzamide, acetate, FAB 380.

Similarly, reaction of A with 5-bromomethylbenzot2,1,3] thiadiazole affords 3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- [4 (benzol 2,1, 3] thiadiazol-5-ylmethyl) piperazin-1-ylmethyloxazolin-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-ylmethanesulfonic 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] oxazolin-2-one , with benzylpiperazine

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

3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- [4-benzo [2,1,3] thiadiazol-5-yl) piperazin-1- 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- (pyrimidin-2-one). y1) piperazin-1-ylmethyl] oxazolin-2-one

4- [2-hydroxy-3- (4- (pyrimidin-2-ylpiperazin-1-yl) propylamino) benzamidine, acetate, FAB 356, of 3- [4- (5-methyl [ 1,2,4] oxadiazol-3-yl) phenyl] -5- [4-benzylpiperazin-1-ylmethyl] oxazolin-2-one

4- [2-hydroxy-3- (4-benzylpiperazin-1-yl) propylamino] benzamine, acetate, FAB 368, of 3- [4- (5-methyl [1,2,4] oxadiazole) -3-yl) phenyl] -5- [4-benzo [2,1,3] thiazol-5-yl) piperazin-1-ylmethyl] oxazolin-2-one 4- [2- hydroxy-3- (4- [4-benzo [2,3,3] thiazadiazol-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-dimethoxybenzylpiperazin-1-ylmethyl) oxazolin-2-one]

- (2-hydroxy-3- [4- (3,5-dimethoxybenzylpiperazin-1-yl) propylaminolbenzamidine. 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-pyridin-4-yl) piperazin-1-ylmethyl] oxazolidin-3-ylbenzamidine, FAB acetate 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 aminomethylpolystyrol and stir for an additional 12 hours. The polystyrol and solvent were removed and the usual work-up gave 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-butylamino-piperazin-1-ylmethyl) -oxazolidine- 2-on.

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

3- [4- (5-methyl [1,2,41-oxadiazol-3-yl) phenyl] -5- (4-cyclohexyl aminocarbonylpiperazin-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) aminocarbonylpiperazin-1-ylmethylloxazolin-2-one), se 4-trifluoromethylphenyl isocyanate

3- [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] -5- (4-N- (4-trifluoromethylphenyl) aminocarbonyl] piperazin-1-ylmethyl) oxazole di-2-one, with 4-chlorophenyl isocyanate

3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl] -phenyl] -5- (4-N- (4-chloro-phenyl) -amino-carbonyl-3-piperazin-1-ylmethyl) -oxazolidin-1-one 2-one, with 3-ethoxycarbonylphenylisocyanate

3- [4- (5-methyl- [1,2,41-oxadiazol-3-yl] phenyl] -5- (4-N- (3-ethoxycarbonylphenyl) amino) carbonyl] piperazin-1-ylmethyl-1-oxazolin-2-one; 1-naphthylisocyanate

84: -: *

3- [4- (5-methyl-11,2,4] oxadiazol-3-yl) phenyl] -5- [4- (naphthyl) aminocarbonylpiperazin-1-ylmethyl] oxazolin-2-one.

Hydrogenation analogous to Example 2 gave 3-14- (5-methyl-1,2,4) oxadiazol-3-yl) phenyl] -5- (4- [N- (4-methoxyphenyl) amino) carbonyl piperazin-1-ylmethyl) oxazolidin-2-one,

4- (2-ΟΧΟ-5- (4-1N- (4-methoxyphenyl) aminocarbonyl) piperazin-1-ylmethylioxazolidin-3-ylibenzamidine, acetate, FAB 453,

from 3-14- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -5- (4- [N- (4-trifluoromethylphenyl) amino] carbonylpiperazin-1-ylmethyl) oxazole din-2-one,

4- (2-oxo-5- (4- [N- (4-trifluoromethylphenyl) aminocarbonylpiperazin-1-ylmethyl) oxazolidin-3-yl) benzamine diacetate, FAB 473 of 3-14- ( 5-methyl-1,11,4,4] oxadiazol-3-yl) phenyl] -5- (4- [N- (4-chlorophenyl) aminocarbonylpiperazin-1-ylmethyl) oxazolin-2-one,

4- (2-oxo-5- (4- [N- (4-chlorophenyl) amino) carbonylpiperazin-1-ylmethylloxazolidin-3-yl) benzamidine, acetate, FAB 457, from 3-14- (5-methyl [1,2] 41-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, of 3- [4- (5-methyl [1,2,4] oxad) azol-3-yl) phenyl] -5- (4- [N- (3-ethoxycarbonylphenyl) amino-carbonyl] piperazin-1-ylmethyl) oxazolin-2-one,

Qí- · _ * · · <_Ό · · · ·

4- (2-oxo-5- (4- [N- (3-ethoxycarbonylphenyl) amino) carbonyl] piperazin-1-ylmethyl) oxazolidin-3-yl] benzamidine acetate, FAB 495, from 3-14- (5-methyl11,2) 4] oxadiazol-3-yl) phenyl-5- (4- (naphthylaminocarbonyl) piperazin-1-ylmethyl) oxazolin-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) piperazoline is obtained as a per- 1-ylmethyl) oxazolidin-2-one

4- [3- (4-Butylaminocarbonyl) piperazin-1-yl) -2-hydroxypropylamino] benzamidide, acetate, FAB 377, of 3- [4- (5-methyl [1,2,4] Thiazol-3-yl) phenyl] -5- (4-cyclohexylaminocarbonyl) piperazin-1-ylmethyl) oxazolidin-2-one

4- [3- (4-cyclohexylaminocarbonyl) piperazin-1-yl) -2-hydroxypropylaminolbenzamidine, acetate, FAB 403

Example 14

A solution of 1 equivalent of (3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl-phenyl) -2-oxo-oxazolazol-5-yl) -methanesulfonic acid methyl ester, 3 equivalents of glycine benzyl ester, methanesulfonate, and 3 equivalents of bicarbonate sodium acetonitrile was heated at reflux for 18 hours to give ({3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl-phenyl) -2-oxo-oxazolidin-5-yl) -benzyl ester. ylmethylJ amino J acetic acid (G)

Similarly, benzyl ester {N- [6-chloro-naphth-2-ylsulfonyl] -N- {3- [4- <5-methyl- [1,2,4] oxadiazole-] is obtained by reaction of G with 6-chloro-naphth-2-ylsulfonyl chloride. 3-yl) phenyl (2-oxooxazolidin-5-ylmethyl) amino) acetic acid.

Hydrogenation similar to Example 2 gives {N- [6-chloro-naph-2-ylsulfonyl] -N- [3- (4-aminophenyl) -2-oxooxazolin-5-ylmethyl] amino) acetic acid, acetate, FAB 517 and benzyl ester 1 N - 1 6-chloronaphth-2-ylsulfonyl] -N- [3- (4-arsidinophenyl) -2-oxooxazolidine- 5-ylmethyl] amino) acetic acid.

Similarly obtained by reaction of G with naphth-2-ylsulfonyl chloride followed by hydrogenation of (N-naphth-2-ylsulfonyl) -N- [3- (4-amidinophenyl) -2-oxooxazolin-5-ylmethyl-amino) acetic acid, acetate FAB 483

with 4-methoxybenzolsulfonyl chloride followed by hydrogenation. N- [4-methoxybenzolsulfonyl-Ν-E 3- (4-amidino phenyl) -2-oxooxazolidin-5-ylmethylamino) acetic acid, acetate. FAB 453, with phenyl in vinylsulfonyl chloride followed by hydrogenation with benzyl ester (N - [phenylvinylsulfonyl] -N- [3- (4-aminophenyl) -2-oxooxazolidin-5-ylmethyl] amino acetic acid, acetate, FAB 549, with 4-biphenylylsulfonyl chloride followed by hydrogenation of {N- [4-biphenylylsulfonyl] -N- [3- (4-amidinophenyl) -2-oxooxazol-5-ylmethyl-amino] acetic acid acetate, FAB 509, with 4-propylbenzenesulfonyl chloride and subsequent hydrogenation {N-14-propylbenzenesulfonyl] -N- [3- (4-aminophenyl) -2-oxooxazolin-5-ylmethylamino-acetic acid, acetate, FAB 565, benzyl ester.

Example 15

A solution of 4-oxiranylmethoxybenzonitrile and BOC-piperazine in methanol was stirred and refluxed for four hours. Conventional work-up gives 4- [2-hydroxy-3- (4-BOC-piperazin-1-yl) -propoxy] -benzonitrile benzyl ester. Subsequent reaction with hydroxylamine in hydrochloride affords N-hydroxy-4- [2-hydroxy-3- (4-BOC-piperazin). η-1-yl) propoxybenzamidine. Subsequent acylation with acetic anhydride affords 2-acetoxy-1- (4-BOC-piperazin-1-yl) -3,4- (5-methyl- [1,2,41-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] -3-14- (5-methyl11,2) is obtained by treatment with 4-propylphenylsulfonyl chloride. 4] oxadiazol-3-yl) phenoxy] propane.

Similar to Examples 3 and 4, it was obtained

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

Similarly, the following compounds are obtained:

3- [2-hydroxy-3- [4- (4-biphenylcarbonyl) piperazin-1-yl] propoxybenzamidine, acetate, FAB 459,

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

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

3- {2-hydroxy-3- [4- (4-propylphenylsulfonyl) piperazin-1-yl] propoxybenzamidine, acetate, FAB 461,

3- (2-hydroxy-3- [4- (4-isopropylphenylsulfonyl) piperazin-1-yl) propoxylbenzamidine, acetate, FAB 461,

3- [2-hydroxy-3- [4- (4-methoxyphenylsulfonyl) piperazin-1-yl] propoxylbenzamidine, acetate, FAB 449,

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

3- (2-hydroxy-3- [4-benzoylpiperazin-1-yl] propoxylbenzamidine acetate, FAB 383,

3- (2-Hydroxy-3- [4- (7-methoxy-2-naphthylsulfonylpiperazin-1-yl) propoxylbenzamidine, acetate, FAB 499).

3- {2-hydroxy-3- [4- (3,5-dimethoxybenzylpiperazin-1-yl) propoxylbenzamidine, acetate, FAB 429,

3- {2-hydroxy-3- [4- (4-biphenylylsulfonylpiperazin-1-yl) propoxybenzamidine, diacetate, FAB 495,

3- (2-hydroxy-3- [4-naphth-2-ylmethyl) piperazin-1-yl-propoxy) benzamide, diacetate, FAB 419,

3- (2-hydroxy-3- [4- (2-naphthylcarbonyl) piperazin-1-yl-3-propoxy) benzamidide, diacetate, FAB 433,

3- {2-Hydroxy-3- [4- (biphenyl-4-ylmethyl) piperazin-1-yl-3-propoxy) benzamidide, diacetate, FAB 445.

Example 16

10.0 g of 3-oxiranylmethoxybenzomtril (H) and 7.1 g of 3-cyanophenium are melted together with 173 mg of cesium fluoride at 130 ° C. Usual® processing® is obtained 11. ' phenoxy) -2-dihydroxypropane. Subsequent reaction with chloride® yields 1,3-bis- [3- (N-hydroxyamidino) phenoxy-2-hydroxypropane. Hydrogenation similar to Example 2 yields 1,3-bis-β-amidinophenoxy) -2-hydroxypropane. diacetate, FAB 329 g 1,3-bis- (3-cyano-hydroxy-ammonium)

Similarly, they are obtained

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,

9o:

4-methylphenol, phenol,

4-methoxyphenol,

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

- (3-araidinophenoxy) -2-hydroxy-3- (4-chlorophenoxy) propane, 1- (3-amidophenoxy) -2-hydroxy-3- (4-methylphenoxy) propane

- (3-amidinophenoxy) -2-hydroxy-3-phenoxypropane,

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

Example i 7

A solution of 1 equivalent of N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-ylphenyl-2-oxooxazolidin-5-ylmethyl)] - (6-chloro-2-naphthyl) sulfonamide (I ') [obtainable by reacting 5-aminoethyl-3- [4- (5-methyl- [1,2,4-oxadiazol-3-yl) phenyl] oxazolidin-2-one] with 6-chloro-2-naphthylsulfonyl chloride], 1.1 in each case of N, N'-dimethylchloroacetamide and cesium carbonate in dimethylformamide was stirred at room temperature for 12 hours. Conventional work-up gives 2 - ((6-chloro-2-naphthylsulfonyl) - {3- [4- (5-methyl- [1,24] oxadiazol-3-yl) phenyl] -2-oxooxazolidin-5-ylmethyl) amino ) -Ν, N 'dimethylacetam i.

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

HN

OH

Cl

Similarly, they are obtained by reacting I with compounds from the group comprising it

N, N‘-diethylchloroacetamide,

N, N'-dipropylchloroacetamide,

N-phenylchloroacetamide,

Ν, N '-diphenylchloroacetamide and chloroacetic acid ethyl ester followed by cleavage of the oxazolidinone and oxadiazole rings by the method of Examples 3 and 4 of the following compound

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

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

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

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl-1- (6-chloro-2-naphthylsulfonyl) amino] -1 ', N'-diphenylacetamide and

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

Similarly, it is obtained by reacting N- {3- [4- (5-methyl- [1,2,4] oxadiazol-3-ylphenyl] -2-oxooxazol-5-ylmethyl)] - (4-isopropylphenyl) sulfonamide with a compound selected from the group consisting of

N, N‘-dimethylchloroacetamide,

Ν, Ν'-diethylchloroacetamide,

Ν, N * -dipropylchloroacetamide,

N-phenylchloroacetamide,

Ν, Ν'-diphenylchloroacetamide, benzyl bromide, iodobutane,

4-chloromethyl-2-methylthiazole,

4-methoxybenzylbromide, ethyl chloroacetate, ethyl 4-chloromethyl ester, ethyl 3-chloromethylbenzoate, ethyl 4-chloromethylbenzoate,

3,5-dimethoxybenzyl bromide,

- (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] -Ν, N'-diacetyl acetamide

2 - [[3- (4-amidinophenylamino) -2-hydroxypropyl] - (4-isopropylsulfonyl) amino] -Ν, ’-diethyl acetyl d

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

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

2 - [[3- (4-aminophenylamino) -2-hydroxypropyl] - (4-isopropylsulfonyl) amino] -1, N'-diphenylacetamide

4 - {(2-hydroxy) -3 - [(4-isopropylbenzol sulfonyl) benzylamino] propylamino) benzamide, acetate, FAB 481,

4 - {(2-hydroxy) -3 - [(4-isopropylbenzol sulfonyl) butylamino] propylamino) benzamide, 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) benzamide, acetate, FAB 511,

2- (13- (4-aminophenylamino) -2-hydroxypropyl] - (4-isopropylbenzenesulfonyl) amino] acetic acid, acetate, FAB 449,

4-113- (4-aminophenylamino) -2-hydroxypropyl- (4-isopropylbenzenesulfonyl) amino] butyric acid acetate. FAB 477,

3- (113- (4-Aminophenylamino) -2-hydroxypropyl] - (4-isopropylbenzenesulfonyl) amino] methyl) benzoic acid, diacetate,

FAB 525,

4 - ((13- (4-aminophenylamino) -2-hydroxypropyl) - (4-isopropylbenzenesulfonyl) amino] methyl) benzoic acid, diacetate,

FAB 525,

4 - ((2-hydroxy) - o - (((4-isopropylbenzenesulfonyl) benzyl) amino) propylaminolbenzamidine, acetate,

- (3,5-di-methoxy FAB 541),

4- (2-hydroxy) -3-1 ((4-isopropylbenzenesulfonyl) - (4-amidobenzyl) amino] propylamino) benzamide, triacetate, FAB 523,

- ((2-hydroxy) -3-1 ((4-isopropylbenzole sulfonyl) - (3-amidinobenzyl) amino) propylaminolbenzamide, triacetate, FAB 523,

4 - {(2-hydroxy) -3 - [((4-isopropylbenzenesulfonyl) - (2-fluorobenzyl) amino] propyl aminolbenzamine di diacetate, FAB 499.

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

4-methoxybenzylbromide,

2-bromomethylnaphthalene,

4-chloromethyl-2-methylthiazole and 4-methoxybenzylchloride followed by cleavage of the oxazolidinone and oxadiazole rings by the method of Examples 3 and 4 of the following compound

4- (3-1 (6-chloro-2-naphthylsulfonyl) ethylamino] -2-hydroxypropylamino) benzamide

4- (3 - [(6-chloro-2-naphthylsulfonyl) benzylamino] -2-hydroxypropylamino) benzamidine,

4- (3-1 (6-chloro-2-naphthylsulfonyl) - (4-methoxybenzyl) amino] -2-hydroxypropylamino) benzamidine.

4- (3-1 (6-chloro-2-naphthylsulfonyl) - (naphth-2-ylmethyl) amino] -2-hydroxypropylamino-benzamidine,

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

4- (3 - [(6-chloro-2-naphthylsulfonyl) - (4-methoxybenzylamino) -2-hydroxypropyl aminobenzamidine, diacetate, FAB 553.

Similarly, it is obtained by reacting N- (3- [4- (5-methyl- [1,2,4] oxadiazol-3-ylphenyl-2-oxooxazolin-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-hydroxypropyl aminobenzamidine, acetate, FAB 435.

Similarly, it is obtained by reacting N- (3- [4- (5-methyl-1,2,2,41-oxadiazol-3-ylphenyl) -2-oxooxazolidin-5-ylmethyl) 1- (2-naphthyl) sulfamide, iodide 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) benzamine, 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:

96?

3- (3-Ν-hydroxyamidinophenyl) -5- (4-Ν-hydroxyamino-phenoxy) methyl 1-oxazolidin-2-one, m.p. 201-205 ° C;

- (3-N-hydroxyamidinophenyl) -5 - [(3-N-hydroxyamidinophenoxy) methyl] oxazolin-2-one,

3- (4-N-hydroxyamidinophenyl) -5- (3-N-hydroxyamidinobenzyloxy) methylloxazolidin-2-one;

3- (3-N-hydroxyamidinophenyl) -5 - [(3-N-hydroxyamidinobenzyloxy) methylloxazolidin-2-one,

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

3- (3-Aminophenyl) -5 - [(4-aminophenoxy) methyl] oxazolidin-2-one

diacetate. mp 150-166 ° C (dec.). FAB 354.

3- (3-Aminophenyl) -5 - [(3-amidinophenoxy) methyl] oxazolin-2-one

diacetate, mp 312-318 ° C,

3- (4-Amino-phenyl) -5 - [(3-amidino-benzyloxy) -methyl-oxazolin-2-one, triacetate, m.p. 189 DEG-205 DEG C. (dec.),

FAB 368,

3- (3-Aminophenyl) -5 - [(3-aminobenzoyloxy) methyl] oxazolidino

2-one, triacetate, m.p. 204 DEG-222 DEG C. (dec.),

FAB 368.

Example 19

Similar to Example 16, a reaction of 4-oxiranyl of ethylbenzonitrile and 3-cyanophenol, followed by treatment with hydroxyl ammonium chloride and hydrogenation of 4- [3-hydroxy-4- (3-amidenoxy) butyl] benzamide, diacetate, FAB 327

97 **

NH

Example 20

In a nitrogen atmosphere, 10.0 g of 3- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenol was added to 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 stirred 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 was filtered off and the filtrate was worked up in the usual manner to give N- (2-hydroxy-3- [3- (5-methyl- [1,2,41-oxadiazol-3-yl) phenoxy] propyl) -4-methoxybenzenesulfonamide. d.

Hydrogenation according to the method of Example 2 yields

3- [2-hydroxy-3- (4-methoxybenzenesulfonamino) propoxy] benzamidine, acetate, FAB 380 h ₂ n

NH

O

- w Γ * «J: J Ο» - · · · «.

· R r .. .. .. .. .. ..

• · · * *

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-naphthylsulfonylchloride.

followed by hydrogenation of the following compound

3- 12-hydroxy-3- (4-isopropylbenzenesulfonylamino) propoxylbenz amidine acetate, FAB 392,

3- [2-hydroxy-3- (2-naphthylsulfonylamino) propoxybenzamidine, acetate, FAB 400,

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

3- 12-Hydroxy-3- (7-methoxy-2-naphthylsulfonylamino) propoxy] benzamide, acetate, FAB 430.

Similarly, they are obtained by reacting 1-amino-3-C4- (5-methyl-2,4,4-oxadiazol-3-yl) phenoxy) propan-2-ol with a compound selected from the group consisting of:

4-Methoxyphenyl sulfonyl chloride

4-Isopropylphenylsulfonylchloride

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) propoxybenzamide, acetate, FAB 380,

4- [2-hydroxy-3- (4-isopropylbenzenesulfonylamino) propoxybenzamidine acetate FAB 392,

4- [2-hydroxy-3- (2-naphthylsulfonylamino) propoxybenzamidine, acetate, FAB 400,

4- [2-hydroxy-3- (6-chloro-2-naphthylsulfonylamino) propoxybenzamidine acetate FAB 434,

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

Example 21

Add 10.7 g of sodium methylate (30% in methanol) to 30 ml of methanol, add 4- (5-methyl- [1,2,41-oxadiazol-3-yl) aniline under nitrogen and stir the reaction mixture for 30 min. for 10 minutes e

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 DEG C. 440 mg of sodium borohydride are added and the reaction mixture is stirred for one hour at room temperature; The reaction mixture is subsequently mixed twice more with 1.44 g of paraformaldehyde, 3.1 g of sodium methylate and 220 mg of sodium borohydride.

After two hours, hydrolysis is carried out by adding 1N sodium hydroxide solution and the mixture is worked up in the usual manner. 1.93 g of N-methyl-4- (5-methyl- [1,2,41-oxadiazol-3-yl) aniline are obtained as a crude product.

A solution of 1.35 g of N-methyl-4- (5-methyl-1,2,41-oxadiazol-3-yl) aniline and 10 ml of epichlorohydrin in 5 ml of ethanol and 3.5 ml of water

100 is refluxed for 12 hours. The usual work-up gives 0.4 g of N-methyl-N-oxiranomethyl-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 (133% in ethanol) in 10 ml of ethanol is added Stir for c

hours at 65 [deg.] C. The usual work-up gives 0.44 g of 1-methylamino-3- (methyl- [4- (5-methyl- [1,2,41-oxadiazol-3-yl) -phenyl-amino) -propan-2]. -o1 (BC).

Stir 100 mg of BC and S7 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) benzamidium 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 formulations.

Example A, Injection Vials

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

Example B. Suppositories

A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 2 mg of active ingredient.

Example C. Solution

Prepare a solution of 1 g of the active compound of the formula I, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of dihydrogen phosphate with 12 molecules of water and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. per liter and sterilized by irradiation. This solution can be used as eye drops.

Example D. Mast

500 mg of an active compound of the formula I are mixed

99, petroleum jelly under aseptic conditions.

io2:

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, so that each tablet contains 10 mg of active ingredient.

Example F. Dragees

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

Example G Capsules 2 kg of active ingredient of the formula I are filled into hard gelatine capsules in a manner known per se so that each capsule contains 20 mg of active ingredient.

Example H. Ampoules

A solution of 1 kg of 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 are sealed. Each ampoule contains 10 mg of the active substance.

Industrial usability

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

Claims (9)

PATENT CLAIMS 1. A benzamidine derivative of the formula I: R ¹ where is R ¹ is -C (= HH) -NH 2, which optionally has one substituent selected from the group consisting of -COA, -CO- [C (R ⁵ ) 23m-Ar, -COOA, -OH, or is a group 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-COOR ⁵ , R ³ and X together also -CO-N to form a five-membered ring, where R ³ is -C = O and X is N, R ⁴ a, cycl oa 1 1 verifies alkyl, - [C ^(R) 21 m -Ar, - [C (R ⁵⁾ 2 Itr. -Het or -CR ⁵ = CR ⁵ -Ar. R @ ⁵ is hydrogen, A or benzyl, 104 “· X is oxygen, NR ⁵ or CH 3, Y oxygen atom, NR ⁵ group, NEC (R ⁵ ) 31m - Ar, NEC (R ⁵ ) 31m N [C (R ⁵ ) ₂ ] _m -COOR ⁵ --N ^? Ν—, N [C (R ⁵ ) 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, -C0- -SO3-, -COO- or -CONR ⁵ A is a C 1 -C 20 alkyl group in which one or two CH 3 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 groups selected from the group consisting of R ¹ · A, Ar ', OR ⁵ , N (R ⁵ ) ₂ , NO ₂ , CN, Hal, NHCOA, NHCOAr', NHSO3A, NHSO ₂ Ar ', COOR ⁵ , CON (R ⁵ ) 2, COHHAr '. COR ⁵ , COAr ', S (O) nA and S (0) _n Ar, Ar 1 phenyl or naphthyl bo substituted with one of NO ₂ , CN, Hal. NHCOA, COOR ⁵ S (O) _n A, unsubstituted by the bride or three groups A, OR ⁵ , N (R ⁵ ) ₂ , COR ⁵ , COAr 'and R ¹ , CON (R ⁵ ) ₂ , Het unsubstituted or by one or more of Hal, A, Ar ', OR ⁵ , COOR ⁵ , - 105 • CN, N (R ⁵⁾ second NO2, NHCOA, NHCOAr 'and oxo substituted single or double ring saturated or unsaturated ring system containing one, two, three or four identical or different heteroatoms such as nitrogen, oxygen and sulfur, Hal is a fluorine, chlorine, bromine or iodine atom, m is 0, 1, 2, 3 or 4, n is 0, 1 or 2, and its salts. A compound according to claim 1, selected from the group consisting of (a) 4- (3- [4- (2,6-dichloro-4-methoxybenzolsulfonyl) piperazin-1-yl] -2-hydroxypropylaminolbenzamidine; (b) 4- {3 - [(4-isopropylbenzenesulfonyl) methylamino] -2-hydroxypropyl amino) benzamidine; (c) 4- (3- (4- (1-naphthylbenzol sulfonyl) piperazin-1-yl) -2-hydroxypropylaminolbenzamidine); d) 3- (4-aminophenyl) -5 - [(3-aminophenoxy) methyl] oxazolin-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 a salt thereof, characterized in that (a) is released from its functional derivative by solvolyzing or hydrogenolyzing agents by: (i) the amidino group is liberated from the oxadiazole derivative by hydrogenolysis; - 106! (i) the conventional amino-protecting group is replaced by hydrogen or treated with a conventional amino-protecting group by treatment with a solvolysing or hydrogenolysing agent; or b) for the preparation of a compound of formula I wherein R ^{1 is a} group R ³ together with X -CO-N to form a five membered ring, Y group or R ⁵ \ N / W is -SO 2 - or -CO-, and R ² and R ⁴ are as defined above, with a compound of formula II R ¹ R ^z wherein R ¹ represents a group (II) 107 * -, R ³ together with X -CO-N to form a five membered ring, Y group NR ⁵ , / -N \ or R ⁵ and R ⁵ and R ^5, as defined above, are reacted with a compound of formula III R ⁴ -W-L (III) where is W is -SO 2 - or -CO-. L is a chlorine, bromine, iodine atom or a free or reactive functionally modified hydroxyl group; and R ⁴ is as defined above, or c) for the preparation of a compound of the general formula I, wherein it is R ¹ group R ³ together with X is -CO-N- to form a five membered ring. Y is an acid. And R ² and R ⁴ are as defined above, with a compound of formula (II) R ¹ R ^z where R ¹ group R ³ together with X -CO-N to form a five membered ring, Y is oxygen and R ² is as defined above, is reacted with a compound of formula IV R ⁴ -W-OH (IV) wherein is W binding a R ⁴ is as defined above, or d) for the right R ^{1 is a} group of a compound of formula (I), wherein is R ³ together with X is -CO-N- to form a five membered ring. Y group 109 '• · · · W binding, R ⁴ is - [C (R ⁵ ) 21mAr or - [C (R ⁵ '23mHet, m zero) and R ² is as defined above, with a compound of formula V wherein R ¹ is (V) {- ^N ΝΝ. \ ⁰ HN— neoo N ^: CH, R ³ together with X -CO-N- to form a five-membered ring, L is a chlorine, bromine, iodine atom or a free or reactive functionally modified hydroxyl group; and R ² has the above meaning, is reacted with a compound of formula VI R ⁴ - W - Y - H where t is VI) W binding, Y group 1 IQ The R ⁴ group - [C (R ⁵ ) 21mAr or - [C (R ⁵ ) 21mHet am zero, or e) for the preparation of R ^{1, a} group of a compound of formula I, wherein R is R ³ together with X -CO-N to form a five membered ring, Y group or W is -CONH-, and R ² and R ⁴ has the above meanings, with a compound of formula II R ^z wherein R ¹ represents a group (II) 111 R ³ together with X -CO-11 to form a five membered ring, Y group R ² and R ⁵ has the above meanings, is reacted with a compound 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 with X -CO-N to form a five membered ring, Y is -N [C (R ⁵⁾ 23 m -COOR ^5, W is the -SO 3 - group R ² and R ⁴ have the above meanings, with a compound of formula II 112. · - * (II) where is R ¹ group HN— {N or CH. R ³ together with X is -CO-N- to form a five membered ring. Y is -H, [C (R ⁵⁾ COOR 21 m and ^S R ³ and R ⁵ has the abovementioned meaning, is reacted with a compound of formula VIII R ⁴ - SO ₂ (VIII) wherein is L is a chlorine, bromine, iodine atom or a free or reactive functionally modified hydroxyl group; and R ⁴ is as defined above, or g) for the preparation of a compound of the formula I wherein X is NH, hydrogen and R ^1, R ^2, R ^4, Y and W are as hereinbefore defined, with a compound of formula I uvinuje from its oxazolidinone derivative or so1vo1yzačnim hydrogeno1yzačním agent or h) for the preparation of a compound of formula I wherein R ¹ is -C (= NH) -NH 2. and the other symbols have the meaning given above, the cyano group is converted to an amidino group or an amino group i) one or more Y, R ¹ , R ² , R ³ and / or R ⁴ groups are present in the compound of formula (I ⁾ . into one or more other radicals Y, R ^1, R ^2, R ³ and / or R ^4th taking (i) the ester group is hydrolyzed to a carboxyl group; (i) the nitro group is reduced; (iii) the amino group is acylated; and / or k) converting a base or an acid of formula I into a salt. 4. A process for the preparation of a pharmaceutical composition which comprises treating a compound of formula I, wherein the individual symbols are as defined in claim 1, and / or their physiologically acceptable salts with at least one solid, liquid or semi-liquid carrier or excipient. the dosage form. Pharmaceutical composition, characterized in that it contains, as active ingredient, at least one compound according to claim 1, in which the individual symbols are as defined in claim 1 and / or a physiologically acceptable salt thereof. A compound according to claim 1, wherein each symbol is as defined in claim 1, and physiologically acceptable salts thereof for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and calf muscle pain in walking i. Medicaments according to claim 1, wherein the individual symbols are as defined in claim 1, and their physiologically acceptable salts as inhibitors of coagulation factor Xa. 1: 4 ** * ** 9 · · Use of compounds according to claim 1 of the general formula I, wherein the individual symbols have the meaning given in claim 1, and / or physiologically acceptable salts thereof for the manufacture of medicaments. Use of compounds according to claim 1 of the general formula I, wherein the individual symbols are as defined in claim 1, and / or their physiologically acceptable salts for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and pain in the calf muscles while walking.