AU5164199A

AU5164199A - 2-oxo-(2h)-quinoline derivatives

Info

Publication number: AU5164199A
Application number: AU51641/99A
Authority: AU
Inventors: Soheila Anzali; Sabine Bernotat-Danielowski; Hans-Peter Buchstaller; Dieter Dorsch; Horst Juraszyk; Werner Mederski; Guido Melzer; Hanns Wurziger
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1998-08-29
Filing date: 1999-07-26
Publication date: 2000-03-21
Also published as: NO20010996D0; EP1107954A1; HUP0103212A3; KR20010072862A; HUP0103212A2; SK2652001A3; CN1315942A; WO2000012479A1; PL346045A1; DE19839499A1; HK1042478A1; AR021782A1; ID27863A; NO20010996L; CA2342230A1; BR9913140A; ZA200102565B; JP2002523494A

Description

2 -Oxo- 2H-quinoline derivatives The invention relates to compounds of the formula I R1 R

R

2 -X--Y N 0 R3( CH2) 5 wherein R and R 1 in each case independently of one another are 10 H, A, - (CH 2 ) m-R 4 , - (CH 2 )m-OA or - (CH 2 ) m-Ar, NH NH Ar N HN-H

R

2 is R 6 or R 6

R

3 is Ar, 15 R 4 is CN, COOH, COOA, CONH 2 , CONHA, CONA 2 or C(=NH) -NH 2 , Rs is -C (=NH) -NH 2 , -NH-C(=NH) -NH 2 or

-C(=O)-N=C(NH

2

)

2 , which are unsubstituted or monosubstituted by -COA, -COOA, -OH or by a 20 conventional amino-protective group, HN- N ' or R is H, A or NH 2 , 25 Ar is phenyl, naphthyl or biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, -2 Hal, CN, NO 2 , CF 3 , NH 2 , NHA, NA 2 , pyrrolidin 1-yl, piperidin-1-yl, benzyloxy, SO 2

NH

2 ,

SO

2 NHA, SO 2

NA

2 , - (CH 2 ) n-NH 2 , - (CH 2 ) n-NHA, - (CH 2 ) n-NA 2 , -0- (CH 2 ) n-NH 2 , -0- (CH 2 ) n-NHA, 5 -O- (CH 2 ) n-NA 2 , -0- (CH 2 )m-0- or R 5 , A is alkyl having 1-6 C atoms, X is absent or is alkylene having 1-4 C atoms or carbonyl, Y is absent or is NH, 0 or S, 10 Hal is F, Cl, Br or I, m is 0, 1 or 2 and n is 0, '1, 2 or 3 and salts thereof. 15 The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates of these compounds. 20 The invention was based on the object of discovering new compounds with valuable properties, in particular those which can be used for the preparation of medicaments. 25 It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties, coupled with a good tolerability. In particular, they show Factor Xa-inhibiting properties and can therefore be used for combating and preventing 30 thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens. 35 Compounds of the formula I according to the invention can furthermore be inhibitors of the clotting factors Factor VIIa, Factor IXa and thrombin of the blood clotting cascade.

-3 Aromatic amidine derivatives having an antithrombotic action are known, for example, from EP 0 540 051 Bl. Cyclic guanidines for treatment of thromboembolic diseases are described, for example, in WO 97/08165. 5 Aromatic heterocyclic compounds having a Factor Xa-inhibitory activity are known, for example, from WO 96/10022. Substituted N-[(aminoiminomethyl)phenyl alkyl]-azaheterocyclylamides as Factor Xa inhibitors are described in WO 96/40679. 10 The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibiting action against the activated clotting protease, known by the name Factor Xa, or to the 15 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 process of blood clotting. Factor Xa catalyses 20 the conversion of prothrombin into thrombin. Thrombin splits fibrinogen into fibrin monomers which, after crosslinking, make an elemental contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic diseases. However, an 25 inhibition of thrombin can inhibit the fibrin formation involved in thrombus formation. The inhibition of thrombin can be measured, for example, by the method of G.F. Cousins et al. in Circulation 1996, 94, 1705-1712. 30 An inhibition of Factor Xa can thus prevent thrombin being formed. The compounds of the formula I according to the invention and their salts intervene in the blood 35 clotting process by inhibiting Factor X and thus inhibit the formation of thrombi. The inhibition of Factor Xa by the compounds according to the invention and the measurement of the -4 anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 5 63, 220-223. The inhibition of Factor Xa can be measured, for example, by the method of T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319. 10 After binding to tissue factor, clotting Factor VIIa initiates the extrinsic part of the clotting cascade and contributes towards activation of Factor X to Factor Xa. Inhibition of Factor VIIa thus prevents the 15 formation of Factor Xa and therefore a subsequent formation of thrombin. The inhibition of Factor VIIa by the compounds according to the invention and the measurement of the anticoagulating and the antithrombotic activity can be 20 determined by customary in vitro or in vivo methods. A customary method for measuring the inhibition of Factor VIIa is described, for example, by H.F. Ronning et al. in Thrombosis Research 1996, 84, 73-81. 25 Clotting Factor IXa is generated in the intrinsic clotting cascade and likewise participates in the activation of Factor X to Factor Xa. An inhibition of Factor IXa can therefore prevent formation of Factor Xa in another manner. 30 The inhibition of Factor IXa by the compounds according to the invention and the measurement of the anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Chang 35 et al. in Journal of Biological Chemistry 1998, 273, 12089-12094. The compounds of the formula I can be employed as medicament active compounds in human and veterinary -5 medicine, in particular for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and 5 claudicatio intermittens. The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to Claim 1 and 10 their salts, characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent in that 15 i) an amidino group is liberated from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis, 20 ii) a conventional amino-protective group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or an amino group protected by a conventional protective group is liberated, 25 or b) in a compound of the formula I, one or more radical(s) R, R1, R 2 and/or R 3 is or are converted 30 into one or more radical(s) R, R1, R 2 and/or R 3 , in that, for example, i) an ester group is hydrolysed to a carboxyl 35 group, ii) a nitro group is reduced, iii) an amino group is acylated, -6 iv) a cyano group is converted into an amidino group 5 and/or c) a base or acid of the formula I is converted into one of its salts. 10 For all the radicals which occur more than once, such as, for example, Ar, the meanings thereof are independent of one another. Unless expressly stated otherwise, the radicals and 15 parameters R, X, Y, R1, R 2 , R 3 and n above and below have the meanings given in the case of formula I. A is alkyl, is linear or branched and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 C atoms. A is preferably 20 methyl, and moreover ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and furthermore 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 25 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1 methylpropyl, 1-ethyl-2-methylpropyl or 1,1,2- or 1,2,2-trimethylpropyl. Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. 30 Alkylene is preferably methylene, ethylene, propylene or butylene, or furthermore branched alkylene. COA is acyl and is preferably formyl, acetyl or propionyl, or furthermore also butyryl, pentanoyl or 35 hexanoyl. Hal is preferably F, Cl or Br, or also I.

-7 R is H, A, (CH 2 )m-R 4 , - (CH 2 )m-OA or - (CH 2 )m-Ar, preferably H, A, -CH 2

-R

4 or R 4 , and R is particularly preferably H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA. 5

R

1 is H, A, (CH 2 ) m-R 4 , - (CH 2 )m-OA or - (CH 2 ) m-Ar, preferably H, A, -CH 2

-R

4 or R 4 , and R' particularly preferably is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA, and especially preferably H, A or COOH. 10 R2 is preferably Ar, particularly preferably phenyl which is monosubstituted by R 5 , and especially preferably phenyl which is monosubstituted by amidino. 15 R 3 is Ar, preferably phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OA, Hal, CN or CF 3 , or phenyl, benzodioxol-5-yl, naphthyl or biphenyl, which are unsubstituted or mono- or disubstituted by cycloalkyl having 3-6 C atoms, OH, NH 2 , NHA, NA 2 , 20 pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO 2

NH

2 ,

SO

2 NHA, SO 2

NA

2 , - (CH 2 ) n-NH 2 , - (CH 2 ) n-NHA, - (CH 2 ) n-NA 2 , -0- (CH 2 ) n-NH 2 , -0- (CH 2 ) -NHA, -0- (CH 2 )n-NA 2 , or Rs, naphthyl or biphenyl monosubstituted by amidino being preferred. Preferred substituents for biphenyl are 25 amidino, fluorine, SO 2

NH

2 or SO 2 NHA. Ar is phenyl, naphthyl of biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO 2 , 30 CF 3 , NH 2 , NHA, NA 2 , pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO 2

NH

2 , SO 2 NHA, SO 2

NA

2 , phenylsulfonamido, - (CH2)n-NH2, - (CH 2 ) -NHA, - (CH 2 ) n-NA 2 , -O- (CH2) n-NH2,

-O-(CH

2 )n-NHA, -O-(CH 2 )n-NA 2 , -0- (CH 2 )m-0- or Rs 35 Ar is preferably unsubstituted phenyl, naphthyl or biphenyl, and moreover preferably phenyl, naphthyl or biphenyl, which are mono-, di- or trisubstituted, for example by A, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, -8 propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, sulfonamido, methyl 5 sulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenyl sulfonamido, aminomethyl, aminoethyl, N-methylaminomethyl, N-ethylaminomethyl, N,N-dimethyl aminomethyl, aminomethyloxy, aminoethyloxy or R , and 10 furthermore benzodioxolyl. Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or 15 p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)-phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)-phenyl, o-, m- or 20 p-(N-ethylamino)-phenyl, o-, m- or p-(N,N-diethyl amino)-phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-(methylsulfonamido)-phenyl, o-, m- or p-amidino phenyl, 7-amidino-2-naphthyl, 3-fluoro-2'-sulfamoyl 25 biphenyl-4-yl, 3-fluoro-2'-N-tert-butyl-sulfamoyl biphenyl-4-yl, 2'-sulfamoyl-biphenyl-4-yl, 2'-N-tert butyl-sulfamoyl-biphenyl-4-yl, o-, m- or p-(pyrrolidin 1-yl)-phenyl, o-, m- or p-(piperidin-1-yl)-phenyl, o-, m- or p-{5-methyl-[1,2,4]oxadiazol-3-yl)}-phenyl, 7-{5 30 methyl-[1,2,4-oxadiazol-3-yl)}-napth-2-yl, o-, m- or p-{5-oxo-[1,2,4]-oxadiazol-3-yl)}-phenyl or 7-{5-oxo [1,2,4]-oxadiazol-3-yl)}-naphth-2-yl, and also preferably 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 35 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- -9 dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4, 5-trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 5 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 10 2, 5-dimethyl-4-chlorophenyl.

R

4 is preferably, for example, COOH, COOA or CONH 2 . R is preferably, for example, unsubstituted 15 -C (=NH) -NH 2 , -NH-C (=NH) -NH 2 , -C (=O) -N=C (NH 2 ) 2 , which can also be monosubstituted by OH, HN N ~OrCHa 0or 20 especially preferably unsubstituted -C(=NH) -NH 2 or { , N

CH

3 X is preferably, for example, absent, or is carbonyl or 25 alkylene, in particular methylene or -CH(CH 3 )-. Y is preferably 0. m is preferably 0 or 1, and furthermore also 2. n is preferably 0 or 1, and furthermore also 2 or 3. 30 The compounds of the formula I can have one or more chiral centres and can therefore occur in various stereoisomeric forms. Formula I includes all these forms.

- 10 The invention accordingly particularly relates to those compounds of the formula I in which at least one of the radicals mentioned has one of the abovementioned 5 preferred meanings. Some preferred groups of compounds can be expressed by the following part formulae Ia to Ih, which correspond to the formula I and wherein the radicals not described in more detail have the meaning given in the case of formula I, but wherein 10 in Ia R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA; in Ib R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , 15 COOH or COOA, R' is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA; in Ic R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , 20 COOH or COOA

R

1 is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA,

R

2 is phenyl which is monosubstituted by R 5 ; 25 in Id R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA, R' is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA, R2 is phenyl which is monosubstituted by R 5 , 30 R 3 is phenyl or naphthyl, which are monosubstituted by CN or R 5 or by phenyl which is mono- or disubstituted by Rs, SO 2

NH

2 , SO 2 NHA or F; 35 in Ie R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA, R' is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA, R2 is phenyl which is monosubstituted by R 5

,

- 11 R 3 is phenyl or naphthyl, which are monosubstituted by CN or Rs or biphenyl which is mono- or disubstituted by R 5 , SO 2

NH

2 , SO 2 NHA or F, 5 R 5 is -C(=NH)-NH 2 or { N N=

CH

3 in If R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , 10 COOH or COOA,

R

1 is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA,

R

2 is phenyl which is monosubstituted by R 5 , R3 is phenyl or naphthyl, 15 which are monosubstituted by CN or R 5 , biphenyl which is mono- or disubstituted by R 5 , SO 2

NH

2 , SO 2 NHA or F,

R

5 is - C (=NH) -NH 2 or { N'O

CH

3 20 n is 0 or 1; in Ig R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , 25 COOH or COOA, R' is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA, R2 is phenyl which is monosubstituted by R 5 ,

R

3 is phenyl or naphthyl, 30 which are monosubstituted by CN or Rs or biphenyl which is mono- or disubstituted by RS, SO 2

NH

2 , SO 2 NHA or F,

R

5 is -C(=NH)-NH 2 or - 12 NsO

CH

3 n is 0 or 1, X is absent or is alkylene or carbonyl, 5 Y is absent or is 0; in Ih R is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , COOH or COOA, R' is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2

-CONH

2 , 10 COOH or COOA,

R

2 is phenyl which is monosubstituted by R 5 ,

R

3 is phenyl or naphthyl, which are monosubstituted by CN or Rs, or biphenyl which is mono- or disubstituted by R 5 , 15 SO 2

NH

2 , SO 2 NHA or F,

R

5 is -C (=NH) -NH 2 , which can also be monosubstituted by OH, or { N. N=

CH

3 20 n is 0 or 1, X is absent, Y is 0. 25 The compounds of the formula I and also the starting substances for their preparation are moreover prepared by methods which are known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der 30 organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the reactions mentioned. It is also possible here - 13 to make use of variants which are known per se and are not mentioned in more detail here. If desired, the starting substances can also be formed 5 in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I. Compounds of the formula I can preferably be obtained 10 by liberating compounds of the formula I from their functional derivatives by treatment with a solvolysing or hydrogenolysing agent. Preferred starting substances for the solvolysis or 15 hydrogenolysis are those which otherwise correspond to the formula I but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protective group instead of an H atom 20 bonded to an N atom, in particular those which carry an R'-N group, wherein R' is an amino-protective group, instead of an HN group, and/or those which carry a hydroxyl-protective group instead of the H atom of a hydroxyl group, for example those which correspond to 25 the formula I but carry a group -COOR", wherein R" is a hydroxyl-protective group, instead of a group -COOH. Preferred starting substances are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds. 30 The liberation of the amidino group from its oxadiazole derivative can be carried out, for example, by treatment with hydrogen in the presence of a catalyst (for example Raney nickel) . Suitable solvents are those 35 mentioned below, in particular alcohols, such as methanol or ethanol, organic acids, such as acetic acid or propionic acid, or mixtures thereof. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 1000 under pressures between about - 14 1 and 200 bar, preferably at 20-300 (room temperature) under 1-10 bar. The oxadiazole group is introduced, for example, by 5 reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformic acid ester, N,N'-carbonyldiimidazole or acetic anhydride. 10 Several - identical or different - protected amino and/or hydroxyl groups can also be present in the molecule of the starting substance. If the protective groups present differ from one another, they can in many cases be split off selectively. 15 The term "amino-protective group" is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but can easily be removed after the desired chemical 20 reaction has been carried out at other points of the molecule. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protective groups are removed after the desired reaction (or reaction 25 sequence), their nature and size is moreover not critical; preferably, however, those having 1-20, in particular 1-8 C atoms are preferred. The term "acyl group" is to be interpreted in the broadest sense in connection with the present process. It includes acyl 30 groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl, and above all aralkoxy carbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and 35 butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2 -trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl) and 2-iodoethoxycarbonyl; - 15 aralkyloxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protective groups are BOC and Mtr, and furthermore CBZ, Fmoc, benzyl and acetyl. 5 The term "hydroxyl-protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical 10 reaction has been carried out at other points of the molecule. Typical such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and furthermore also alkyl groups. The nature and size of the hydroxyl-protective groups is not 15 critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms are preferred. Examples of hydroxyl-protective groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluene 20 sulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred. The liberation of the compounds of the formula I from their functional derivatives is effected - depending on 25 the protective group used - with, for example, strong acids, expediently with TFA or perchloric acid, or also with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such 30 as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are, preferably, organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or 35 dioxane, amides, such as DMF, halogenated hydrocarbons, such as methylene chloride, and furthermore also alcohols, such as methanol, ethanol or isopropanol, as well as water. Mixtures of the abovementioned solvents are furthermore possible. TFA is preferably used in - 16 excess without addition of a further solvent, and perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9:1. The reaction temperatures for the cleavage are expediently between 5 about 0 and about 500, and the reaction is preferably carried out at between 15 and 300 (room temperature). The groups BOC, OBut and Mtr can preferably be split off, for example, with TFA in methylene chloride or 10 with about 3 to 5n HCl in dioxane at 15-30*, and the FMOC group with an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30*. 15 Protective groups which can be removed by hydrogenolysis (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be split off, for example, by treatment with hydrogen in the presence of a catalyst (for 20 example a noble metal catalyst, such as palladium, expediently on a support, such as charcoal) . Suitable solvents here are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is as a rule 25 carried out at temperatures between about 0 and 1000 under pressures between about 1 and 200 bar, preferably at 20-300 under 1-10 bar. A hydrogenolysis of the CBZ group is effected particularly well, for example, on 5 to 10% Pd/C in methanol or with ammonium formate 30 (instead of hydrogen) on Pd/C in methanol/DMF at 20-30*. Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or 35 xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetra chloride, trifluoromethylbenzene, chloroform or methylene chloride; alcohols, such as methanol, ethanol, isopropanol, n-propanol n-butanol or tert- - 17 butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol 5 dimethyl ether (diglyme) ; ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF) ; nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO) ; carbon disulfide; carboxylic 10 acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the solvents mentioned. 15 The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst, such as, for example, Pd/C. 20 For the preparation of an amidine of the formula I (for example Ar = phenyl which is monosubstituted by C(=NH)

NH

2 ), it is also possible to add ammonia onto a nitrile. The addition reaction is preferably carried out in several stages, by, in a manner known per se, a) 25 converting the nitrile into a thioamide with H 2 S, which is converted with an alkylating agent, for example

CH

3 I, into the corresponding S-alkylimido-thioester, which in turn reacts with NH 3 to give the amidine, b) converting the nitrile with an alcohol, for example 30 ethanol, in the presence of HCl into the corresponding imido-ester and treating this with ammonia, or c) reacting the nitrile with lithium bis-(trimethylsilyl) amide and subsequently hydrolysing the product. 35 It is furthermore possible to convert a compound of the formula I into another compound of the formula I by converting one or more radical(s) R, R 1

R

2 and/or R 3 into one or more radical(s) R, R 1 , R 2 and/or R 3 , for example by acylating an amino group or reducing nitro - 18 groups (for example by hydrogenation on Raney nickel or Pd-charcoal in an inert solvent, such as methanol or ethanol) to amino groups. 5 Esters can be hydrolysed, for example, with acetic acid or with NaOH or KOH in water, water-THF or water dioxane at temperatures between 0 and 1000. Free amino groups can furthermore be acylated in the 10 customary manner with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, expediently in an inert solvent, such as methylene chloride or THF, and/or in the presence of a base, such as triethylamine or pyridine, at 15 temperatures between -60 and +300. A base of the formula I can be converted into the associated acid addition salt with an acid, for example by reaction of equivalent amounts of the base and the 20 acid in an inert solvent, such as ethanol, and subsequent evaporation. Acids which are particularly suitable for this reaction are those which give physiologically acceptable salts. It is thus possible to use inorganic acids, for example sulfuric acid, 25 nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, and furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono 30 or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, 35 gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -disulfonic acids and lauryl- - 19 sulfuric acid. Salts with acids which are not physiologically acceptable, for example picrates, can be used for isolation and/or purification of the compounds of the formula I. 5 On the other hand, compounds of the formula I can be converted with bases (for example sodium hydroxide or carbonate or potassium hydroxide or carbonate) into the corresponding metal salt, in particular alkali metal or 10 alkaline earth metal salts, or into the corresponding ammonium salts. Physiologically acceptable organic bases, such as, for example, ethanolamine, can also be used. 15 Because of their molecular structure, compounds of the formula I according to the invention can be chiral and may accordingly occur in various enantiomeric forms. They can therefore be present in a racemic or in an optically active form. 20 Since the pharmaceutical activity of the racemates and of the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product, or 25 already the intermediate product, can be separated into enantiomeric compounds by chemical or physical measures known to the expert or can be already employed as such in the synthesis. 30 In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active separating agent. Suitable separating agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid, 35 dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Chromatographic separation of enantiomers with the aid - 20 of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates, or chirally derivatized methacrylate polymers fixed on silica gel) 5 is also advantageous. Suitable mobile phases for this are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in a ratio of 82:15:3. 10 The invention furthermore relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by a non-chemical route. For this use, they can be brought into a suitable 15 dosage form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and optionally in combination with one or more further active compounds. 20 The invention furthermore relates to pharmaceutical formulations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts. 25 These formulations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the new compounds, 30 for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc and Vaseline. Tablets, pills, coated tablets, capsules, powders, granules, 35 syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants for parenteral use and ointments, creams or powders for topical use. The - 21 new compounds can also be lyophilized and the lyophilisates obtained can be used, for example, for the preparation of injection preparations. The formulations mentioned can be sterilized and/or 5 comprise auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavourings and/or several further active compounds, for example 10 one or more vitamins. The compounds of the formula I and their physiologically acceptable salts can be used in combating and preventing thromboembolic diseases, such 15 as thrombosis, miocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens. The substances according to the invention are as a rule 20 preferably administered here in dosages of between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg/kg of bodyweight. However, the specific dose for each patient depends on the most 25 diverse factors, for example on the activity of the specific compound employed, on the age, bodyweight, general state of health, sex, on the diet, on the administration time and route, and on the rate of excretion, medicament combination and severity of the 30 particular disease to which the treatment applies. Oral administration is preferred. All temperatures above and below are stated in OC. In the following examples, "customary working up" means: 35 water is added, if necessary, the pH is adjusted to between 2 and 10, if necessary, depending on the structure of the end product, the mixture is extracted with ethyl acetate or methylene chloride, the organic phase is separated off, dried over sodium sulfate and - 22 evaporated and the residue is purified by chromatography over silica gel and/or by crystallization. Rf values on silica gel; mobile phase: ethyl acetate/methanol 9:1. 5 Mass spectrometry (MS): EI (electron impact ionization) M+ FAB (Fast Atom Bombardment) (M+H)* Example 1 10 By reaction of 3- (tert-butyldimethylsilyloxy) benzonitrile and 1-fluoro-4-nitrobenzene with tetrabutylammonium fluoride in THF analogously to Synthesis 1988, 378-379, the compound 3-(4-nitro 15 phenoxy)-benzonitrile ("AB") , m.p. 113-114*, is obtained. 90.4 g of sodium bicarbonate and 350 ml of water are added to a suspension of 78.4 g of "AB" and 68.0 g of hydroxylammonium chloride in 1 1 of methanol. The 20 mixture is heated under reflux for 6 hours, while stirring. After cooling, water is added and the crystals which have precipitated out are separated off. After drying, 87.5 g of pale yellow needle-shaped crystals of 3- (4-nitrophenoxy) -N-hydroxybenzamidine 25 ("B"), m.p. 176-177*, E1273 are obtained. A solution of 87.5 g of "B" in 250 ml of acetic anhydride is heated under reflux for 3 hours. After cooling, the mixture is poured onto ice-water and the precipitate is worked up in the customary manner to 30 give 76.8 g of 5-methyl-3-[3-(4-nitrophenoxy)-phenyl] [1,2,4]-oxadiazole ("C"), m.p. 134-135*, E1297. A solution of 58.3 g of "C" in 500 ml of 1,4-dioxane is heated to 800. 97.1 g of sodium sulfide octahydrate in 500 ml of water are then added (Yang-i Lin et al., 35 J. Heterocycl. Chem. 1980, 17, 1273). After the mixture has been stirred for 2 hours, it is worked up in the customary manner to give 50.6 g of 5-methyl-3-[3-(4 aminophenoxy) -phenyl] - [1,2,4] -oxadiazole (%"D") , m.p. 88-89*, E1267.

- 23 7.1 ml of 2,2,6-trimethyl-1,3-dioxin-4-one are added dropwise at 1200 to a solution of 14.4 g of "D" in 130 ml of xylene and the mixture is subsequently stirred for 3 hours. After cooling, it is worked up in 5 the customary manner to give 16.5 g of N-{4-[3-(5 methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-phenyl}-3-oxo butyramide ("E"), m.p. 104-105*, E1351. O'N N 0 0 N "" H 10 A solution of 8.2 g of "E" in 23 ml of concentrated sulfuric acid is stirred at 80* for 3 hours. After cooling and customary working up, 7.1 g of 6-[3-(5 methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo 15 2H-quinoline ("F"), m.p. 234-235*, E1333 are obtained. O'N N 0 N 0 7"F". H 0.81 g of potassium tert-butylate and then 2.28 g of 20 3-(3-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole are added to a solution of 2.0 g of "F" in 50 ml of DMF and the mixture is subsequently stirred for 2 hours. After customary working up, in addition to 0.7 g of 0-alkylation product, 1.66 g of 1-[3-(5-methyl 25 [1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-1,2,4] oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline ("G"), m.p. 167-1684, FAB 506 are obtained.

- 24 O'N N N O N-O N "" Analogously, reaction of "F" gives with 3-(2-bromomethyl-naphthalene-7-yl)-5-methyl 5 [1,2,4]oxadiazole, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen 2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl) phenoxy]-4-methyl-2-oxo-2H-quinoline, m.p. 103-104*; 10 with 3- (4-bromomethylphenyl) -5-methyl- [1,2,4]oxadiazole 1- [4- (5-methyl- [1,2,4]oxadiazol-3-yl) -benzyl] -6 [3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methyl 2-oxo-2H-quinoline, m.p. 204-205*. 15 Example 2 1 drop of acetic acid and water-moist Raney nickel are added to a solution of 0.37 g of "G" in 30 ml of methanol and the mixture is stirred under an H 2 20 atmosphere for 24 hours. After removal of the catalyst and customary working up, 0.12 g of 1- (3-amidinobenzyl) -6- (3-amidinophenoxy) -4-methyl 2-oxo-2H-quinoline, FAB 426 is obtained. NH

H

2 N N 0 NH

NH

2 25 - 25 The following amidine derivatives are obtained analogously by hydrogenation with Raney nickel 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino 5 phenoxy)-4-methyl-2-oxo-2H-quinoline, m.p. 281-282*, FAB 476; 1-(4-amidinobenzyl)-6-(3-amidino-phenoxy)-4 methyl-2-oxo-2H-quinoline, m.p. 141-145*, FAB 426. 10 Example 3 2 eq. of N-bromosuccinimide and benzoyl peroxide are added to a solution of "F" in methanol and the mixture 15 is stirred under reflux for 16 hours. After customary working up, 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl) phenoxy]-4-dibromomethyl-2-oxo-2H-quinoline are obtained. The compound is then reacted with sodium formate and 20 the product is subsequently oxidized by known methods to give 6-[3-(5-methyl[1,2,4]oxadiazol-3-yl)-phenoxy] 4-methoxycarbonyl-2-oxo-2H-quinoline ("H"). Reaction of "H" analogously to Example 1 gives, 25 with 3-(3-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole ("1"), with 3-(2-bromomethylnaphthalene-7-yl)-5-methyl [1,2,4]oxadiazole ("2"), 30 with 3-(4-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole ("%3") , with 3-(4'-bromomethylbiphenyl)-2-yl-5-methyl-[1,2,4] oxadiazole ("4"), 35 in addition to the 0-alkylation products, the following compounds - 26 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 6-[3-(5-methyl-[1,2,41-oxadiazol-3-yl)-phenoxy]-4 methoxycarbonyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) 5 naphthalene]-2-ylmethyll-6-[3-(5-methyl-[1,2,4] oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4 10 methoxycarbonyl-2-oxo-2H-quinoline, 1-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl 4'-ylmethyl-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl) phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 15 from which the following carboxylic acid derivatives are obtained by customary ester hydrolysis 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4 20 carboxy-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalene]-2-ylmethyl]-6-[3-(5-methyl-[1,2,4] oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 25 6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4 carboxy-2-oxo-2H-quinoline, 1-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl 4'-ylmethyl-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl) phenoxy]-4-carboxy-2-oxo-2H-quinoline. 30 The following amidino derivatives are obtained therefrom by hydrogenation analogously to Example 2 1-(3-amidinobenzyl)-6-(3-amidino-phenoxy)-4 35 carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3 amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-6-(3-amidino-phenoxy)-4 carboxy-2-oxo-2H-quinoline, - 27 1-(2-amidino-biphenyl[4'-ylmethyl)-6-(3 amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline. Alternatively, the carboxylic acid esters can first be 5 alkylated, then hydrogenated to the amidino derivatives and finally hydrolysed. Example 4 10 2.13 mol of potassium carbonate are added to a solution of 0.425 mol of 4-methyl-3-nitro-phenol in 2 1 of pyridine. 0.425 mol of copper (I) chloride is added and the mixture is heated under reflux for 0.5 hour. 0.5 mol of 3-bromobenzonitrile is then added and the 15 mixture is heated under reflux for 3 days. After customary working up 3- (4-methyl-3-nitrophenoxy) benzonitrile is obtained. Analogously to Example 1, the compound 5-methyl-3- [3- (4-methyl-3-nitro-phenoxy) phenyl]-[1,2,4]-oxadiazole is obtained therefrom with 20 hydroxylammonium chloride and by heating in acetic anhydride. By reduction of the nitro group analogously to Example 1 and oxidation of the methyl group analogously to Example 3, the compound 5-methyl-3-[3 (4-formyl-3-amino-phenoxy)-phenyl]-[1,2,4]-oxadiazole 25 is obtained therefrom. By Friedl&nder condensation analogously to the method of del mar Blanco et al., Heterocycles, 1993, 1397 et seq., the compound 7-[3-(5 methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3 ethoxycarbonyl-2-oxo-2H-quinoline ("I") is obtained 30 therefrom. Analogously to Example 3, by reaction of "I" with compounds "1", "2", "3" and "4" and subsequent hydrogenation, the following compounds are obtained 35 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3 amidino-phenoxy) -3-ethoxycarbonyl-2-oxo-2H-quinoline, - 28 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy) 3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl-4'-ylmethyl)-7-(3 amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline. 5 Ester hydrolysis gives therefrom the compounds 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 3-carboxy-2-oxo-2H-quinoline, 10 1-(7-amidino-naphthalen-2-ylmethyl) 7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy) 3-carboxy-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl-4'-ylmethyl) 15 7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline. Example 5 By reaction of 3-hydroxybenzonitrile with 3-bromo 20 nitrobenzene analogously to Example 4, the compound 3-(3-nitro-phenoxy)-benzonitrile is obtained. Analogously to Example 1, the compound 7-[3-(5-methyl [1,2,4]oxadiazol-3-yl)-phenoxyl-4-methyl-2-oxo-2H quinoline ("K") is obtained by reduction of the nitro 25 group, formation of the oxadiazole ring, reaction with 2,2,6-trimethyl-1,3-dioxin-4-one and cyclization with concentrated sulfuric acid. Analogously to Example 3, 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4 methoxycarbonyl-2-oxo-2H-quinoline ("L") is obtained 30 therefrom by oxidation of the 4-methyl group. By reaction of "L" analogously to Example 1 gives, with "1", "2" and "3", 35 in addition to the 0-alkylation products, the following compounds - 29 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyll 7- [3- (5-methyl- [1,2,4]oxadiazol-3-yl) -phenoxy] 4 -methoxycarbonyl -2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) 5 naphthalen-2-ylmethyl)-7-[3-(5-methyl-[1,2,4] oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H quinoline. 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7 [3- (5-methyl- [1,2,4]oxadiazol-3-yl) -phenoxy) 10 4-methoxycarbonyl-2-oxo-2H-quinoline, from which the following carboxylic acid derivatives are obtained by customary ester hydrolysis 15 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy] 4 -carboxy-2 -oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalen-2-ylmethyl]-7-[3-(5-methyl 20 [1,2,4] -oxadiazol-3-yl) -phenoxy] -4-carboxy-2-oxo-2H quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7 [3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-carboxy 2-oxo-2H-quinoline. 25 By hydrogenation analogously to Example 2, the following amidino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 30 4-carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl) 7-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy) 4-carboxy-2-oxo-2H-quinoline. 35 By reaction of "K" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained - 30 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy] 4-methyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) 5 naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4] oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline. 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7 [3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxyl-4-methyl 2-oxo-2H-quinoline. 10 By hydrogenation analogously to Example 2, the following amino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 15 4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl) 7-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy) 4-methyl-2-oxo-2H-quinoline, 20 Example 6 By reaction of 3-hydroxybenzonitrile with 3-bromo nitrobenzene analogously to Example 4, the compound 25 3-(3-nitro-phenoxy)-benzonitrile is obtained. Analogously to Example 1, the compound 7-[3-(5-methyl [1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo 2H-quinoline ("M") is obtained by reduction of the nitro group, formation of the oxadiazole ring, reaction 30 with 2,2,6-trimethyl-5-ethyl-1,3-dioxin-4-one and cyclization with concentrated sulfuric acid. By reaction of "M" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 35 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl 4-methyl-2-oxo-2H-quinoline, - 31 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4] oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H quinoline, 5 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7 [3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl 4-methyl-2-oxo-2H-quinoline. By hydrogenation analogously to Example 2, the 10 following amidino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl) 15 7-(3-amidino-phenoxy)-3-ethyl-4-methyl-2-oxo-2H quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy) 3-ethyl-4-methyl-2-oxo-2H-quinoline. 20 The following compounds are obtained analogously 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidinonaphthalene)-2-ylmethyl) 25 7-(3-amidino-phenoxy)-3-methoxycarbonylmethyl-4-methyl 2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy) 3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 30 3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7 (3-amidino-phenoxy)-3-carboxymethyl-4-methyl-2-oxo-2H quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy) 35 3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy) 3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline, - 32 1- (7-amidino-naphthalen-2-ylmethyl) 7- (3-amidino-phenoxy) -3 -aminocarbonylmethyl-4-methyl 2-oxo-2H-quinoline, 1- (4-amidino-benzyl) -7- (3-amidino-phenoxy) 5 3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline. Example 7 4.3 g of potassium carbonate are added to a suspension 10 of 1.0 g of 6-hydroxyquinolin-2-one in 25 ml of DMF and the mixture is subsequently stirred at room temperature for 0.5 hour. 0.6 g of copper (I) chloride is then added and the mixture is heated under reflux for 0.5 hour. After addition of 3-bromobenzonitrile in 15 25 ml of pyridine, the reaction mixture is heated under reflux for 18 hours. It is worked up in the customary manner to give, after chromatography over silica gel, the two compounds 6-(3-cyanophenoxy)-2-oxo-2H-quinoline ("N"), m.p. 20 221-222*, EI 262 and 1- (3-cyanophenyl) -6- (3-cyanophenoxy) -2-oxo-2H quinoline ("0"), m.p. 82-84*, EI 363. By reaction of "N" with "1", "2" and "3", in addition 25 to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 6-[3-cyanophenoxy]-2-oxo-2H-quinoline, 30 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalen-2-ylmethyl]-6-[3-cyanophenoxy]-2-oxo-2H quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 6-[3-cyanophenoxy]-2-oxo-2H-quinoline. 35 By reaction with hydroxylammonium chloride and subsequent reduction with H 2 and Raney nickel, the following compounds are obtained therefrom - 33 1- (3-amidinobenzyl) -6- (3-amidino-phenoxy) 2-oxo-2H-quinoline, FAB 413; m.p. 160-1620, 1-(7-amidinonaphthalen-2-ylmethyl) 6- (3-amidino-phenoxy) -2-oxo-2H-quinoline, 5 1-(4-amidino-benzyl)-6-(3-amidino-phenoxy) 2-oxo-2H-quinoline. An analogous procedure, starting from 7-hydroxyquinoline-2-one, gives the compounds 10 1- (3-amidinobenzyl) -7- (3-amidino-phenoxy) 2-oxo-2H-quinoline, 1-(7-amidinonaphthalene)-2-ylmethyl) 7- (3-amidino-phenoxy) -2-oxo-2H-quinoline, 15 1-(4-amidinobenzyl)-7-(3-amidino-phenoxy) 2-oxo-2H-quinoline. 0.19 g of hydroxylammonium chloride and 0.22 g of sodium bicarbonate is added to a suspension of 0.12 g 20 of "0" in 5 ml of ethanol. After further addition of 0.5 ml of water, the mixture is boiled under reflux for 2 hours. After customary working up, 1-(3-N hydroxyamidino-phenyl)-6-(3-N-hydroxyamidino-phenoxy) 2-oxo-2H-quinoline, EI 429 is obtained. 25 By oxadiazole formation and hydrogenation, 1-(3-amidino-phenyl)-6-(3-amidino-phenoxy)-2-oxo-2H quinoline, FAB 398; m.p. 62-64* is obtained therefrom. 1- (3-Amidino-phenyl) -7- (3-amidino-phenoxy) -2-oxo-2H 30 quinoline is obtained analogously. Example 8 A suspension of 1 g of 6-hydroxy-2-oxo-2H-quinoline in 35 30 ml of DMF is cooled to about 100 and 0.84 g of potassium tert-butylate is then added. 2.0 g of 3-(3-bromomethyl-phenyl)-5-methyl-[1,2,4]oxadiazol (m.p. 54-550) are added and the mixture is subsequently stirred for 2 hours and worked up in the customary - 34 manner. 6-[3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-benzyl oxy]-2-oxo-2H-quinoline ("P"), m.p. 208-209*, E1333 is obtained. 5 By reaction of "P" with 3-bromobenzonitrile analogously to Example 7, the compound 1-(3-cyanophenyl)-6-[3-(5 methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H quinoline. By reaction with hydroxylammonium chloride and 10 subsequent reduction with H 2 and Raney nickel, 1-(3-amidino-phenyl)-6-(3-amidinobenzyloxy)-2-oxo-2H quinoline is obtained therefrom. By reaction of "P" with "1", "2" and "3", in addition 15 to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy] 20 2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4} oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 25 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy-2-oxo 2H-quinoline. By subsequent reduction with H 2 and Raney nickel, the following compounds are obtained therefrom 30 1-(3-amidinobenzyl)-6-(3-amidinobenzyloxy 2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl) 6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline, 35 1-(4-amidinobenzyl)-6-(3-amidinobenzyloxy) 2-oxo-2H-quinoline.

- 35 Example 9 Analogously to Example 8, by reaction of 7-hydroxy 2-oxo-2H-quinoline with 3-(3-bromomethyl-phenyl) 5 5-methyl-[1,2,4]oxadiazole, the compound 7-[3-(5 methyl [1,2,4]oxadiazol-3-yl) -benzyloxy] -2-oxo-2H quinoline ("Q"), m.p. 168-170*, EI 333 is obtained. By reaction of "Q" with 3-bromobenzonitrile analogously 10 to Example 7, the compound 1- (3- (cyanophenyl) -7- [3- (5 methyl- [1,2,4]oxadiazol-3-yl) -benzyloxy] -2-oxo-2H quinoline is obtained. By reaction with hydroxylammonium chloride and subsequent reduction with H 2 and Raney nickel, 15 1-(3-amidino-phenyl)-7-(3-amidinobenzyloxy)-2-oxo-2H quinoline is obtained therefrom. By reaction of "Q" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds 20 are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 7- [3- (5-methyl- [1,2,4] -oxadiazol-3-yl) -benzyloxy] 2-oxo-2H-quinoline, 25 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4] oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl] 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo 30 2H-quinoline. By subsequent reduction with H 2 and Raney nickel, the following compounds are obtained therefrom 35 1-(3-amidinobenzyl)-7-(3-amidinobenzyloxy) 2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7 (3-amidinobenzyloxy) -2-oxo-2H-quinoline, - 36 1- (4-amidinobenzyl) -7- (3-amidinobenzyloxy) 2-oxo-2H-quinoline. Example 10 5 By reaction of 6-hydroxy-2-oxo-2H-quinoline with acetic anhydride in pyridine in a known manner, 6-acetoxy-2 oxo-2H-quinoline, m.p. 221-222* is obtained. By subsequent alkylation with "1", in addition to the 10 0-alkylation product, the compound 1- (3- (5-methyl [1,2,4]oxadiazol-3-yl)-benzyl]-6-acetoxy-2-oxo-2H quinoline, m.p. 157-1584 is obtained. By deacetylation in a known manner, 1-[3-(5-methyl-[1,2,4]oxadiazol-3 yl)-benzyl]-6-hydroxy-2-oxo-2H-quinoline, m.p. 271-273* 15 ("R") is obtained. By reaction of "R" with 3-[5-methyl-[1,2,4] oxadiazol-3 yl]-benzoyl chloride with the addition of caesium carbonate in DMF, after customary working up the compound 1-[3-(5-methyl- [1,2,4]oxadiazol-3-yl)-benzyl] 20 6- [3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo 2H-quinoline is obtained. By subsequent hydrogenation analogously to Example 2, 1- (3-amidinobenzyl) -6- (3-amidinobenzyloxy) -2-oxo-2H quinoline is obtained therefrom. 25 By reaction of "R" with 1-{3-[5-methyl-[1,2,4] oxadiazol-3-yl]-phenyl)methyl bromide and subsequent hydrogenation, the compound 1- (3-amidinobenzyl) -6- [1 (3-amidinophenyl)methoxy) -2-oxo-2H-quinoline, m.p. 30 125-127* is obtained analogously. NH 0

NH

2 N NH NH 2 - 37 The compound 1- (3-amidinobenzyl) -7- (1- (3-amidino phenyl)methyloxy) -2-oxo-2H-quinoline, m.p. 146-150* is obtained analogously. 5 Example 11 By reaction of "R" with 3-(5-methyl-[1,2,4]oxadiazol-3 yl)-phenylboronic acid, 1- [3-(5-methyl-[1,2,4] oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl 10 [1,2,4]oxadiazol-3-yl)-phenoxy]-2-oxo-2H-quinoline and therefrom, by hydrogenation, 1-(3-amidinobenzyl)-6-(3 amidino-phenoxy) -2-oxo-2H-quinoline are obtained. The other compounds mentioned in Example 7 are also 15 obtained analogously. Example 12 By reaction of 3-methyl-4-nitro-phenol with acetic 20 anhydride and sulfuric acid, 1-acetoxy-3-methyl 4-nitro-benzene is obtained. Subsequent bromination with NBS with irradiation gives 1-acetoxy-3-dibromo methyl-4-nitro-benzene, m.p. 130-1314, EI 353. By reaction with sodium formate in water and ethanol, 25 3-formyl-4-nitro-phenol, m.p. 145-146*, EI 167 is obtained, and is converted by reaction with benzyl bromide with addition of potassium carbonate in DMF into 1-benzyloxy-3-formyl-4-nitro-benzene, m.p. 120-121*, EI 257. By reduction of the nitro group with 30 Na 2 S in dioxane and water at 80*, 1-benzyloxy-3-formyl 4-amino-benzene, EI 245 is obtained. By reaction with diethyl malonate in piperidine and heating, the compound 6-benzyloxy-3-ethoxycarbonyl-2-oxo-2H quinoline ("S"), m.p. 155-1560, EI 323 is obtained 35 therefrom. By reaction of "S" with "2", 1-[7-(5-methyl] [1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6 benzyloxy-3-ethoxycarbonyl-2-oxo-2H-quinoline is - 38 obtained, and is converted by hydrogenation with Raney nickel into 1-[7-amidino-naphthalen-2-ylmethyl]-6 benzyloxy-3-ethoxycarbonyl-2-oxo-2H-quinoline. 5 By ester hydrolysis, 1-(7-amidino-naphthalen-2 ylmethyl)-6-benzyloxy-3-carboxy-2-oxo-2H-quinoline is obtained therefrom. Example 13 10 The regio-isomeric carboxylic acid derivatives (3-carboxy-...) from Example 3 are obtained as follows: a) By reaction of 4-methyl-3-nitro-phenol with acetic 15 anhydride and sulfuric acid, 1-acetoxy-4-methyl-3 nitro-benzene is obtained. Subsequent bromination with NBS with irradiation gives 1-acetoxy-4-dibromo-methyl 3-nitro-benzene. By reaction with sodium formate in water and ethanol, 4-formyl-3-nitro-phenol is obtained 20 therefrom, and is converted by reaction with tert butyl-dimethylsilyl chloride with the addition of imidazole in methylene chloride into 1-tert-butyl dimethylsiloxy-4-formyl-3-nitro-benzene. By reduction of the nitro group with Na 2 S in dioxane and water at 25 800, 1-tert-butyl-dimethylsilyloxy-4-formyl-3-amino benzene is obtained. By reaction with dimethyl malonate with addition of piperidine, the compound 7-tert-butyl dimethylsilyloxy-3-methoxycarbonyl-2-oxo-2H-quinoline ("T") is obtained therefrom. 30 By reaction of "T" with "2", 1-[7-(5-methyl [1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-tert butyl-dimethylsilyloxy-3-methoxy-carbonyl-2-oxo-2H quinoline is obtained, which is converted into 1-[7-(5 35 methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7 hydroxy-3-methoxycarbonyl-2-oxo-2H-quinoline ("U") by splitting off of the silyl group.

- 39 By reaction of "U" with 3-bromobenzonitrile and further reaction analogously to Example 1, 1-[7-(5-methyl [1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl-6-[3-(5 methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-methoxy 5 carbonyl-2-oxo-2H-quinoline is obtained therefrom, and 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino phenoxy)-3-methoxy-carbonyl-2-oxo-2H-quinoline is obtained therefrom by hydrogenation. 10 By ester hydrolysis, 1-(7-amidino-naphthalen-2 ylmethyl)-6-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H quinoline is obtained therefrom. b) By reaction of "U" with 3-(3-bromomethyl-phenyl) 15 5-methyl-[1,2,4]-oxadiazole analogously to Example 8, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2 ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl) benzyloxy]-3-methoxycarbonyl-2-oxo-2H-quinoline is obtained, and is converted by hydrogenation into 1-(7 20 amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzyloxy) 3-methoxy-carbonyl-2-oxo-2H-quinoline. By ester hyrolysis, 1-(7-amidino-naphthalen-2 ylmethyl)-6-(3-amidino-benzyloxy)-3-carboxy-2-oxo-2H 25 quinoline is obtained therefrom. c) By reaction of "U" with 3-[5-methyl-[1,2,4] oxadiazol-3-yl]-benzoyl chloride analogously to Example 10, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2 30 ylmethyl)-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl) benzoyloxy]-3-methoxycarbonyl-2-oxo-2H-quinoline is obtained, and is converted by hydrogenation into 1-(7 amidino-naphthalen-2-ylmethyl)-6-(3-amidino benzoyloxy)-3-methoxycarbonyl-2-oxo-2H-quinoline. 35 By ester hydrolysis, 1-(7-amidino-naphthalen-2 ylmethyl)-6-(3-amidino-benzoyloxy)-3-carboxy-2-oxo-2H quinoline is obtained therefrom.

- 40 The regio-isomeric 7-isomers are obtained analogously starting from 3-methyl-4-nitro-phenol. Example 14 5 The following compounds are obtained analogously to Example 12 1- (3-amidino-benzyl) -6-benzyloxy-3-ethoxycarbonyl 10 2-oxo-2H-quinoline, m.p. 176.90, and 1-(3-amidino benzyl) -6-benzyloxy-3-carboxy-2-oxo-2H-quinoline, m.p. >3000 therefrom by ester hydrolysis, and the compound 1- (7-cyano-naphthalen-2-ylmethyl) 15 7- (7-cyano-naphthalen-2-ylmethyl) -3-ethoxycarbonyl 2-oxo-2H-quinoline, m.p. 216.4*. Example 15 20 Analogously to Example 4, the compound 1-(7-cyano naphthalen-2-ylmethyl)-7-(3-cyano-phenoxy] 3-ethoxycarbonyl-2-oxo-2H-quinoline, m.p. 183.50 is obtained, and 1- [7- (N-hydroxy-amidino) -naphthalen 2-ylmethyl] -7- [3- (N-hydroxy-amidino) -phenoxy) 25 3-carboxy-2-oxo-2H-quinoline m.p. >300* is obtained therefrom. Example 16 30 800 mg of molecular sieve (0.4 nm) are added to a solution of 200 mg of 6-[3-(5-methyl-[1,2,4]oxadiazol 3-yl) -benzyloxy] -2-oxo-2H-quinoline, 265 mg of 3-cyanophenylboronic acid and 220 mg of Cu(II) acetate in 15 ml of methylene chloride and the mixture is 35 stirred under nitrogen at room temperature. After addition of 0.145 ml of pyridine and 0.25 ml of triethylamine, the mixture is subsequently stirred for 18 hours. After addition of 50 ml of water, the mixture is worked up in the customary manner and 190 mg of - 41 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-1-(3 cyanophenyl)-2-oxo-2H-quinoline ("V"), EI 434 are obtained. 140 mg of "V" are suspended in 10 ml of ethanol, and 5 91 mg of hydroxylammonium chloride and 108 mg of sodium bicarbonate are added. 1 ml of water is then added and the mixture is heated under reflux for 8 hours. It is taken up in 20 ml of ice-water. The monohydroxyamidine is hydrogenated analogously to Example 2. 6-(3-amidino 10 benzyloxyl-1-(3-amidinophenyl)-2-oxo-2H-quinoline is obtained. The following examples relate to pharmaceutical formulations: 15 Example A: Injection glasses A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is 20 adjusted to pH 6.5 with 2 N hydrochloric acid in 3 1 of doubly distilled water, subjected to sterile filtration, bottled in injection glasses, lyophilized under sterile conditions and closed under sterile conditions. Each injection glass contains 5 mg of 25 active compound. Example B: Suppositories A mixture of 20 g of an active compound of the formula 30 I is melted with 100 g of soya lecithin and 1400 g of cocoa butter and the mixture is poured into moulds and allowed to cool. Each suppository comprises 20 mg of active compound. 35 Example C: Solution A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH 2

PO

4 -2 H20, 28.48 g of Na 2

HPO

4 -12 H 2 0 and 0.1 g of benzalkonium chloride in - 42 940 ml of doubly distilled water. The solution is adjusted to pH 6.8, topped up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops. 5 Example D: Ointment 500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions. 10 Example E: Tablets 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 15 talc and 0.1 kg of magnesium stearate is pressed to tablets in the customary manner such that each tablet comprises 10 mg of active compound. Example F: Coated tablets 20 Tablets are pressed analogously to Example E and are then coated in the customary manner with a coating of sucrose, potato starch, talc, tragacanth and dyestuff. 25 Example G: Capsules 2 kg of active compound of the formula I are introduced into hard gelatine capsules in the customary manner such that each capsule contains 20 mg of the active 30 compound. Example H: Ampoules A solution of 1 kg of active compound of the formula I 35 in 60 1 of doubly distilled water is subjected to sterile filtration, bottled into ampoules, lyophilized under sterile conditions and closed under sterile conditions. Each ampoule contains 10 mg of active compound.

Claims

1. Compounds of the formula I RR R R

2 -X-Y N 0 R3 CH2)n 5 wherein R and R1 in each case independently of one 10 another are H, A, - (CH 2 )m-R 4 , - (CH 2 )m-OA or - (CH 2 ) m-Ar, NH NH Ar, { N HN H R2 is R6 or R6 15 R 3 is Ar, R 4 is CN, COOH, COOA, CONH 2 , CONHA, CONA 2 or C(=NH) -NH 2 , R 5 i s -C(=NH)-NH 2 , -NH-C(=NH)-NH 2 or -C (=O) -N=C (NH 2 ) 2 , which are unsubstituted 20 or monosubstituted by -COA, -COOA, -OH or by a conventional amino-protective group, { N. O{ N, 0 N,0 HN4 N-$ CH or CH 3 0or 25 R6 is H, A or NH 2 , - 44 Ar is phenyl, naphthyl or biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having

3-6 C atoms, OH, OA, Hal, CN, NO 2 , CF 3 , 5 NH 2 , NHA, NA 2 , pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, S0 2 NH 2 , SO 2 NHA, SO 2 NA 2 , - (CH 2 ) n-NH 2 , - (CH 2 ) n-NHA, - (CH 2 )n-NA 2 , -0- (CH 2 )n-NH 2 , -0- (CH 2 )n-NHA, -O-(CH 2 )n-NA 2 , -0-(CH 2 )m-0- or Rs 10 A is alkyl having 1-6 C atoms, X is absent or is alkylene having 1-4 C atoms or carbonyl, Y is absent or is NH, 0 or S, Hal is F, Cl, Br or I, 15 m is 0, 1 or 2 and n is 0, '1, 2 or 3 and salts thereof. 20 2. Compounds according to Claim 1, a) 1-(3-amidinobenzyl)-6-(3-amidinophenoxy)

4-methyl-2-oxo-2H-quinoline, b) 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3 25 amidino-phenoxy) -4-methyl-2-oxo-2H-quinoline and salts thereof. 3. Process for the preparation of compounds of the formula I according to Claim 1 and their salts, 30 characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent in that 35 i) an amidino group is liberated from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis, - 45 ii) a conventional amino-protective group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or 5 an amino group protected by a conventional protective group is liberated, or 10 b) in a compound of the formula I, one or more radical(s) R, R 1 , R 2 and/or R 3 is or are converted into one or more radical(s) R, R', 2 3 R and/or R 15 in that, for example, i) an ester group is hydrolysed to a carboxyl group, 20 ii) a nitro group is reduced, iii) an amino group is acylated, 25 iv) a cyano group is converted into an amidino group and/or 30 c) a base or acid of the formula I is converted into one of its salts. 4. Process for the preparation of pharmaceutical formulations, characterized in that a compound of 35 the formula I according to Claim 1 and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary. - 46

5. Pharmaceutical formulation, characterized by a content of at least one compound of the formula I according to Claim 1 and/or one of its 5 physiologically acceptable salts.

6. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts or solvates as medicament active compounds. 10

7. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts for combating thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina 15 pectoris, restenosis following angioplasty and claudicatio intermittens.

8. Medicaments of the formula I according to Claim 1 and their physiologically acceptable salts as 20 inhibitors of coagulation factor Xa.

9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the preparation of a medicament. 25

10. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts in combating thromboses, myocardial infarction, arteriosclerosis, inflammations, 30 apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens.