the present invention relates to novel highly selective inhibitors of the urokinase plasminogen activator ( upa , ec 3 . 4 . 21 . 31 ) of the arylguanidine type . the urokinase - type plasminogen activator ( upa ) plays a key part in tumor invasion and formation of metastases ( schmitt et al ., j . obst . gyn . 21 ( 1995 ), 151 – 165 ) upa is overexpressed in various types of tumor cells ( kwaan , cancer metastasis rev . 11 ( 1992 ), 291 – 311 ) and binds to the tumor - associated upa receptor ( upa - r ) in which activation of plasminogen to plasmin takes place . plasmin is capable of degrading various components of the extracellular matrix ( ecm ) such as fibronectin , laminin and collagen type iv . it also activates some other ecm - degrading enzymes , in particular matrix metalloproteinases . high amounts of tumor - associated upa correlate with a higher risk of metastasizing in cancer patients ( stephens et al ., breast cancer res . & amp ; treat . 52 ( 1998 ), 99 – 111 ). therefore , inhibition of the proteolytic activity of upa is a good starting point for an anti - metastatic therapy . a common feature of many known synthetic upa inhibitors is a basic residue containing amidino or guanidino groups , which can bind to asp 189 in the upa s1 specificity pocket and which acts as an arginine mimetic there ( spraggon et al ., structure 3 ( 1995 ), 681 – 691 ). however , most of the known inhibitors are not selective for upa but also inhibit other serine proteases such as trypsin , thrombin , plasmin or tissue plasminogen activator ( tpa ). p - aminobenzamidine is a moderately selective upa inhibitor having an inhibition constant of 82 μm . billstroem et al . ( int . j . cancer 61 ( 1995 ), 542 – 547 ) could show a distinct decrease in the growth rate of du145 tumors ( a prostate adenocarcinoma cell line ) in scid mice when administering orally a daily dose of 125 to 250 mg of p - aminobenzamidine / kg / day . the side effects were negligible . some monosubstituted phenylguanidines have proved effective and selective upa inhibitors in vitro . these small molecules have inhibition constants in the micromolar range but they bind only in the s1 pocket of upa ( yang et al ., j . med . chem . 33 ( 1990 ), 2956 – 2961 ). biological studies using these compounds were not carried out . the diuretic amiloride is a selective upa inhibitor ( ki , upa = 7 μm ) which prevents the formation of lung metastases after i . v . inoculation of rat breast adenocarcinoma cells ( kellen et al ., anticancer res . 8 ( 1988 ), 1373 – 1376 ). some 3 - amidinophenylalanine derivatives have likewise proved effective inhibitors of serine proteases but these compounds generally have only low selectivity for upa ( stürzebecher et al ., j . med . chem . 40 ( 1997 ), 3091 – 3099 ; stürzebecher et al ., j . enzyme inhib . 9 ( 1995 ), 87 – 99 ). currently the most effective and most selective upa inhibitors are benzo [ b ] thiophene - 2 - carboxamidine derivatives ( b428 and b623 : ki , upa = 0 . 32 and 0 . 07 μm , respectively ; u . s . pat . no . 5 , 340 , 833 ). rabbani et al . ( int . j . cancer 63 ( 1995 ), 840 – 845 ) and also xing et al . ( cancer res . 57 ( 1997 ), 3585 – 3593 ) could show , after administration of 4 - iodobenzo [ b ] thiophene - 2 - carboxamidine ( b428 ), a decrease of tumor growth and metastases formation in a syngeneic model of rat prostate cancer and mouse breast cancer , respectively . the latter studies showed a further decrease in primary tumor growth when b428 was administered together with the antiestrogen tamoxifen . the german patent application 199 40 389 . 9 proposes the use of arylguanidine and in particular phenylguanidine derivatives as selective upa inhibitors . these compounds contain a further substituent on the aromatic ring system , preferably in para position to the guanidine group , which substituent contains an unsubstituted or substituted methylene group followed by hydrogen donor / acceptor functionalities . owing to this substitution pattern ; the compounds are particularly effective and selective for upa . it is assumed that these compounds interact as arginine mimetics with the asp 189 amino acid residue in the s1 pocket of upa and can interact with the s2 and / or s3 pockets of upa . surprisingly , further aryl guanidine derivatives have now been identified which can interact even more specifically with upa , in particular with the amino acid residues gln 192 and / or ser 214 . in addition to the guanidine group these compounds contain another substituent on the aromatic ring system , which contains an unsubstituted or substituted methylene group followed by a hydrogen donor function , a hydrogen acceptor function and again a hydrogen donor function . the present invention relates to the use of compounds of the formula ( i ) ar is an aromatic or heteroaromatic ring system , x 1 is a radical of the formula ( iia ), ( iib ) or ( iic ): r 1 is h , an unsubstituted or substituted alkyl , alkenyl , alkynyl , aryl or / and heteroaryl radical , r 2 is halogen , c ( r 3 ) 3 ), c 2 ( r 3 ) 5 , oc ( r 3 ) 3 or oc 2 ( r 3 ) 5 , r 3 is in each case independently h or halogen , in particular f , r 4 and r 5 are h or an unsubstituted or substituted alkyl , alkenyl or alkynyl radical , where at least one of the radicals r 4 and r 5 contains a hydrogen bond donor group , for example oh , nh 2 , sh , or 1 , nhr 1 , n ( r 1 ) 2 , sr 1 , co , cs , r 6 and r 7 are h or an unsubstituted or substituted alkyl , alkenyl or alkynyl radical , where at least one of the radicals r 6 and r 7 contain a hydrogen bond donor group , for example oh , nh 2 , sh , or 1 , nhr 1 , n ( r 1 ) 2 , sr 1 , co , cs , and where r 4 or r 5 may be bridged with r 6 or r 7 , r 8 is h or an unsubstituted or substituted alkyl , alkenyl , alkynyl , aryl or / and heteroaryl radical or — so 2 — r 9 , where r 6 may or may not be bridged with r 6 or r 7 , r 9 is h or an unsubstituted or substituted alkyl , alkenyl , alkynyl , aryl or / and heteroaryl radical , x 2 is a hydrogen bond acceptor group , in particular nh , nr 10 , o or s , r 10 is an unsubstituted or substituted alkyl , alkenyl or alkynyl radical , and or salts of said compounds for preparing an agent for inhibition of the urokinase plasminogen activator . the compounds may be present as salts , preferably as physiologically tolerated acid salts , for example as salts of mineral acids , particularly preferably as hydrochlorides or as salts of suitable organic acids . the guanidinium group may carry , where appropriate , protective functions which are removable by cleavage , preferably under physiological conditions . the compounds may be present as optically pure compounds or as mixtures of enantiomers or / and diastereoisomers . in the compounds of the formula ( i ), ar is preferably an aromatic or heteroaromatic ring system having a single ring , in particular a benzene ring . in this ring system the substituents chx 1 r 1 and nhc ( nh ) nh 2 are preferably arranged in meta or para position and particularly preferably in para position . in addition , ar may further contain other , non - hydrogen substituents r 2 . the number of substituents r 2 is preferably 0 , 1 , 2 or 3 , particularly preferably 0 or 1 and most preferably 0 . preferred examples of r 2 are halogen atoms ( f , cl , br or i ), ch 3 , cf 3 , oh , och 3 or ocf 3 . the substituent — chx 1 r 1 is critical for inhibitor activity . r 1 may be h or an unsubstituted or substituted alkyl , alkenyl , alkynyl , aryl or / and heteroaryl radical . the alkyl radical may be a straight - chain or branched c 1 – c 10 - alkyl group , in particular a c 2 – c 4 - alkyl group or a c 3 – c 8 - cycloalkyl group which may be substituted with , for example , c 1 – c 3 - alkoxy , hydroxyl , carboxyl , amino , sulfonyl , nitro , cyano , oxo or / and halogen or else with aryl or heteroaryl radicals . alkenyl and alkynyl radicals are preferably c 2 – c 10 groups , in particular c 2 – c 4 groups which may be unsubstituted or substituted as described above . aryl and heteroaryl radicals may be substituted , for example , with c 1 – c 6 - alkyl , c 1 – c 3 - alkoxy , hydroxyl , carboxyl , sulfonyl , nitro , cyano or / and oxo . the x 1 group preferably contains at least one or two substituents ( r 4 or r 5 or / and r 6 or r 7 ), which contain a hydrogen bond donor group and also a substituent x 2 which contains a hydrogen bond acceptor group . the hydrogen bond donor substituents contain a group which provides a hydrogen atom or / and an electron pair for a hydrogen bond . the distance of the hydrogen bond donor group from the carbon atom to which the substituents 4 and r 5 and , respectively , r 6 and r 7 are bound is preferably 1 to 3 carbon atoms , particularly preferably 1 to 2 carbon atoms and most preferably 1 carbon atom . examples of hydrogen bond donor groups are oh , nh 2 , sn , or 1 , nhr 1 , n ( r 1 ) 2 , sr 1 . preferred examples of substituents containing hydrogen bond donor groups are hydroxymethyl , 2 - hydroxyethyl , — co 2 h , — co 2 r 1 , where r 1 is defined as above and is preferably an alkyl group or an aryl group such as , for example , the benzyl group , e . g . — co 2 ch 2 — ph , conh 2 , — conhr 1 , conr 1 , where r 1 is as defined above , e . g . conhch 3 , — con ( ch 3 ) 2 , csoh , csor 1 , — cosh , cosr 1 , cor 1 and csr 1 , where r 1 is as defined above . it is also possible that two substituents containing hydrogen bond donor groups are bridged , for example via a c 2 – c 3 bridge . examples of substituents bridged in this way are 1 , 2 - dihydroxyethylene or 1 , 3 - dihydroxypropylene . a substituent r 4 / r 5 and , respectively , r 6 / r 7 which contains no hydogen bond donor group is preferably hydrogen or an halogen - substituted or not halogen - substituted methyl or ethyl group . a particularly preferred substituent of this kind is hydrogen . the hydrogen bond acceptor substituent x 2 is preferably nh or o , particularly preferably o . furthermore , the x 1 group contains a substituent r 8 which preferably carries out a steric function . r 8 may be hydrogen , an alkyl , alkenyl , alkynyl , aryl , heteroaryl , carboxyalkyl , carboxyalkenyl , carboxy - alkynyl , carboxyaryl or carboxyheteroaryl radical or — so 2 — r 9 , where r 9 may have the same meaning as stated for r 8 . advantageously , r 8 and r 9 are different from hydrogen and contain at least 4 , for example 6 to 20 , carbon atoms . r 8 may or may not be bridged with r 6 or r 7 . the substituents r 8 and r 9 contain preferably space - filling groups which may be selected from the group comprising unsubstituted or substituted aryl radicals , in particular phenyl and substituted phenyl radicals and unsubstituted or substituted branched alkyl , alkenyl or alkynyl radicals , in particular with tertiary carbon atoms such as tert - butyl or neopentyl , or unsubstituted or substituted cycloalkyl radicals , in particular bi - or tricycloalkyl radicals such as adamantyl . the compounds of the formula ( i ) may be prepared , for example , starting from p - aminobenzylamine according to the reaction schemes shown in the german patent application 199 40 389 . 9 . for example , 4 - aminobenzyl - amine may be reacted with a protective reagent for amino groups , for example di - tert - butyl pyrocarbonate , to give a protected intermediate , 4 -( n - boc - aminomethyl ) aniline , boc meaning tert - butyloxycarbonyl . the aromatic amino function of this compound can be reacted with a guanidinylation reagent , for example n , n ′- di - z - n ″- triflylguanidine , resulting in 1 -[ 4 -( n - boc - aminomethyl ) phenyl ]- 2 , 3 - di - z - guanidine , z being benzyloxycarbonyl . this compound can be converted to 1 -[ 4 -( aminomethyl ) phenyl ]- 2 , 3 - di - z - guanidinium hydrochloride by removing the boc protective group by cleavage . this compound may in turn be reacted with reactive compounds such as , for example , chloroformic esters , isocyanates or n - hydroxysuccinimide esters to give the desired final products . to prepare hydrogenation - labile compounds , 4 - amino - benzylamine can be reacted with a protective reagent for amino groups , for example benzyloxycarbonyl - oxysuccinimide to give a protected intermediate and then with a further guanidinylation reagent , for example n , n ′- di - boc - 1 - guanylpyrazole this compound can be hydrogenated and then be reacted with reactive compounds to give the desired final products . the urokinase inhibitors of the invention may be used , where appropriate , together with suitable pharmaceutical excipients or carriers for producing medicaments or in diagnostics . in this connection , administration in combination with other active substances , for example other urokinase inhibitors such as , for example , antibodies or / and peptides , is possible . the medicaments may be administered in humans and animals topically , orally , rectally or parenterally , for example subcutaneously or intravenously , for example in the form of tablets , coated tablets , capsules , pellets , suppositories , solutions or transdermal systems such as plasters . the compounds of the invention are suitable for controlling disorders which are associated with pathological overexpression of upa or / and upar . they are , for example , capable of very effectively inhibiting the growth or / and spreading of malignant tumors and also metastasizing of tumors . it is possible to use the upa inhibitors , where appropriate , together with other tumor agents or with other types of treatment , for example radiation or surgery . furthermore , the inhibitors of the invention are also effective in other upa - associated disorders . upa inhibitors of the invention are preferably characterized in that they have a k i which is at least two times , preferably at least five times and particularly preferably at least 10 times and up to 1000 times lower for upa than for tpa . it is furthermore remarkable that the compounds of the invention only marginally affect blood clotting , since their k i values are too high for effective inhibition of thrombin , plasmin and factor xa . the inventive substances of the formula ( i ) may be used in the form of conjugates with physiologically effective substances , for example radiolabels or cytotoxic agents , e . g . chemotherapeutics such as cisplatin or 5 - fluoruracil , or with peptides . furthermore , it is also possible to incorporate the substances into the membrane of carrier vesicles , for example liposomes , and thus to make possible targeting of active substances enclosed in said carrier vesicles , for example cytotoxic agents such as doxorubicin . the present invention provides a method for inhibiting urokinase in living creatures , in particular in humans , by administering an effective quantity of at least one compound of the formula ( i ). the dosing of the compound is commonly in the range from 0 . 01 to 100 mg / kg of body weight per day . the length of treatment depends on the seriousness of the disorder and may range from a single dose up to a treatment lasting several weeks or even several months , which may be repeated at intervals , where appropriate . finally , the present invention relates to novel arylguanidine derivatives of the formula ( i ). the invention is intended to be illustrated in more detail by the following examples and figures in which : fig1 shows examples for 5 compounds of the formula ( i ) of the invention , and fig2 shows examples for further preferred compound classes of the formula ( i ). all solvents and reagents used for the synthesis of upa inhibitors were of the highest commercially available quality and were , if necessary , further purified and dried by standard methods . analytical hplc was carried out on nucleosil 100 / c18 columns ( macherey - nagel , düren , germany ) using a linear acetonitrile / 2 % h 3 po 4 gradient ( from 5 : 95 to 90 : 10 in 13 min ). ms spectra were measured in a perkin elmer api 165 mass spectrometer . 2 -( 1h - benzotriazol - 1 - yl )- 1 , 1 , 3 , 3 - tetramethyluronium tetrafluoroborate ( tbtu ) ( 23 mg ; 0 . 07 mmol ) was added to a solution of 1 -[ 4 -( aminomethyl ) phenyl ]- 2 , 3 - di - z - guanidine hydrochloride ( 30 mg ; 0 . 064 nmol ), d , l - tropic acid ( 10 . 6 mg ; 0 . 064 mmol ), 1 - hydroxybenzotriazole ( hobt ) ( 10 mg ; 0 . 07 mmol ) and triethylamine ( 10 μl ; 0 . 192 mmol ) in dichloromethane ( 3 ml ) and the solution was stirred at room temperature . after 2 h , tbtu ( 15 mg ; 0 . 047 mmol ) and triethylamine ( 10 μl ; 0 . 192 mmol ) were added once more . after another 3 h , the solution was diluted with 30 ml of dichloromethane , and washed 3 × with 5 % nahco 3 solution , 2 × with 0 . 1 hcl and 1 × with saturated nacl solution . the organic phase was dried ( na 2 so 4 ) and the solvent was stripped off under reduced pressure . the z protective groups ( benzyloxycarbonyl ) are removed by dissolving the compound in methanol , stirring the solution and hydrogenating the compound over a 10 % palladium - activated carbon catalyst for 3 h . after removing the catalyst by filtration , the solvent was evaporated under reduced pressure . the product was recrystallized from isopropanol / diisopropyl ether after adding 1 equivalent of hcl in dioxane . yield : 13 mg ( 58 %); hplc : tk 5 . 6 min ; ms 313 ( m + h ) + calculated 312 for c 17 h 20 n 4 o 2 tbtu ( 88 mg ; 0 . 274 mmol ) was added to a solution of 1 -[ 4 -( aminomethyl ) phenyl ]- 2 , 3 - di - tert - butyloxycarbonyl - guanidine hydrochloride ( 8 ) ( 100 mg ; 0 . 249 mmol ), monobenzyl 2 - phenylmalonate ( 67 . 3 mg ; 0 . 249 mmol ), hobt ( 37 mg ; 0 . 274 mmol ) and triethylamine ( 104 μl ; 0 . 747 mmol ) in dmf ( 5 ml ), and the solution was stirred at room temperature overnight . after stripping off the solvent under reduced pressure , the residue was taken up in ethyl acetate ( 20 ml ) and washed 3 × with 5 % nahco 3 solution , 3 × with 0 . 5 m hcl and 1 × with saturated nacl solution . the organic phase was dried ( na 2 so 4 ) and the solvent was stripped off under reduced pressure . the product was recrystallized from ethanol / water . yield : 78 mg ( 51 %); hplc : t r 13 . 0 min ; ms 617 ( m + h ) + , calculated 616 for c 34 h 40 n 4 o 7 the boc protective groups were removed by dissolving the compound st399 ( 12 mg ; 19 . 5 μm ) in 7 m hcl / dioxane ( 2 ml ). after 8 h the solvent was stripped off under reduced pressure and the product was recrystallized from isopropanol / diisopropyl ether . yield : 4 mg ( 454 %); hplc : t r 9 . 0 min ; ms ( m + h ) + , calculated 416 for c 24 h 24 n 4 o 3 the benzyl group was removed from compound st399 ( 150 mg ; 0 . 244 mmol ) by catalytic hydrogenation in a solution of isopropanol ( 30 ml ) and dichloromethane on a pd / activated carbon catalyst . after 5 h the catalyst was filtered off and the solvent was stripped off . treatment with methyl tert - butyl ether in an ultrasound bath gave the product as a light yellow powder . subsequently , the boc protective groups were removed , as described for st401 , and the crude product was purified by preparative hplc . yield : 37 mg ( 42 %); hplc : t r 4 . 6 min ; ms 327 ( m + h ) + , calculated 326 for c 17 h 18 n 4 o 3 the upa inhibitor activity was determined by incubating 200 μl of tris buffer ( 0 . 05 mol / l , containing the inhibitor , 0 . 154 mol / l nacl , 5 % ethanol , ph 8 . 0 ), 25 μl of substrate ( pefachrome uk or bz - β - ala - gly - arg - pna in h 2 o ; pentapharm ltd , basle , switzerland ) and 50 μl of sc - urokinase ( ribosepharm gmbh , haan , germany ) or another corresponding protease at 25 ° c . after 3 min , the reaction was interrupted by adding 25 μl of acetic acid ( 50 %) and absorbance at 405 nm was determined by means of a microplate reader ( mr 5000 , dynatech , denkendorf , germany ). the k i values were determined by linear regression according to dixon by means of a computer program . the k i values are the average of at least three determinations , and the standard deviation was below 25 %. owing to their structure , the compounds shown in fig1 and 2 can interact with the active site of upa . the results for selected compounds of the formula ( i ) are listed in table 1 .
a method is described for inhibiting urokinase plasminogen activator in a human or animal patient . the method involves administering to the patient a urokinase plasminogen activator inhibiting effective amount of a compound of the formula :