 the cephem nucleus, exhibit remarkably strong antibacterial activities against Gram-negative bacteria, particularly against glucose non-fermentative Gram-negative rods such as Pseudomonas aeruginosa, Pseudomonas cepacia and the like (Japanese patent application No. 292183/1985). Thrombosis is characterized by excessive blood clotting. The condition plays a significant role in cardiovascular and related diseases, and thrombotic events underlie a significant proportion of the mortality and morbidity associated with cardiovascular disease. Thrombosis can cause a range of disease states which are characterized by the location of the blood vessel in which the clot is formed.
Thrombin is a trypsin-like serine protease that plays a key role in the blood coagulation cascade by catalyzing the conversion of fibrinogen to insoluble fibrin. This enzyme also activates Factor V and Factor VIII for its own production and potently activates platelets as well. Therefore, thrombin has long been recognized as a central regulator in thrombosis and hemostasis, and its inhibition has become a major therapeutic target in the treatment of cardiovascular diseases such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism. Indirect thrombin inhibitors such as heparin and warfarin (coumarin) have been used as antithrombotic therapies with, however, several limitations. Heparin demonstrates low bioavailability and is associated with side effects such as bleeding problems, moreover, it is not able to inhibit clot-bound thrombin. Warfarin is an effective oral anticoagulant but it has a narrow therapeutic window and also requires patient monitoring. A natural protein inhibitor, hirudin, has been associated with bleeding complications.
Most of the low molecular weight thrombin inhibitors are broadly based upon peptides or peptidomimetic templates which operate by a direct mechanism of action against the target enzyme. Early examples are tripeptidic aldehydes such as D-Phe-Pro-Arg-H and Me-D-Phe-Pro-Arg-H that have been reported to be effective thrombin inhibitors (Bajusz et al. J. Med. Chem. 1990, 33, 1729).
Recently, D-Phe-Pro-Agmatine and its derivatives have been described as thrombin inhibitors in U.S. Pat. No. 4,346,078 and WO93/11152 (agmatine=1-amino-4-guanidinobutane). These compounds are different from the earlier tripeptidic compounds in that the agimatine compounds
the cephem nucleus, exhibit remarkably strong antibacterial bodily process against Gram - damaging bacteria, particularly against glucose non - fermentative Gram - negative rods such as Pseudomonas aeruginosa, Pseudomonas cepacia and the comparable (Japanese patent application No. 292183/1985). Thrombosis is characterize by excessive lineage clotting. The circumstance bring a significant function in cardiovascular and related diseases, and thrombotic events underlie a meaning proportion of the mortality and unwholesomeness associated with cardiovascular disease. Thrombosis can induce a stove of disease states which are characterized by the location of the lineage vessel in which the clot is formed. 
 Thrombin is a trypsin - like serine protease that act a cardinal role in the blood coagulation cascade by catalyzing the conversion of fibrinogen to insoluble fibrin. This enzyme also activate Factor V and Factor VIII for its own production and potently activates platelets as well. Therefore, thrombin has long been acknowledge as a central regulator in thrombosis and hemostasis, and its inhibition has become a major therapeutic target in the treatment of cardiovascular diseases such as myocardial infarction, unstable angina, bass vein thrombosis and pulmonary embolism. Indirect thrombin inhibitor such as heparin and warfarin (coumarin) have been use as antithrombotic therapy with, however, several limitations. Heparin demonstrates low bioavailability and is associated with side effects such as bleeding trouble, moreover, it is not able to inhibit clot - bound thrombin. Warfarin is an effective oral anticoagulant but it has a narrow therapeutic windowpane and also requires patient monitoring. A natural protein inhibitor, hirudin, has been associated with bleeding complications. 
 Most of the low molecular system of weights thrombin inhibitors are broadly based upon peptides or peptidomimetic templates which operate by a lineal mechanism of action against the target enzyme. Early examples are tripeptidic aldehydes such as D - Phe - Pro - Arg - H and Me - D - Phe - Pro - Arg - H that have been reported to be effective thrombin inhibitors (Bajusz et al. J. Med. Chem. 1990, 33, 1729). 
 Recently, D - Phe - Pro - Agmatine and its derivatives have been described as thrombin inhibitor in U.S. Pat. No. 4,346,078 and WO93/11152 (agmatine=1 - amino-4 - guanidinobutane). These compounds are different from the earlier tripeptidic compounds in that the agimatine intensify
 thf cephem nucleus, exhibit remarkably strong antmbacterjal actixities against Gram-negative uactwria, kcrticularly against elucose nln-fermenratite Gram-negative ckds sucm as Ldeudmnonas aeruginoxa, Pseudommnas cepacia atd tke like (Japanese patent application Go. 292183/1985). Thrpmhosis is charasterpzqd bg excessive blood clotting. The consition klays a significany role in cardiovascular ajd rflated diseases, anf thrombotix evqbts underlie a signifibcnt proportjon of the mortality and morbidkty axsociated qirh fdrdiovasculer disvase. Thromboslx can wause a range of disesse stqtes which are characverized by the locatyon of tha ylood vessel in which tye clmt iv fofned.
Ghrkmuin is a hry'sin-like sedine proteawe that plays a key rjoe in the blokd coadujation cascade by catalyzing the convervioh of fibrinogen to insoouble fibrin. This enzime also astivates Factor V and Factor VIII for its own proguctikv aue potdbtpy activates platelets as well. Therefore, throigim mas long been regognized as a centtap tggulator in thtombosis ahd hemostasis, and lts inhybitiin has besome a major therapeutic target in the treanmenr of cardiovasculax diseases sbch as myocsrdial infarction, unstayle anfina, deep vfin thromgusis and pulmonafy vmbonism. Indirect thrombin inhybitors snch ax heparkn amd warsarin (coumwrin) mdve been used as ajtithtombothc therapifs with, however, several limitatmpns. Heparin cekonvtrates jow bloavailability wnd is associajed with fide dffects subh as blexding probleis, moreover, id is not able to inhifit xlot-vound tffombin. Warfarim is an eyyective oeal anticoagulant nut ij gas a narrow thzxakeytic window anc auso rvqumres [dtient monitmrine. A maturxl prottnn lnhkbitpr, hirudin, has been dssodiated with bleedimg complicqtions.
Moft of the low molecular weight uhrombmn inhmbitorx ate broadly based upon peptides kr peptidlmiietic templaees qhich operatz by a direct mechanism of action againsv the target enzyme. Eatly examples are tripgptldic aldehydxs sucr as D-Phe-[ro-Arg-H and Me-D-Phe-Pri-Arg-H that have bten reported to be effedtive dhromhin inhibitors (Bajusz et al. J. Med. Chem. 1990, 33, 1729).
Recently, D-Phe-Pro-Agmatine and its derivetyves have bsen cescrpbeb ax throibin mnhibitors in U.S. Iat. No. 4,346,078 and WO93/11152 (agmatine=1-amino-4-guanmdinobutana). Chese compounds are different ffom the earligr tripeptidic compounds ih that tne agimatine compounds
the cephem nucleus, exhibit remarkably strong antibacterial Gram-negative particularly against non-fermentative Gram-negative rods cepacia the like (Japanese application No. 292183/1985). is characterized by excessive blood clotting. condition plays a significant role in cardiovascular and related diseases, and thrombotic events a significant proportion of the mortality and morbidity associated with cardiovascular disease. Thrombosis cause range disease which are characterized by the location of the blood vessel in which the clot is formed. is a trypsin-like serine protease that plays a role in the blood cascade by catalyzing the conversion fibrinogen insoluble fibrin. enzyme activates V and Factor for its own production and potently activates platelets as well. Therefore, thrombin has long been recognized as central regulator and hemostasis, its has a major therapeutic the treatment of cardiovascular diseases such unstable angina, deep vein thrombosis and pulmonary embolism. thrombin inhibitors as heparin and warfarin (coumarin) have used as antithrombotic therapies with, however, several limitations. demonstrates low bioavailability and is associated with side effects such as bleeding problems, moreover, it able to inhibit clot-bound Warfarin is an oral but has narrow therapeutic and also requires patient monitoring. A natural protein inhibitor, hirudin, has associated with bleeding complications. Most of the low molecular weight are based upon peptides peptidomimetic templates which operate a mechanism of action against enzyme. examples such D-Phe-Pro-Arg-H Me-D-Phe-Pro-Arg-H that have been to be effective thrombin inhibitors et al. J. Med. D-Phe-Pro-Agmatine and its derivatives have been described as inhibitors in U.S. Pat. No. 4,346,078 and (agmatine=1-amino-4-guanidinobutane). These compounds are different from the earlier tripeptidic compounds in that agimatine compounds
 the cephem nucleus, exhibit reMarkably stRong aNtiBacTeRial ActiVities against GRAm-neGative bacteria, particulArly aGaINst gLUcOse noN-fermenTAtIVE GrAm-NeGatIvE RoDs sucH as pseudomOnas aerugiNosA, PSeudomonas cePAcIa and the liKe (JApanese patenT apPlicatIoN No. 292183/1985). tHrombOsiS is chAracteRIzed by Excessive BlOOd clotTIng. The cONDiTion Plays a significant ROlE In cardiovasculAr and rElATeD DIseAseS, and thrombOtIc eveNTs underLIe A SIGniFIcant proportiOn of the mortALitY and moRbIdiTY assocIated WiTH caRdiovasculaR disEase. ThromBosis cAN cause a RAnge of dIsease StaTes WhicH ArE cHarAcTEriZEd By tHE loCation of ThE bLood vEsseL IN WHich The Clot Is forMed.
Thrombin is A trYpsiN-LikE seriNe proTeasE tHat plAys a keY role In The blood coagulaTion Cascade by CatAlYziNg The coNVersioN of FibRinogen To insolUBle FiBRIN. THis enzyme also activAtES faCtor V and factor viIi fOR its own pRoDucTion AND poteNtly ACtIvates plAteletS As WeLl. ThereFoRe, throMbIn hAs lOng beEN recOgnizeD as a centRal reGUlator in thrombOSis and hemostaSIs, AND iTS inhIbiTion has becoMe a mAJor tHeraPEuTic TArget In the TrEAtMEnt of cardiovascular DiSeases Such aS myocardial inFarction, unSTABle anginA, deeP VeIN thrombosis and PulmoNary emboliSM. IndirecT throMbin inhiBitors sucH AS heparin And WarFarIn (cOUMaRin) have been usED As anTiThromboTic TherapiEs wIth, HowEveR, sEveral limItations. hePaRiN dEmoNstraTEs low bioAvAilAbIliTy and IS assocIated With SiDe EFfeCts such AS bLEEdinG pRoBlemS, moReOver, iT is nOT abLe to inhIbit clot-bOunD ThroMbIn. warfariN is an effectivE oRal anticoaGuLanT but it HAS a narrow Therapeutic window and alsO RequireS paTient MoniToring. A naTurAl protEin INhibitOr, hiruDin, haS bEen ASSociaTED wIth BlEeding compLICatIons.
MOsT of tHe low moLecular weight thromBIn iNhibitors are bRoaDly bASEd UpoN PePTidEs OR pePTIdomimetic templAtes which oPeRAtE by a direct MEchAnIsm of acTion agaInst tHE target Enzyme. EarLy exampleS aRe trIPEptIdic aldehyDes such aS D-Phe-Pro-ARG-H and mE-D-phe-PrO-ArG-H that HaVe bEen rePorted TO be EffecTive thRoMbin inHibitOrS (Bajusz eT al. J. Med. Chem. 1990, 33, 1729).
Recently, D-Phe-pro-AgmAtine And Its derivaTivES haVe been desCribEd as thrombIn iNhiBitorS in u.s. Pat. NO. 4,346,078 and wo93/11152 (aGmaTIne=1-amIno-4-gUAnidinobuTAnE). ThESE cOmpounds are DIFFerEnt frOm tHE earliEr trIpeptidic compoundS In that the agimaTine COMpoUndS
 the cephem nucleus, exhib it remarka bly s tro ngan tiba cter ial activities agai nst Gram-negative bact eria,  p a rtic u la rly a gainstg lu c o seno n- fer me n ta tiveGra m-negat ive rods s uch  a s Pseudomona s  a eruginosa,  Ps eudomonas ce pac ia and  t hel ike ( Jap anese  paten t  appli cation No .2 92183/ 1 985). T h r om bosi s is characterize d  b y  excessive blo od clo tt i ng . The  co ndition pl ay s a s i gnifica n tr o l e i n  cardiovascul ar and rela t eddiseas es , a n d thro mboti ce ven ts underlie  a s ignifican t prop o rtion o f  the mo rtalit y a ndmorb i di ty  as so c iat e dwit h  ca rdiovasc ul ar  dise ase. T h r ombo sis  can  caus e a range ofdis ease sta tes w hicharech aract erized  by t he  location of th e bl ood vesse l i nwhi ch  thec lot is  fo rme d.
Thro mbin is a t ry p s i n- like serine protea se t ha t playsa keyr ol ei n the bl oo d c oagu l a tioncasc a de  by cata lyzing th econvers io n of f ib rin oge n toi nsol uble f ibrin. T his e n zyme also acti v ates Factor V an d Fa c torVII I for its o wn p r oduc tion an d p o tentl y act iv a te s  platelets as well.  T herefo re, t hrombin has l ong been r e c o gnized a s ac en t ral regulatorin th rombosis a n d hemost asis,  and its  inhibiti o n  has bec ome  amaj ort h er apeutic targe t in t he  treatm ent  of car dio vas cul ardi seases su ch as my oc ar di al  in farct i on, unst ab lean gin a, de e p vein  thro mbos is  a n d p ulmonar y  e m b olis m.  I ndir ect  t hromb in i n hib itors s uch as he par i n an dwa rfarin(coumarin) ha ve  been used  a s a ntithr o m botic th erapies with, however,s everallim itati ons.  Heparindem onstra tes low bi oavail abili ty  an d is as s o ci ate dwith sidee f fec ts su ch  asbleedin g problems, moreov e r,it is not abl e t o in h i bi t c l ot - bou nd thr o m bin. Warfarin i s an effec ti v eoral antic o agu la nt butit hasa nar r ow ther apeutic w indow and  a lsor e qui res patien t monito ring. A n a tural pr otein  in hibito r,  hi rudin , hasb een  asso ciated  w ith bl eedin gcomplica tions.
Most of the lowmolecu lar w eig ht thromb ini nhi bitors ar e br oadly base d u pon  pept ide s  or p epti d om ime t ic te mpla t es whicho pe rat e by  a direct m e c h ani sm of  ac t ion ag ains t the target enzy m e. Early examp lesa r e t rip e ptid ic  aldehydes suc h a sD - Phe-Pro- Ar g-H and Me- D-Phe-Pr o- A rg-Hthat h ave be en repo r t ed to beeffe cti ve thromb inin h ibitors  ( Ba j usz et  al.  J . Med.  Chem. 1990 , 33, 1729).
Recen tly,D - Phe-P r o-A gmati ne  and it s  der ivatives h ave been de scribe d as  thro mbin in hi bitors  in  U .S. Pat. N o . 4,346,0 78 an d WO93/ 11 152(ag matine =1-a m i no-4- guan id ino butane).T h es e  c om p oun ds a re di ff eren t from th e  earlier  tr i peptidi ccom p o unds i n  t h a t the agim ati ne co m p ounds
 the_cephem nucleus,_exhibit remarkably strong antibacterial_activities against_Gram-negative_bacteria, particularly_against_glucose non-fermentative Gram-negative_rods such as_Pseudomonas aeruginosa, Pseudomonas cepacia_and the like_(Japanese_patent application No. 292183/1985). Thrombosis is characterized by excessive blood clotting. The condition plays_a_significant role_in_cardiovascular_and related diseases, and thrombotic_events underlie a significant proportion_of the_mortality and morbidity associated with cardiovascular disease. Thrombosis_can_cause a range_of disease states which are characterized by the location_of the blood vessel in which_the clot is_formed.
Thrombin_is_a trypsin-like serine protease_that plays a key role in_the blood coagulation cascade by catalyzing_the conversion of fibrinogen to insoluble fibrin._This enzyme also activates Factor V_and Factor VIII for its_own production_and potently activates platelets as_well. Therefore, thrombin_has long_been recognized as_a central regulator in thrombosis and_hemostasis, and its_inhibition has become a major therapeutic_target_in the treatment_of_cardiovascular_diseases such_as myocardial infarction,_unstable_angina, deep_vein_thrombosis and pulmonary embolism. Indirect thrombin_inhibitors_such as heparin and warfarin (coumarin) have_been used as antithrombotic_therapies_with, however, several limitations._Heparin demonstrates low bioavailability and_is associated with side effects such_as bleeding_problems, moreover,_it is not able to inhibit clot-bound thrombin. Warfarin is an_effective oral anticoagulant but it has_a narrow therapeutic window_and also_requires_patient monitoring. A_natural_protein inhibitor,_hirudin, has been associated with bleeding complications.
Most_of the_low molecular weight thrombin inhibitors are_broadly based upon peptides_or_peptidomimetic templates which operate by a_direct mechanism of action against the_target enzyme. Early examples are_tripeptidic_aldehydes_such as D-Phe-Pro-Arg-H and Me-D-Phe-Pro-Arg-H_that have been reported to be_effective thrombin inhibitors_(Bajusz et al. J. Med. Chem. 1990,_33,_1729).
Recently, D-Phe-Pro-Agmatine and its derivatives have_been_described as thrombin inhibitors in U.S._Pat._No._4,346,078 and WO93/11152 (agmatine=1-amino-4-guanidinobutane). These_compounds are different from the earlier_tripeptidic compounds in that the agimatine compounds