Abstract:
The invention relates to novel amidines and quanidines, the production and use thereof and the use thereof as trypsine-type serine protease competitive inhibitors, especially thrombine and compliment proteases CIs and C1r. The invention also relates to pharmaceutical compositions which contain said compounds as active ingredients, in addition to the use of the compounds as thrombine inhibitors, anticoagulants, compliment inhibitors and anti-inflammatory agents. The novel compositions are characterised by the linkage of a serine protease inhibitor having amidine or quanidine functions with an alkyl radical having two or more hydroxyl functions, whereby said alkyl radical is derived from sugar derivates.Several sugar structural components or components derived from sugar can therefore be linked to each other. Said principle of linking sugar derivates enables oral active compounds to be obtained.

Description:
DESCRIPTION  
         [0001]    The present invention relates to novel amidines and guanidines, to the production thereof, and to the use thereof as competitive inhibitors of trypsin-like serine proteases, particularly thrombin and the complement proteases C1s and C1r.  
           [0002]    The invention also relates to pharmaceutical compositions containing said compounds as active ingredients, and also to the use of said compounds as thrombin inhibitors, anticoagulants, complement inhibitors, or anti-inflammatory agents. A characteristic of the novel compounds is their ability to link a serin protease inhibitor having an amidine or guanidine function to an alkyl group having two or more hydroxyl functions and derived from sugar derivatives. Thus a number of sugar building blocks or building blocks derived from sugars can be linked. This principle of coupling with sugar derivatives provides orally active compounds.  
           [0003]    Preferred sugar derivatives include all types of reductive sugars which reductively react with a terminal amine function of the inhibitor.  
           [0004]    Reductive sugars are sugars which are capable of reducing Cu(II) ions in solution to Cu(I) oxide.  
           [0005]    Reductive sugars include:  
           [0006]    Any of the aldoses (whether in open-chain or cyclic form) (eg, trioses; or tetraoses such as erythrose and threose; or pentoses such as arabinose, xylose, rhamnose, fucose, and ribose; or hexoses such as glucose, mannose, galactose, and 2-deoxy-D-glucose, etc.);  
           [0007]    any of the (hydroxy)ketoses. Hydroxyketoses contain a HOCH 2 —CO group. Fructose and ribulose are examples thereof.  
           [0008]    Di-, oligo- and poly-saccharides containing a hemiacetal, such as lactose, melibiose, maltose, maltotriose, maltotetraose, maltohexaose, or cellulose oligomers such as cellobiose, cellotriose or dextran oligomers or pullulan oligomers or inulin oligomers, etc.  
           [0009]    Sugar derivatives and complex oligosaccharides containing a hemiacetal, such as glucuronic acid, galacturonic acid, 2-deoxy-D-glucose, 2-deoxy-2-fluoro-D-glucose, glucosamine, N-acetyl-D-glucosamine, oligomers of pectin and hyaluronic acid.  
           [0010]    Examples of other preferred sugar derivatives are sugar acids which react with a terminal amine function of the inhibitor via the acyl function.  
           [0011]    Thrombin is a member of the group of serine proteases and plays a central role as terminal enzyme in the blood coagulation cascade. Both the intrinsic and the extrinsic coagulation cascades cause, via a number of intensification stages, the production of thrombin from prothrombin. Thrombin-catalyzed cleavage of fibrinogen to fibrin then triggers blood coagulation and aggregation of the thrombocytes, which in turn increase the formation of thrombin by binding platelet factor 3 and coagulation factor XIII as well as via a whole series of highly active mediators.  
           [0012]    The formation and action of thrombin are central events in the genesis of both white arterial thrombi and red venous thrombi and are therefore potentially effective points of attack for pharmacological agents. Thrombin inhibitors are, unlike heparin, capably of completely inhibiting, simultaneously, the action of free thrombin and thrombin bound to thrombocytes, irrespective of co-factors. They can prevent, in the acute phase, thrombo-embolic events following percutane transluminal coronary angioplasty (PTCA) and cell lysis and serve as anticoagulants in extracorporeal recirculation (heartlung apparatus, haemodialysis). They can also serve in a general way for the prophylaxis of thrombosis, for example, after surgical operations.  
           [0013]    Inhibitors of thrombin are suitable for the therapy and prophylaxis of  
           [0014]    diseases whose pathogenetic mechanism is based, directly or indirectly, on the proteolytic action of thrombin,  
           [0015]    diseases whose pathogenetic mechanism is based on the thrombin-dependent activation of receptors and signal transductions,  
           [0016]    diseases accompanying the stimulation or inhibition of gene expressions in somatic cells,  
           [0017]    diseases due to the mitogenetic action of thrombin,  
           [0018]    diseases caused by a thrombin-dependent change in contractility and permeability of epithel cells,  
           [0019]    thrombin-dependent thrombo-embolic events,  
           [0020]    disseminated intravascular coagulation (DIC),  
           [0021]    re-occlusion, and for shortening the reperfusion time in cases of co-medication with thrombolytics,  
           [0022]    early re-occlusion and later restenosization following PTCA,—thrombin-induced proliferation of smooth muscle cells,—the accumulation of active thrombin in the CNS,  
           [0023]    tumor growth, and to counteract adhesion and carcinosis of tumor cells.  
           [0024]    A number of thrombin inhibitors of the D-Phe-Pro-Arg type is known for which good thrombin inhibition in vitro has been described: WO 9702284-A, WO 9429336-A1, WO 9857932-A1, WO 9929664-A1, U.S. Pat. No. 5,939,392-A, WO 200035869-A1, WO 200042059-A1, DE 4421052-A1, DE 4443390-A1, DE 19506610-A1, WO 9625426-A1, DE 19504504-A1, DE 19632772-A1, DE 19632773-A1, WO 9937611-A1, WO 9937668-A1, WO 9523609-A1, U.S. Pat. No. 5,705,487-1, WO 9749404-A1, EP-669317-A1, WO 9705108-A1, EP 0672658. However, some of this compounds exhibit low oral activity.  
           [0025]    In WO 9965934 and Bioorg. Med. Chem. Lett., 9(14), 2013-2018, 1999, benzamidine derivatives of the NAPAP type are described which are coupled through a long spacer to pentasaccharides and thus show a dual antithrombotic principle of action. However, no oral activity of these compounds is described.  
           [0026]    Activation of the complement system ultimately leads, through a cascade of ca 30 proteins, inter alia, to lysis of cells. Simultaneously, molecules are liberated which, like C5a, can lead to an inflammatory reaction. Under physiological conditions, the complement system provides a defence mechanism against foreign bodies, such as viruses, fungi, bacteria, or cancer cells. Activation by various routes takes place initially via proteases. By activation, these proteases are made capable of activating other molecules of the complement system, which may in turn be inactive proteases. Under physiological conditions, this system, like blood coagulation, is under the control of regulatory proteins, which counteract exuberant activation of the complement system. In such cases it is not advantageous to take measures to inhibit the complement system.  
           [0027]    In some cases the complement system overreacts, however, and thus contributes to the pathologic physiology of diseases. In such cases, therapeutic action on the complement system causing inhibition or modulation of the exuberant reaction is desirable. Inhibition of the complement system is possible at various levels in the complement system by inhibition of various effectors. The literature provides examples of the inhibition of serine proteases at the C1 level with the aid of the C1 esterase inhibitor as well as inhibition at the level of C3 or C5 convertases by means of soluble complement receptor CR1 (sCR1), inhibition at the level of C5 by means of antibodies, and inhibition at the level of C5a by means of antibodies or antagonists. The tools used for achieving inhibition in the above examples are proteins. In the present invention, low-molecular substances are described which are used for inhibition of the complement system.  
           [0028]    For such inhibition of the complement system some proteases utilizing various activation routes are particularly suitable. Of the class of thrombin-like serine proteases, such proteases are the complement proteases C1r and C1s for the classical route, factor D and factor B for the alternative route, and also MASP I and MASP II for the MBL route. The inhibition of these proteases then leads to a re-establishment of the physiological control of the complement system in the above diseases or pathophysiological states.  
           [0029]    Generally speaking, all inflammatory disorders accompanied by the immigration of neutrophilic blood cells must be expected to involve activation of the complement system. Thus it is expected that with all of these disorders an improvement in the pathophysiological state will be achieved by causing inhibition of parts of the complement system.  
           [0030]    The activation of complement is associated with the following diseases or pathophysiological states:  
           [0031]    reperfusion syndrome following ischaemia; ischemic states occur during, say, operations involving the use of heartlung apparatus; operations in which blood vessels are generally compressed to avoid severe haemorrhage; myocardial infarction; thrombo-embolic cerebral infarct; pulmonary thrombosis, etc.;  
           [0032]    hyper-acute rejection of an organ; specifically in the case of xenotransplantations;  
           [0033]    failure of an organ, for example multiple failure of an organ or ARDS (adult respiratory distress syndrome);  
           [0034]    diseases caused by injuries (skull injuries) or multiple injuries, such as thermal injuries (burns), and anaphylactic shock;  
           [0035]    sepsis; “vascular leak syndrom”: with sepsis and following treatment with biological agents, such as interleukin 2, or following transplantation;  
           [0036]    Alzheimer&#39;s disease and also other inflammatory neurological diseases such as Myastenia graevis, multiple sclerosis, cerebral lupus, Guillain Barré syndrome; forms of meningitis; forms of encaphilitis;  
           [0037]    systemic Lupus erythematosus (SLE);  
           [0038]    rheumatoid arthritis and other inflammatory diseases in the rheumatoid disease cycle, such as Behcet&#39;s syndrome; juvenile rheumatoid arthritis;  
           [0039]    renal inflammation of various geneses, such as glomerular nephritis, or Lupus nephriti;  
           [0040]    pancreatitis;  
           [0041]    asthma; chronic bronchitis;  
           [0042]    complications arising in dialysis for renal insufficiency; vasculitis; thyroiditis;  
           [0043]    ulcerative colitis and also other inflammable disorders of the gastro-intestinal tract;  
           [0044]    auto-immune disorders.  
           [0045]    inhibition of the complement system; for example, the use of the C1s inhibitors of the invention can alleviate the side effects of pharmaceutical preparations based on activation of the complement system and reduce resultant hypersensitivity reactions.  
           [0046]    Accordingly, treatment of the above mentioned diseases or pathophysiological states with complement inhibitors is desirable, particularly treatment with low-molecular inhibitors.  
           [0047]    PUT and FUT derivatives are amidinophenol esters and amidinonaphthol esters respectively and have been described as complement inhibitors (eg, Immunology (1983), 49(4), 685-91).  
           [0048]    Inhibitors are desired which inhibit C1s and/or C1r, but not factor D. Preferably, there should be no inhibition of lysis enzymes such as t-PA and plasmin.  
           [0049]    Special preference is given to substances which effectively inhibit thrombin or C1s and C1r. 
       
    
    
     PHARMACOLOGICAL EXAMPLES  
     Example A  
       [0050]    Thrombin Time  
         [0051]    Reagents: thrombin reagent (List No. 126,594, Boehringer, Mannheim, Germany)  
         [0052]    Preparation of citrate plasm:  
         [0053]    9 parts of venous human blood from the V. cephalica are mixed with 1 part of sodium citrate solution (0.11 mol/L), followed by centrifugation. The plasma can be stored at −20° C.  
         [0054]    Experimental method:  
         [0055]    50 μl of the solution of the test probe and 50 μl of citrate plasma are incubated for 2 minutes at 37° C. (CL8, ball type, Bender &amp; Hobein, Munich, FRG). Then 100 μl of thrombin reagent (37° C.) are added. The time taken for the fibrin clot to form is determined. The EC 100  values give the concentration at which the thrombin time is doubled.  
       Example B  
       [0056]    Chromogenic Test for Thrombin Inhibitors  
         [0057]    Reagents: human plasma thrombin (No. T 8885, Sigma, Deisenhofen, Germany)  
         [0058]    substrate: H-D-Phe-Pip-Arg-pNA2HCl (S-2238, Chromogenix, Mölndahl, Sweden)  
         [0059]    buffer: Tris 50 mmol/L, NaCl 154 mmol/L, pH 8.0  
         [0060]    Experimental procedure:  
         [0061]    The chromogenic test can be carried out in microtitration plates. 10 μl of the solution of substance in dimethyl sulfoxide are added to 250 μl of buffer containing thrombin (final concentration 0.1 NIH units/mL) and incubated over a period of 5 minutes at from 20° to 28° C. The test is initiated by the addition of 50 μL of substrate solution in buffer (final concentration 100 μmmol/L), the mixture being incubated at 28° C., and, following a period of 5 minutes, the test is stopped by the addition of 50 μL of citric acid (35%). The absorption is measured at 405/630 nm.  
       Example C  
       [0062]    Platelet Aggregation in the Platelet-Enriched Plasma  
         [0063]    Reagents: human plasma thrombin (No. T-8885, Sigma, Deisenhofen, Germany)  
         [0064]    Production of the citrate-enriched platelet-enriched plasm:  
         [0065]    Venous blood from the Vena cephalica of healthy drug-free test persons is collected. The blood is mixed 9:1 with 0.13M trisodium citrate.  
         [0066]    Platelet-enriched plasma (PRP) is produced by centrifugation at 250×g (for 10 minutes at room temperature). Platelet-impoverished plasma (PPP) is produced by centrifugation for 20 minutes at 3600×g. PRP and PPP can be kept in sealed PE vessels for a period of 3 hours at room temperature. The platelet concentration is measured with a cytometer and should be from 2.5 to 2.8·10 −8 /mL.  
         [0067]    Experimental method:  
         [0068]    The platelet aggregation is measured by turbitrimetric titration at 37° C. (PAP 4, Biodata Corporation, Horsham, Pa., USA). Before thrombin is added, 215.6 μL of PRP are incubated for 3 minutes with 2.2 μL of test probe and then stirred over a period of 2 minutes at 1000 rpm. At a final concentration of 0.15 NIH units/mL, 2.2 μL of thrombin solution produce the maximum aggregation effect at 37° C./1000 rpm. The inhibited effect of the test probes is determined by comparing the rate (rise) of aggregation of thrombin without test substance with the rate of aggregation of thrombin with test substance at various concentrations.  
       Example D  
       [0069]    Color Substrate Test for C1r Inhibition  
         [0070]    Reagents: C1r from human plasma, activated, two-chain(dual-chain) form (purity: ca 95% according to SDS gel). No foreign protease activity could be detected.  
         [0071]    substrate: Cbz-Gly-Arg-S-Bzl, Product No. WBAS012, (Polypeptide, D38304 Wolfenbüttel, Germany).  
         [0072]    color reagent: DTNB (5.5′-dinitro-bis(2-nitrobenzoic acid)) (No. 43,760, Fluka, CH 9470 Buchs, Switzerland). buffer: 150 mM Tris/HCl, pH 7.50  
         [0073]    Test procudure:  
         [0074]    The color substrate test for determining the C1s activity is carried out in 96-well microtitration plates.  
         [0075]    10 μL of inhibitor solution in 20% strength dimethyl sulfoxide (dimethyl sulfoxide diluted with 15 mM Tris/HCl, pH 7.50) are added to 140 μL of test buffer containing C1s in a final concentration of 0.013 U/mL and DTNB in a final concentration of 0.27 mM/L. Incubation was carried out over a period of 10 minutes at from 20° to 25° C.  
         [0076]    The test is started by the addition of 50 μL of a 1.5 mM substrate solution in 30% strength dimethyl sulfoxide (final concentration 0.375 mM/L). Following an incubation period of 30 minutes at from 20° to 25° C., the absorbance of each well at 405 nm is measured in a double-beam microtitrimetric plate photometer against a blank reading (without enzyme).  
         [0077]    Measuring criterion:  
         [0078]    IC 50 : inhibitor concentration required in order to reduce the amidolytic C1r activity to 50%.  
         [0079]    Statistical results:  
         [0080]    Calculation is based on the absorbance as a function of inhibitor concentration.  
       Example E  
       [0081]    Material and Methods: Color Substrate Test for C1s Inhibition  
         [0082]    Reagents: C1s from human plasm, activated, two-chain(dual-chain) form (purity: ca 95% according to SDS gel). No foreign protease activity could be detected.  
         [0083]    Substrate: Cbz-Gly-Arg-S-Bzl, Product No. WBAS012, (PolyPeptide, D38304 Wolfenbüttel, Germany)  
         [0084]    Color reagent: DTNB (5.5′-dinitro-bis(2-nitrobenzoic acid)) (No. 43,760, Fluka, CH 9470 Buchs, Switzerland) buffer: 150 mM Tris/HCl, pH 7.50  
         [0085]    Test procedure:  
         [0086]    The color substrate test for determining the C1s activity is carried out in 96-well microtitration plates.  
         [0087]    10 μL of the inhibitor solution in 20% strength dimethyl sulfoxide (dimethyl sulfoxide diluted with 15 mM Tris/HCl, pH 7.50) are added to 140 μL of test buffer containing C1s in a final concentration of 0.013 U/mL and DTNB in a final concentration of 0.27 mM/L. Incubation is carried out over a period of 10 minutes at from 20° to 25° C. The test is started by the addition of 50 μL of a 1.5 mM substrate solution in 30% strength dimethyl sulfoxide (final concentration 0.375 mmol/L). Following an incubation period of 30 minutes at from 20° to 25° C., the absorbance of each well at 405 nm is measured in a double-beam microtitrimetric plate photometer against a blank reading (without enzyme).  
         [0088]    Measuring criterion:  
         [0089]    IC 50 : inhibitor concentration required in order to reduce the amidolytic C1s activity to 50%.  
         [0090]    Statistical results:  
         [0091]    Calculation is based on the absorbance as a function of inhibitor concentration.  
       Example F  
       [0092]    Confirmation of the Inhibition of Complement by the Classical Route Employing a Hemolytic Test  
         [0093]    For measuring potential complement inhibitors use is made, in the manner of diagnostic tests, of a test for measuring the classical route (literature: Complement, A practical Approach; Oxford University Press; 1997; pp 20 et seq). The source of complement used for this purpose is human serum. A test of similar layout is, however, also carried out on various serums of other species in a similar manner. The indicating system used comprises erythrocytes of sheep. The antibody-dependent lysis of these cells and the thus exuded haemoglobin are a measure of the complement activity.  
                                                     Reagents, biochemical products:               Veronal   Merck   #2760500       Na-Veronal   Merck   #500538       NaCl   Merck   #1.06404       MgCl 2  × 6H 2 O   Baker   #0162       CaCl 2  × 6H 2 O   Riedel de Haen   #31307       Gelatin   Merck   #1.04078.0500       EDTA   Roth   #8043.2       Alsevers soln.   Gibco   #15190-044       Penicillin   Gruenenthal   #P1507 10 mega       Ambozeptor   Behring   #ORLC            Stock solutions:           VBS stock solution:   2.875 g/L Veronal; 1.875 g/L Na-Veronal;           42.5 g/L NaCl       Ca/Mg stock solution:   0.15 M Ca++, 1 M Mg++       EDTA stock solution:    0.1 M, pH 7.5       Buffer:           GVBS buffer:   VBS stock solution diluted 1:5 with Finn Aqua;           1 g/L of gelatin dissolved in some buffer at           elevated temperature       GVBS++ buffer:   Ca/Mg stock solution diluted 1:1000 in GVBS           buffer       GVBS/EDTA buffer:   EDTA stock solution diluted 1:10 in GVBS           buffer                  
 
         [0094]    Biogenic components:  
         [0095]    Sheep erythrocytes (SRBC): the blood of a wether was mixed 1:1 (v/v) with Alsevers solution and filtered through glass wool. There was added {fraction (1/10)} volume of EDTA stock solution and 1 spatula tip of penicillin. Human serum: after centrifuiging off the clotted portions at 4° C., the supernatant liquor was stored in aliquot portions at −70° C. All of the measurements were carried out on one batch. No essential deviations from serum of other test objects were found.  
         [0096]    Procedure:  
         [0097]    1. Sensitization of the erythrocytes:  
         [0098]    SRBC&#39;s were washed three times with GVBS buffer. The number of cells was then adjusted to 5.00E+08 cells/mL in GVBS/EDTA buffer. Ambozeptor was added in a dilution of 1:600 and the SRBC&#39;s were then sensitized with antibody by incubation for 30 min at 37° C. with agitation. The cells were then washed three times with GVBS buffer at 4° C., then absorbed in GVBS++ buffer and adjusted to a cell count of 5×10 8 .  
         [0099]    2. Lysis batch:  
         [0100]    Inhibitors were pre-incubated in GVBS++ for 10 min at 37° C. in a volume of 100 μL in various concentrations with human serum or serum of other species in suitable dilutions (for example 1:80 for human serum a suitable dilution is one at which ca 80% of the maximum cell lysis attainable with serum is achieved). 50 μL of sensitized SRBC&#39;s in GVBS++ were then added. Following incubation for one hour at 37° C. with agitation, the SRBC&#39;s were removed by centrifugation (5 minutes, 2500 rpm, 4° C.). 130 μL of the cell-free supernatant were transferred to a 96-well plate. The results were gained by measuring at 540 nm against GVBS++ buffer.  
         [0101]    Evaluation was based on the absorption values at 540 nm.  
         [0102]    (1): background; cells without serum  
         [0103]    (3): 100% cell lysis; cells with serum  
         [0104]    (x): readings on test probes  
         [0105]    Calculation:  
         %                 cell                 lysis     =         (   x   )     -       (   1   )     ×   100      %           (   3   )     -     (   1   )                               
 
       Example G  
       [0106]    Inhibitors Tested for Inhibition of Protease Factor D  
         [0107]    Factor D plays a central role in the alternative route of the complement system. By reason of the low plasma concentration of factor D, the enzymatic step of cleavage of factor B by factor D represents the rate-limiting step in the alternative way of achieving complement activation. On account of the limiting role played by this enzyme in the alternative route, factor D is a target for the inhibition of the complement system.  
         [0108]    The commercial substrate Z-Lys-S-Bzl * HCl is converted by the enzyme factor D (literature: C. M. Kam et al, J. Biol. Chem. 262 3444-3451, 1987). Detection of the cleaved substrate is effected by reaction with Ellmann&#39;s reagent. The resulting product is detected spectrophotometrically. The reaction can be monitored on-line. This makes it possible to take enzyme-kinetic readings.  
         [0109]    Material:  
                                                                         Chemicals:               Factor D   Calbiochem   341273       Ellmann&#39;s Reagent   Sigma   D 8130       Z-Lys-S-Bzl * HCl (= substrate)   Bachem   M 1300           50 mg/mL           (MeOH)       NaCl   Riedel De Haen   13423       Triton-X-100   Aldrich   23,472-9       Tris(hydroxymethyl)aminomethane   Merck       Dimethylformamide (DMF)            Buffer:            50 mM   Tris       150 mM   NaCl       0.01%   triton-X-100       pH 7.6            Stock solutions:           Substrate   20 mM (8.46 mg/mL = 16.92 μL (50 mg/mL) +           83.1 μL H 2 O)       Ellmann&#39;s Reagent   10 mM (3.963 mg/mL) in DMF       Factor D   0.1 mg/mL       Samples (inhibitors)   10 −2 M DMSO            Procedure:           Batches:       Blank reading:   140 μL of buffer + 4.5 μL of substrate (0.6 mM) +           4.5 μL of Ellmann&#39;s reagent (0.3 mM)       Positive control:   140 μL of buffer + 4.5 μL of substrate (0.6 mM) +           4.5 μL of Ellmann&#39;s reagent (0.3 mM) + 5 μL of           factor D       Sample readings:   140 μL of buffer + 4.5 μL of substrate (0.6 mM) +           4.5 μL of Ellmann&#39;s reagent (0.3 mM) + 1.5 μL of           sample (10 −4  M) + 5 μL of factor D                  
 
         [0110]    The batches are pipetted together into microtitration plates. After mixing the buffer, substrate and Ellmann&#39;s reagent (inhibitor when required), the enzyme reaction is initiated by the addition of 5 μL of factor D in each case. Incubation takes place at room temperature for 60 min.  
         [0111]    Readings:  
         [0112]    Readings are taken at 405 nm over a period of 1 hour at intervals of 3 minutes.  
         [0113]    Evaluation:  
         [0114]    The results are plotted as a graph. The change in absorption per minute (Delta OD per minute; rising) is relevant for the comparison of inhibitors, since K i  value of inhibitors can be ascertained therefrom.  
         [0115]    In this test, the serin protease inhibitor FUT-175; Futhan, Torii; Japan was co-used as effective inhibitor.  
       Example H  
       [0116]    Confirmation of the inhibition of complement by the alternative route was obtained using a hemolytic test (literature: Complement, A practical Approach; Oxford University Press; 1997, pp 20 et seq).  
         [0117]    The test is carried out on the lines of clinical tests. The test can be modified by additional activation by means of, say, Zymosan or cobra venom factor.  
                                                                         Material:            EGTA (ethylene-bis(oxyethylenenitrilo)   Boehringer   1093053       tetracetic acid   Mannheim       MgCl 2 .6 H 2 O   Merck   5833,0250       NaCl   Merck   1.06404.1000       D-glucose   Cerestar       Veronal   Merck   2760500       Na-Veronal   Merck   500538            VBS - stock solution (5x)   gelatin Veronal buffer PD           Dr. Kirschfink; University of           Heidelberg, Institute for           Immunology;            Gelatin   Merck   1.04078.0500       Tris(hydroxymethyl)aminomethane   Merck   1.08382.0100       CaCl 2      Merck   No. 2382                  
 
         [0118]    Human serum was either procured from various contractors (eg, Sigma) or obtained from test persons in the polyclinic department of BASF Süd.  
         [0119]    Guinea pig&#39;s blood was extracted and diluted 2:8 in citrate solution. Several batches were used without apparent differences.  
                                       Stock solutions:           VBS stock solution:   2.875 g/L Veronal           1.875 g/L Na-Veronal            42.5 g/L NaCl       GVBS:   VBS stock solution diluted 1:5 with water (Finn           Aqua) 0.1% gelatin added and heated until           gelatin had dissolved and then cooled       100 mM EGTA:   38.04 mg EGTA diluted in 500 mL of Finn           Aqua and slowly treated with 10 M NaOH to raise           the pH to 7.5 until dissolved, then made up to 1 L.       Saline:   0.9% NaCl in water (Finn Aqua)       GTB:   0.15 mM CaCl 2              141 mM NaCl            0.5 mM MgCl 2 .6 H 2 O             10 mM Tris           0.1% gelatin           pH 7.2-7.3                  
 
         [0120]    Procedure:  
         [0121]    1. Cell preparation:  
         [0122]    The erythrocytes in the guinea pig&#39;s blood were washed with GTB a number of times by centrifugation (5 minutes at 1000 rpm) until the supernatant liquor was clear. The cell count was adjusted to 2·10 9  cells/mL.  
         [0123]    2. Procedure: the individual batches were incubated with agitation over a period of 30 minutes at 37° C. The assay was then stopped with 480 μL of ice-cold saline (physical solution of common salt) and the cells were removed by centrifugation at 5000 rpm over a period of 5 minutes. 200 μL of the supernatant liquor were measured at 405 nm by transfer thereof to a microtitration plate and evaluation in a microtitration plate photometer.  
                                                                                   Pipetting table (quantities in μL)                            Background +               Background       100% Lysis +   factor D (−   Max. lysis           (−serum)   100 % Lysis   factor D   serum   (water)                        Cells   20   20   20   20   20       Serum   20   20       Mg-EGTA   480   480   480   480       Factor D           0.5 μg   0.5 μg       Saline (to stop   480   480   480   480       the test       H 2 O                   980                                                          
 
         [0124]    Calculation:  
         %                 cell                 lysis     =         (   x   )     -       (   1   )     ×   100      %           (   3   )     -     (   1   )                               
 
       Example I  
       [0125]    Pharmacokinetics and Clotting Parameters in Rats  
         [0126]    The test probes are dissolved in isotonic salt solution just prior to administration to Sprague Dawley rats in an awake state. The administration doses are 1 ml/kg for intravenous Bolus injection into the cercal vein and 10 ml/kg for oral administration, which is carried out per pharyngeal tube. Withdrawals of blood are made, if not otherwise stated, one hour after oral administration of 21.5 mg·kg −1  or intravenous administration of 1.0 mg·kg −1  of the test probe or corresponding vehicle (for control). Five minutes before the withdrawal of blood, the animals are narcotized by i.p. administration of 25% strength urethane solution (dosage 1 g·kg −1  i.p.) in physiological saline. The A. carotis is prepared and catheterized, and blood samples (2 mL) are taken in citrate tubules (1.5 parts of citrate plus 8.5 parts of blood). Directly after blood sampling, the ecarin clotting time (ECT) in whole blood is determined. Following preparation of the plasma by centrifugation, the plasma thrombin time and the activated partial thromboplastin time (APTT) are determined with the aid of a coagulometer.  
         [0127]    Clotting parameters:  
         [0128]    Ecarin clotting time (ECT): 100 μL of citrate blood are incubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender &amp; Hobein, Munich, German Federal Republic). Following the addition of 100 μL of warmed (37° C.) ecarin reagent (Pentapharm), the time taken for a fibrin clot to form is determined.  
         [0129]    Activated thromboplastin time (APTT): 50 μL of citrate plasma and 50 μL of PTT reagent (Pathrombin, Behring) are mixed and incubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender &amp; Hobein, Munich, German Federal Republic). Following the addition of 50 μL of warmed (37° C.) calcium chloride, the time taken for a fibrin clot to form is determined.  
         [0130]    Thrombin time (TT): 100 μL of citrate-treated plasma are incubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender &amp; Hobein, Munich, German Federal Republic). Following the addition of 100 μL of warmed (37° C.) thrombin reagent (Boehringer Mannheim), the time taken for a fibrin clot to form is determined.  
       Example J  
       [0131]    Pharmacokinetics and Clotting Parameters in Dogs  
         [0132]    The test probes are dissolved in isotonic salt solution just prior to administration to half-breed dogs. The administration doses are 0.1 ml/kg for intravenous Bolus injection and 1 ml/kg for oral administration, which is carried out per pharyngeal tube. Samples of venous blood (2 mL) are taken in citrate tubules prior to and also 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, and 360 min (if required, 420 min, 480 min, and 24 H) after intravenous administration of 1.0 mg/kg or prior to and also 10, 20, 30, 60, 120, 180, 240, 300, 360, 480 min and 24 h after oral dosage of 4.64 mg/kg. Directly after blood sampling, the ecarin clotting time (ECT) in whole blood is determined. Following preparation of the plasma by centrifugation, the plasma thrombin time and the activated partial thromboplastin time (APTT) are determine with the aid of a coagulometer.  
         [0133]    In addition, the anti-F-IIa activity (ATU/mL) and the concentration of the substance are determined by their anti-F-IIa activity in the plasma by means of chromogenic (S 2238) thrombin assay, calibration curves with r-hirudin and the test substance being used.  
         [0134]    The plasma concentration of the test probe forms the basis of calculation of the pharmacokinetic parameters: time to maximum plasma concentration (T max), maximum plasma concentration; plasma half-life, t 0.5 ; area under curve (AUC); and resorbed portion of the test probe (F).  
         [0135]    Clotting parameters:  
         [0136]    Ecarin clotting time (ECr): 100 μL citrate-treated blood are incubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender &amp; Hobein, Munich, German Federal Republic). Following the addition of 100 μL of warmed (37° C.) ecarin reagent (Pentapharm), the time taken for a fibrin clot to form is determined.  
         [0137]    Activated thromboplastin time (APTT): 50 μL citrate-treated plasma and 50 μL of PTT reagent (Pathrombin, Behring) are mixed and incubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender &amp; Hobein, Munich, German Federal Republic). Following the addition of 50 μL of warmed (37° C.) calcium chloride, the time taken for a fibrin clot to form is determined.  
         [0138]    Thrombin time (TT): 100 μL of citrate-treated plasma is incubated for 2 min at 37° C. in a coagulometer (CL 8, ball type, Bender &amp; Hobein, Munich, German Federal Republic). Following the addition of 100 μL of warmed (37° C.) thrombin reagent (Boehringer Mannheim), the time taken for a fibrin clot to form is determined.  
         [0139]    The present invention relates to peptide substances and peptidomimetic substances, to the preparation thereof, and to the use thereof as thrombin inhibitors or complement inhibitors. In particular, the substances concerned are those having an amidine group as terminal group on the one hand and a polyhydroxyalkyl or polyhydroxcycloalkyl group—which can comprise several units as the second terminal group on the other hand.  
         [0140]    The invention relates to the use of these novel substances for the production of thrombin inhibitors, complement inhibitors, and, specifically, inhibitors of C1s and C1r.  
         [0141]    In particular, the invention relates to the use of chemically stable substances of the general formula I, to their tautomers and pharmacologically compatible salts and prodrugs for the production of medicinal drugs for the treatment and prophylaxis of diseases which can be alleviated or cured by partial or complete inhibition, particularly selective inhibition, of thrombin or C1s and/or C1r.  
         [0142]    Formula I has the general structure 
         A—B—D—E—G—K—L  (I), 
         [0143]    in which  
         [0144]    A stands for H, CH 3 , H—(R A1 )i A  in which  
         [0145]    R A1  denotes  
                         
 
         [0146]     in which R A2  denotes H, NH 2 , NH—COCH 3 , F, or NHCHO,  
         [0147]    R A3  denotes H or CH 2 OH,  
         [0148]    R A4  denotes H, CH 3 , or COOH,  
         [0149]    [0149] i A is 1 to 20,  
         [0150]    [0150] j A is 0, 1, or 2,  
         [0151]    [0151] k A is 2 or 3,  
         [0152]    [0152] l A is 0 or 1,  
         [0153]    [0153] m A is 0, 1, or 2,  
         [0154]    [0154] n A is 0, 1, or 2,  
         [0155]    the groups R A1  being the same or different when  i A is greater than 1;  
         [0156]    B denotes  
                         
 
         [0157]    A—B can stand for  
                         
 
         [0158]     or for a neuraminic acid radical or N-acetylneuraminic acid radical bonded through the carboxyl function,  
         [0159]     in which  
         [0160]    R B1  denotes H, CH 2 OH, or C 1-4  alkyl,  
         [0161]    R B2  denotes H, NH 2 , NH—COCH 3 , F, or NHCHO,  
         [0162]    R B3  denotes H, C 1-4  alkyl, CH 2 —O—(C 1-4  alkyl), COOH, F, NH—COCH 3 , or CONH 2 ,  
         [0163]    R B4  denotes H, C 1-4  alkyl, CH 2 —O—(C 1-4  alkyl), COOH, or CHO, in which latter case intramolecular acetal formation may take place,  
         [0164]    R B5  denotes H, C 1-4  alkyl, CH 2 —O—(C 1-4  alkyl), or COOH,  
         [0165]    [0165] k B is 0 or 1,  
         [0166]    [0166] l B is 0, 1, 2, or 3 ( l B≠0 when A=R B1 =R B3 =H,  m B= k B=0 and D is a bond),  
         [0167]    [0167] m B is 0, 1, 2, 3, or 4,  
         [0168]    [0168] n B is 0, 1, 2, or 3,  
         [0169]    R B6  denotes C 1-4  alkyl, phenyl, or benzyl, and  
         [0170]    R B7  denotes H, C 1-4  alkyl, phenyl, or benzyl;  
         [0171]    D stands for a bond or for  
                         
 
         [0172]     in which  
         [0173]    R D1  denotes H or C 1-4  alkyl,  
         [0174]    R D2  denotes a bond or C 1-4  alkyl,  
         [0175]    R D3  denotes  
                         
 
         [0176]     in which  l D is 1, 2, 3, 4, 5, or 6,  
         [0177]    R D5  denotes H, C 1-4  alkyl, or Cl, and  
         [0178]    R D6  denotes H or CH 3 ,  
         [0179]    and in which a further aromatic or aliphatic ring can be condensed onto the ring systems defined for R D3 , and  
         [0180]    R D4  denotes a bond, C 1-4  alkyl, CO, SO 2 , or CH 2 —CO;  
         [0181]    E stands for  
                         
 
         [0182]     in which  
         [0183]    [0183] k E is 0, 1, or 2,  
         [0184]    [0184] l E is 0, 1, or 2,  
         [0185]    [0185] m E is 0, 1, 2, or 3,  
         [0186]    [0186] n E is 0, 1, or 2,  
         [0187]    [0187] p E is 0, 1, or 2,  
         [0188]    R E1  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, aryl (particularly phenyl or naphthyl), heteroaryl (particularly pyridyl, thienyl, imidazolyl, or indolyl), and C 3-8  cycloalkyl having a phenyl ring condensed thereto, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6  alkyl, OH, O—(C 1-6  alkyl), F, Cl, and Br,  
         [0189]    R E1  may also denote R E4 OCO—CH 2 — (where R E4  denotes H, C 1-12  alkyl, or C 1-3  alkylaryl),  
         [0190]    R E2  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, aryl (particularly phenyl or naphthyl), heteroaryl (particularly pyridyl, furyl, thienyl, imidazolyl, or indolyl), tetrahydropyranyl, tetrahydrothiopyranyl, diphenylmethyl, and dicyclohexylmethyl, C 3-8  cycloalkyl having a phenyl ring condensed thereto, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6  alkyl, OH, O—(C 1-6  alkyl), F, Cl, and Br, and may also denote CH(CH 3 )OH or CH(CF 3 ) 2 ,  
         [0191]    R E3  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, aryl (particularlyphenylornaphthyl), heteroaryl (particularly pyridyl, theinyl, imidazolyl, or indolyl), and C 3-8  cycloalkyl having a phenyl ring condensed thereto, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6  alkyl, OH, O—(C 1-6  alkyl), F, Cl, and Br,  
         [0192]    the groups defined for R E1  and R E2  may be interconnected through a bond, and the groups defined for R E2  and R E3  may also be interconnected through a bond,  
         [0193]    R E2  may also denote COR E5  (where R E5  denotes OH, O—(C 1-6  alkyl), or O—(C 1-3  alkylaryl)), CONR E6 R E7  (where R E6  and R E7  denote H, C 1-6  alkyl, or C 0-3  alkylaryl), or NR E6 R E7 ,  
         [0194]    E may also stand for D-Asp, D-Glu, D-Lys, D-Orn, D-His, D-Dab, D-Dap, or D-Arg;  
         [0195]    G stands for  
                         
 
         [0196]     where  l G is 2, 3, 4, or 5, and one of the CH 2  groups in the ring is replaceable by O, S, NH, N(C 1-3  alkyl), CHOH, CHO(C 1-3  alkyl), C(C 1-3  alkyl) 2 , CH(C 1-3  alkyl), CHF, CHCl, or CF 2 ,  
                         
 
         [0197]     in which  
         [0198]    [0198] m G is 0, 1, or 2,  
         [0199]    [0199] n G is 0, 1, or 2,  
         [0200]    [0200] p G is 0, 1, 2, 3, or 4,  
         [0201]    R G1  denotes H, C 1-6  alkyl, or aryl,  
         [0202]    R G2  denotes H, C 1-6  alkyl, or aryl,  
         [0203]    and R G1  and R G2  may together form a —CH═CH—CH═CH— chain,  
         [0204]    G may also stand for  
                         
 
         [0205]     in which  
         [0206]    [0206] q G is 0, 1, or 2,  
         [0207]    [0207] r G is 0, 1, or 2,  
         [0208]    R G3  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, or aryl,  
         [0209]    R G4  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, or aryl (particularly phenyl or naphthyl);  
         [0210]    K stands for 
         NH—(CH 2 ) n K—Q K   
         [0211]     in which  
         [0212]    [0212] n K is 0, 1, 2, or 3,  
         [0213]    Q K  denotes C 2-6 alkyl, whilst up to two CH 2  groups may be replaced by O or S,  
         [0214]    Q K  also denotes  
                         
 
         [0215]     in which  
         [0216]    R K1  denotes H, C 1-3  alkyl, OH, O—C( 1-3  alkyl), F, Cl, or Br,  
         [0217]    R K2  denotes H, C 1-3  alkyl, O—(C 1-3  alkyl), F, Cl, or Br,  
         [0218]    X K  denotes O, S, NH, N—(C 1-6  alkyl),  
         [0219]    Y K  denotes  
                         
 
         [0220]    Z K  denotes  
                         
 
         [0221]    U K  denotes  
                         
 
         [0222]    V K  denotes  
                         
 
         [0223]    W K  denotes  
                         
 
         [0224]     but in the latter case L may not be a guanidine group,  
         [0225]    [0225] n K is 0, 1, or 2,  
         [0226]    [0226] p K is 0, 1, or 2, and  
         [0227]    [0227] q K is 1 or 2;  
         [0228]    L stands for  
                         
 
         [0229]     in which  
         [0230]    R L1  denotes H, OH, O—(C 1-6  alkyl), O—(CH 2 ) 0-3 -phenyl,  
         [0231]    CO—(C 1-6  alkyl), CO 2 —(C 1-6  alkyl), or CO 2 —(C 1-3  alkylaryl).  
         [0232]    Preference is given to the following compounds of formula I 
         A—B—D—E—G—K—L  (I), 
         [0233]    in which  
         [0234]    A stands for H or H—(R A1 )i A   
         [0235]     in which  
         [0236]    R A1  denotes  
                         
 
         [0237]     in which R A4  denotes H, CH 3 , or COOH,  
         [0238]    [0238] i A is 1 to 6,  
         [0239]    [0239] j A is 0, 1, or 2,  
         [0240]    [0240] k A is 2 or 3,  
         [0241]    [0241] m A is 0, 1, or 2,  
         [0242]    [0242] n A is 0, 1, or 2,  
         [0243]    the groups R A1  being the same or different when  i A is greater than 1;  
         [0244]    B denotes  
                         
 
         [0245]    A—B stands for  
                         
 
         [0246]     in which  
         [0247]    R B1  denotes H or CH 2 OH,  
         [0248]    R B2  denotes H, NH 2 , NH—COCH 3 , or F,  
         [0249]    R B3  denotes H, CH 3 , CH 2 —O—(C 1-4  alkyl), or COOH,  
         [0250]    R B4  denotes H, C 1-4  alkyl, CH 2 —O—(C 1-4  alkyl), COOH, or CHO, in which latter case intramolecular acetal formation may take place,  
         [0251]    R B5  denotes H, CH 3 , CH 2 —O—(C 1-4  alkyl), or COOH,  
         [0252]    [0252] k B is 0 or 1,  
         [0253]    [0253] l B is 0, 1, 2, or 3 ( l B≠0 when A=R B1 =R B3 =H,  m B= k B=0, and D is a bond),  
         [0254]    [0254] m B is 0, 1, 2, or 3,  
         [0255]    [0255] n B is 0, 1, 2, or 3,  
         [0256]    R B6  denotes C 1-4  alkyl, phenyl, or benzyl, and  
         [0257]    R B7  denotes H, C 1-4  alkyl, phenyl, or benzyl;  
         [0258]    D stands for a bond or for  
                         
 
         [0259]     in which  
         [0260]    R D1  denotes H or C 1-4  alkyl,  
         [0261]    R D2  denotes a bond or C 1-4  alkyl,  
         [0262]    R D3  denotes  
                         
 
         [0263]    R D4  denotes a bond, C 1-4  alkyl, CO, SO 2 , or —CH 2 —CO;  
         [0264]    E stands for  
                         
 
         [0265]     in which  
         [0266]    [0266] k E is 0, 1, or 2,  
         [0267]    [0267] m E is 0, 1, 2, or 3,  
         [0268]    R E1  denotes H, C 1-6  alkyl, or C 3-8  cycloalkyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6  alkyl, OH, and O—(C 1-6  alkyl),  
         [0269]    R E2  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, aryl (particularly phenyl or naphthyl), heteroaryl (particularly pyridyl, furyl, or thienyl), tetrahydropyranyl, diphenylmethyl, or dicyclohexylmethyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6  alkyl, OH, O—(C 1-6  alkyl), F, Cl, and Br, and may also denote CH(CF 3 ) 2 ;  
         [0270]    R E3  denotes H, C 1-6  alkyl, or C 3-8  cycloalkyl, and  
         [0271]    R E2  may also denote COR E5  (where R E5  denotes OH, O—C 1-6  alkyl, or O—(C 1-3  alkylaryl)), CONR E6 R E7  (where R E6  and R E7  each denote H, C 1-6  alkyl, or C 0-3  alkylaryl), or NR 6 R E7 ;  
         [0272]    E may also stand for D-Asp, D-Glu, D-Lys, D-Orn, D-His, D-Dab, D-Dap, or D-Arg;  
         [0273]    G stands for  
                         
 
         [0274]     where  l G is 2, 3, or 4, and one of the CH 2  groups in the ring is replaceable by O, S, NH, N(C 1-3  alkyl), CHOH, or CHO(C 1-3  alkyl);  
                         
 
         [0275]     in which  
         [0276]    [0276] m G is 0, 1, or 2;  
         [0277]    [0277] n G is 0 or 1;  
         [0278]    K stands for 
         NH—(CH 2 ) n K—Q K   
         [0279]     in which  
         [0280]    [0280] n K is 1 or 2,  
         [0281]    Q K  denotes  
                         
 
         [0282]     in which  
         [0283]    R K1  denotes H, C 1-3  alkyl, OH, O—(C 1-3  alkyl), F, Cl, or Br,  
         [0284]    R K2  denotes H, C 1-3  alkyl, O—(C 1-3  alkyl), F, Cl, or Br,  
         [0285]    X K  denotes O, S, NH, N—(C 1-6  alkyl),  
         [0286]    Y K  denotes  
                         
 
         [0287]    Z K  denotes  
                         
 
         [0288]    U K  denotes  
                         
 
         [0289]    and  
         [0290]    L stands for  
                         
 
         [0291]     in which  
         [0292]    R L1  denotes H, OH, O—(C 1-6  alkyl), or CO 2 —(C 1-6  alkyl).  
         [0293]    Preferred thrombin inhibitors are compounds of formula I 
         A—B—D—E—G—K—L  (I), 
         [0294]    in which  
         [0295]    A stands for H or H—(R A1 )i A  in which  
         [0296]    R A1  denotes  
                         
 
         [0297]     in which R A4  denotes H or COOH,  
         [0298]    [0298] i A is 1 to 6,  
         [0299]    [0299] j A is 0 or 1,  
         [0300]    [0300] k A is 2 or 3,  
         [0301]    [0301] n A is 1 or 2,  
         [0302]    the groups R A1  being the same or different when  i A is greater than 1;  
         [0303]    B denotes  
                         
 
         [0304]     in which  
         [0305]    R B3  denotes H, CH 3 , or COOH,  
         [0306]    R B4  denotes H, CH 3 , COOH, or CHO, in which latter case intramolecular acetal formation may take place,  
         [0307]    [0307] k B is 0 or 1,  
         [0308]    [0308] l B is 1, 2, or 3,  
         [0309]    [0309] m B is 0, 1, 2, or 3, and  
         [0310]    [0310] n B is 1, 2, or 3;  
         [0311]    D stands for a bond;  
         [0312]    E stands for  
                         
 
         [0313]     in which  
         [0314]    [0314] m E is 0 or 1,  
         [0315]    R E2  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, phenyl, diphenylmethyl, or dicyclohexylmethyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-4  alkyl, OH, O—CH 3 , F, and Cl;  
         [0316]    G stands for  
                         
 
         [0317]     where  l G is 2, 3, or 4 and one of the CH 2  groups in the ring is replaceable by O, S, NH, or N(C 1-3  alkyl),  
                         
 
         [0318]     in which  
         [0319]    [0319] n G is 0 or 1;  
         [0320]    K stands for 
         NH—CH 2 —Q K   
         [0321]     in which  
         [0322]    Q K  denotes  
                         
 
         [0323]     in which  
         [0324]    R K1  denotes H, CH 3 , OH, O—CH 3 , F, or Cl,  
         [0325]    X K  denotes O, S, NH, N—CH 3 ,  
         [0326]    Y K  denotes  
                         
 
         [0327]    Z K  denotes  
                         
 
         [0328]    L stands for  
                         
 
         [0329]     in which  
         [0330]    R L1  denotes H, OH, or CO 2 —(C 1-6  alkyl).  
         [0331]    Preferred complement inhibitors are compounds of formula I 
         A—B—D—E—G—K—L  (I), 
         [0332]    in which  
         [0333]    A stands for H or H—(R A1 )i A  in which  
         [0334]    R A1  denotes  
                         
 
         [0335]     in which R A4  denotes H or COOH,  
         [0336]    [0336] i A is 1 to 6,  
         [0337]    [0337] j A is 0 or 1,  
         [0338]    [0338] k A is 2 or 3,  
         [0339]    [0339] n A is 1 or 2,  
         [0340]    the groups R A1  being the same or different when  i A is greater than 1;  
         [0341]    B denotes  
                         
 
         [0342]    A—B stands for  
                         
 
         [0343]     in which  
         [0344]    R B3  denotes H, CH 3 , or COOH,  
         [0345]    R B4  denotes H, CH 3 , COOH, or CHO, in which latter case intramolecular acetal formation may take place,  
         [0346]    [0346] k B is 0 or 1,  
         [0347]    [0347] l B is 1, 2, or 3,  
         [0348]    [0348] m B is 0, 1, 2, or 3,  
         [0349]    [0349] n B is 1, 2, or 3,  
         [0350]    R B6  denotes C 1-4  alkyl, phenyl, or benzyl, and  
         [0351]    R B7  denotes H, C 1-4  alkyl, phenyl, or benzyl,  
         [0352]    D stands for  
                         
 
         [0353]     in which  
         [0354]    R D1  denotes H or C 1-4  alkyl,  
         [0355]    R D2  denotes a bond or C 1-4  alkyl,  
         [0356]    R D3  denotes  
                         
 
         [0357]     in which  
         [0358]    R D4  denotes a bond, C 1-4  alkyl, CO, SO 2 , or —CH 2 —CO, and  
         [0359]    R D6  denotes H or CH 3 ;  
         [0360]    E stands for  
                         
 
         [0361]     in which  
         [0362]    [0362] m E is 0 or 1,  
         [0363]    R E2  denotes H, C 1-6  alkyl, or C 3-8  cycloalkyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-4  alkyl, OH, O—CH 3 , F, and Cl;  
         [0364]    G stands for  
                         
 
         [0365]     where  l G is 2, 3, or 4 and one of the CH 2  groups in the ring is replaceable by O, S, NH, or —N(C 1-3  alkyl), or  
                         
 
         [0366]     in which  
         [0367]    [0367] n G is 0 or 1;  
         [0368]    K stands for 
         NH—CH 2 —Q K   
         [0369]     in which  
         [0370]    Q K  denotes  
                         
 
         [0371]     in which  
         [0372]    R K1  denotes H, CH 3 , OH, O—CH 3 , F, or Cl,  
         [0373]    X K  denotes O, S, NH, N—CH 3 ,  
         [0374]    Y K  denotes  
                         
 
         [0375]    Z K  denotes  
                         
 
         [0376]    L stands for  
                         
 
         [0377]     in which  
         [0378]    R L1  denotes H, OH, or CO 2 —(C 1-6  alkyl).  
         [0379]    Particularly preferred thrombin inhibitors are compounds of formula I 
         A—B—D—E—G—K—L  (I), 
         [0380]    in which  
         [0381]    A stands for H or H—(R A1 )i A  in which  
         [0382]    R A1  denotes  
                         
 
         [0383]     in which  i A is 1 to 6,  
         [0384]    [0384] j A is 0 or 1,  
         [0385]    [0385] i A is 1 or 2,  
         [0386]    the groups R A1  being the same or different when  i A is greater than 1;  
         [0387]    B denotes  
                         
 
         [0388]     in which  
         [0389]    [0389] l B is 1, 2, or 3,  
         [0390]    [0390] m B is 1 or 2,  
         [0391]    D stands for a bond,  
         [0392]    E stands for  
                         
 
         [0393]     in which  
         [0394]    [0394] m E is 0 or 1,  
         [0395]    R E2  denotes H, C 1-6  alkyl, C 3-8  cycloalkyl, phenyl, diphenylmethyl, or dicyclohexylmethyl,  
         [0396]    building block E preferably exhibiting D configuration,  
         [0397]    G stands for  
                         
 
         [0398]    building block G preferably exhibiting L configuration;  
         [0399]    K stands for 
         NH—CH 2 —Q K   
         [0400]     in which  
         [0401]    Q K  denotes  
                         
 
         [0402]    and  
         [0403]    L stands for  
                         
 
         [0404]     in which  
         [0405]    R L1  denotes H, OH, or CO 2 —(C 1-6  alkyl).  
         [0406]    Particularly preferred complement inhibitors are compounds of formula I 
         A—B—D—E—G—K—L  (I), 
         [0407]    in which  
         [0408]    A stands for H or H—(R A1 )i A  in which  
         [0409]    R A1  denotes  
                         
 
         [0410]     in which R A4  denotes H or COOH,  
         [0411]    [0411] i A is 1 to 6,  
         [0412]    [0412] j A is 0 or 1,  
         [0413]    [0413] k A is 2 or 3,  
         [0414]    [0414] n A is 1 or 2,  
         [0415]    the groups R A1  being the same or different when  i A is greater than 1;  
         [0416]    B denotes  
                         
 
         [0417]    A—B stands for  
                         
 
         [0418]     in which  
         [0419]    R B3  denotes H, CH 3 , or COOH,  
         [0420]    R B4  denotes H, CH 3 , COOH, or CHO, in which latter case intramolecular acetal formation may take place,  
         [0421]    [0421] k B is 0 or 1,  
         [0422]    [0422] l B is 1, 2, or 3,  
         [0423]    [0423] m B is 0, 1, 2, or 3,  
         [0424]    [0424] n B is 1, 2, or 3,  
         [0425]    R B6  denotes C 1-4  alkyl, phenyl, or benzyl, and  
         [0426]    R B7  denotes H, C 1-4  alkyl, phenyl, or benzyl,  
         [0427]    D stands for  
                         
 
         [0428]     in which  
         [0429]    R D1  denotes H,  
         [0430]    R D2  denotes a bond or C 1-4  alkyl,  
         [0431]    R D3  denotes  
                         
 
         [0432]    R D4  denotes a bond, C 1-4  alkyl, CO, SO 2 , or —CH 2 —CO, and  
         [0433]    E stands for  
                         
 
         [0434]     in which  
         [0435]    [0435] m E is 0 or 1,  
         [0436]    R E2  denotes H, C 1-6  alkyl, or C 3-8  cycloalkyl, which groups may carry up to three identical or different substituents selected from the group consisting of F and Cl;  
         [0437]    G stands for  
                         
 
         [0438]     where  l G is 2 
                         
 
         [0439]     in which  
         [0440]    [0440] n G is 0,  
         [0441]    K stands for 
         NH—CH 2 Q K   
         [0442]     in which  
         [0443]    Q K  denotes  
                         
 
         [0444]     in which  
         [0445]    X K  denotes S,  
         [0446]    Y K  denotes ═CH—, or ═N—,  
         [0447]    Z K  denotes ═CH—, or ═N—, and  
         [0448]    L stands for  
                         
 
         [0449]     in which  
         [0450]    R L1  denotes H or OH.  
         [0451]    Preferred building blocks A—B are:  
                                                   D-Fructo                                             D-Turano-                                             3-O-Methyl- D-glucopyrano-                                             D-Galacturo-                                             Glucuronamo-                                             N-Acetyl- neuraminic                                             D-Digitoxo                                             Maltotrio-                                             Maltotetrao-                                             2-Deoxy-D- galacto                                             2-Acetamido- 2-deoxy-3-O- (delta-d-galacto- pyranosyl)-D- glucopyrano                                             D-Mannoheptulo                                             alpha-Spphoro-                                             N-Acetyl-D- Mannosami-                                             6-Acetamido-6- Deoxy-alpha- D-Glucopyrano-                                             3-O-Beta-D- Galatopyranosyl- D-Arabino-                                             D-Glucohepto-                                             Nigero-                                             D-Glucoheptulo-                                             Xylotrio-                                             2-Acetamido-2- Deoxy-6-O-(beta- D-galactopyrano- syl)-D-glucopyrano-                                             4-O-(4-O-[6-O- alpha-D-gluco- pyranosyl-alpha- glucopyranosyl]- alpha-D-glucopyr-                                             2-Acetamido-6-O- (2-acetamido-2- deoxy-beta-D- glucopyranosyl)-2- deoxy-D- glucopyran-                                             6-O-(2-Acetamido- 2-deoxy-beta-D- glucopyranosyl)-D- galactopyrano-                                             2-Acetamido-2- deoxy-4-O-([4-O- beta-D-galacto- pyranosyl]-beta- D-galactopyranosyl)                                             N-Acetyl-D- glucosamin-                                             2-Fluoro-2-deoxy- D-galactopyrano-                                             6-Deoxy-D-gluco-                                             L-Allo-                                             3-O-Methylgluco-                                             D-Allo-                                             6-Fluoro-6- deoxy-D- galactopyrano-                                             D-Gluco-                                             Dextro-                                             N-Acetyl- lactosamin-                                             L-Galacto-                                             L-Gluco-                                             4-O-alpha-D- galactopyrano- syl-D-galacto- pyrano-                                             2-Acetamido-2- deoxy-4-O([4- O-beta-D- galactopyrano- syl]-beta-D- galactopyranosyl)-                                             6-Fluoro-6-deoxy- D-glucopyrano-                                             L-Lyxo-                                             L-Manno-                                             D-Manno-                                             N-Acetyl-D- glucosamin-                                             D-Lyxo-                                             D-Lacto-                                             Maltoheptao-                                             D-Talo-                                             L-Talo-                                             Neohesperido-                                             N-Acetyl-D- galactosamin-                                             Isomalto-                                             Beta-Malto-                                             L-Fructo-                                             6-O-Methyl- D-galactopyrano-                                             2-Deoxy-D- Ribohexopyrano-                                             Alpha-D-Kojibio-                                             2-O-Methyl-D-xylo-                                             L-Fluco-                                             6-O-Beta-D- galactopyrano- syl-D-galacto-                                             L-Gulo-                                             D-Gulo-                                             D-Ido-                                             L-Ido-                                             (4-O-(4-O-Beta- D-galacto- pyranosyl)-beta- D-galacto- pyranosyl)- D-glucopyrano-                                             D-Cellotrio-                                             Laminaribio-                                             3-O-alpha-D- mannopyrano-syl- D-mannopyrano-                                             4-O-beta- Galacto- pyranosyl- D-mannopyrano-                                             Isomaltotrio-                                             D-Galacturonic-                                             L-Rhamno-                                             D-Altro-                                             N,N′-Diacetyl- chitobio-                                             D-Glucuronic-                                             (+)-Digitoxo-                                             6-O-[2-Aceta- mido-2-deoxy-4- O-(beta-D-galacto- pyranosyl)- beta-D-gluco- pyranosyl]-D-                                             4-O-(6-O-[Aceta- mido-2-deoxy- beta-D-gluco- pyranosyl]-beta- D-galacto- pyranosyl)-                                             D-Cellotetrao-                                             Digalacturonic-                                             2′-Fucosyllacto-                                             3-Fucosyllacto-                                             Lacto-N-Tetrao-                                             4-O-(2-O- Methyl-beta-D- galactopyrano- syl)-D-gluco- pyrano-                                             A-Lactulo-                                             Maltohexao-                                             L-Allo-                                             3-Deoxy-D-Gluco-                                             Isomaltotetrao-                                             Xylobio-                                             Maltopentao-                                             Sophoro-                                             D-Lacto-                                             2-Acetamido-2- deoxy-3-O- (alpha-L-fuco- pyranosyl)-D- glucopyrano-                                             2-Acetamido-2- deoxy-4-O- (alpha-L-Fuco- pyranosyl)-D- glucopyrano-                                             D-Mannohepto-                                             Epilacto-                                             Leucro-                                             A-Lactin-                                             Gantoobio-                                             D-Melibio-                                             Dimer-N-acetyl- galactosamin-                                             2-O-alpha-L- Fucosyl-D-galacto                                             Lactodifuco- tetrrao-                                             6-O-alpha-D- Mannopyranosyl- D-mannopyrano-                                             2-Acetamido-2- deoxy-6-O-(beta- D-galacto- pyranosyl)-D- galactopyrano-                                             D-Rhamno-                                             D-Cellohexo-                                             L-Altro-                                             3-O-[2-Aceta- mido-2-deoxy- beta-D-gluco- pyranosyl]-D- mannopyrano-                                             2-Deoxy-2- fluoro-D-manno-                                             4-Deoxy-L-fuco-                                             2-O-(alpba-D- galacto- pyranosyl)-D- galacto-                                             3-O-(alpha- D-Galacto- pyranosyl)-D- galacto-                                             D-Galacto-                                             Globotrio-                                             2-Acetamido-2- deoxy-4-O-beta- D-galacto- pyranosyl-D- mannopyrano-                                             2-Acetamido-2- deoxy-4-O-(beta- D-manno- pyranosyl)-D- glucopyrano-                                             4-O-beta-D- galacto- pyranosyl-D- galactopyrano-                                             4-O-(3-O-alpha- D-Galacto- pyranosyl-beta- D-galacto- pyranosyl)-D- galactopyrano-                                             A1-3, B1-4, A1-3 Galactotetrao-                                             2-O-alpha-D- Mannopyranosyl- D-mannopyrano-                                             4-O-alpla-D- Mannopyranosyl- D-mannopyrano-                                             2-O-(2-Aceta- mido-2-deoxy- beta-D-gluco- pyranosyl)- D-manno-                                             3-O-(alpha-L- Fucopyranosyl)- D-galacto-                                             4-O-(alpha-L- Fucopyranosyl)- D-galacto-                                             2′-Fucosyl-N- acetallactos-ami                                             Laminaritrio-                                             Laminaritetrao-                                             Laminaripentao-                                             Laminarihexao-                                             Lacto-N-bio                                             A1-2-Mannobio-                                             A1-3,A1-6- Mannotrio-                                             A1-3,A1-6- Mannopentao-                                             2-Acetamido-2- deoxy-3-O- methyl-D- glucopyranosi-                                             Fucose alpha A1,2-galactose- beta A1,4-N- acetylglucosami-                                             Fucose alpha 1,6-N-acetylglu- cosami-                                             Galactose beta 1,6-N-acetyl- glucosami-                                             D-Ribulo-                                             D-Threo-                                             Arabinic AC-                                             Lactulo-                                             L-Xylulo-                                             D-Xylulo-                                             D-Fructo-                                             L-Threo-                                             5-Deoxy-D-xylo- furano-                                             2-Fluoro-2- deoxy-D-arabino-                                             Palatino-                                             2-Deoxy-L-ribo-                                                                                           Maltulo-                                             Trehalulo-                                             D-Arabino-                                             L-Arabino-                                             D-Erythro-                                             L-Glycer-                                             L-Erythro-                                             D-Glycer-                                             L-Ribo-                                             D-Ribo-                                             D-Fuco-                                             D-Cellobio-                                             5-Deoxy-L-arabino-                                             D-Xylo-                                             L-Xylo-                                             Cellopentao-                                             Pano-                                             Rutino-                                             Beta-Gentiobio-                                             6-Deoxy-L-talo-                                             L-Iduronic-                                             L-Glycerol-L- galactohepto-                                             L-Glycero-D- glucohepto-                                             D-Lacta-                                             Gluconic-                                             5-Ketogluconic-                                             Heptagluconic-                                             Lactobionic-                                             D-Xylonic-                                             Arabic-                                                
 
         [0452]    The term “C 1-x  alkyl” denotes any linear or branched alkyl chain containing from 1 to x carbons.  
         [0453]    The term “C 3-8  cycloalkyl” denotes carbocyclic saturated radicals containing from 3 to 8 carbons.  
         [0454]    The term “aryl” stands for carbocyclic aromatics containing from 6 to 14 carbons, particularly phenyl, 1-naphthyl, and 2-naphthyl.  
         [0455]    The term “heteroaryl” stands for five-ring and six-ring aromatics containing at least one heteroatom N, O, or S, and particularly denotes pylidyl, thienyl, furyl, thiazolyl, and imidazolyl; two of the aromatic rings may be condensed, as in indole, N—(C 1-3  alkyl)indole, benzothiophene, benzothiazole, benzimidazole, quinoline, and isoquinoline.  
         [0456]    The term “C x-y  alkylaryl” stands for carbocyclic aromatics that are linked to the skeleton through an alkyl group containing x, x+1 . . . y−1, or y carbons.  
         [0457]    The compounds of formula I can exist as such or be in the form of their salts with physiologically acceptable acids. Examples of such acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxysuccinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid, and acetylglycine.  
         [0458]    The novel compounds of formula I are competitive inhibitors of thrombin or the complement system, especially C1s, and also C1r.  
         [0459]    The compounds of the invention can be administered in conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, or rectally). Administration can also be carried out with vapors or sprays applied to the postnasal space.  
         [0460]    The dosage depends on the age, condition, and weight of the patient, and also on the method of administration used. Usually the daily dose of the active component per person is between approximately 10 and 2000 mg for oral administration and between approximately 1 and 200 mg for parenteral administration. These doses can take the form of from 2 to 4 single doses per day or be administered once a day as depot.  
         [0461]    The compounds can be employed in commonly used galenic solid or liquid administration forms, eg, as tablets, film tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams, or sprays. These are produced in conventional manner. The active substances can be formulated with conventional galenic auxiliaries, such as tablet binders, fillers, preserving agents, tablet bursters, flow regulators, plasticizers, wetters, dispersing agents, emulsifiers, solvents, retarding agents, antioxidants, and/or fuel gases (cf H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally contain the active substance in a concentration of from 0.1 to 99 wt %.  
         [0462]    The term “prodrugs” refers to compounds which are converted to the pharmacologically active compounds of the general formula I in vivo (eg, first pass metabolisums).  
         [0463]    Where, in the compounds of formula I, R L1  is not hydrogen, the respective substances are prodrugs from which the free amidine or guanidine compounds are formed under in vivo conditions. If ester functions are present in the compounds of formula I, these compounds can act, in vivo, as prodrugs, from which the corresponding carboxylic acids are formed.  
         [0464]    Apart from the substances mentioned in the examples, the following compounds are very particularly preferred and can be produced according to said manufacturing instructions:  
                                       1.   L-Glycer-D-Cha-Pro-NH-4-amb       2.   D-Glycer-D-Cha-Pro-NH-4-amb       3.   L-Erythro-D-Cha-Pro-NH-4-amb       4.   D-Erythro-D-Cha-Pro-NH-4-amb       5.   L-Threo-D-Cha-Pro-NH-4-amb       6.   D-Threo-D-Cha-Pro-NH-4-amb       7.   L-Arabino-D-Cha-Pro-NH-4-amb       8.   D-Arabino-D-Cha-Pro-NH-4-amb       9.   L-Ribo-D-Cha-Pro-NH-4-amb       10.   D-Ribo-D-Cha-Pro-NH-4-amb       11.   2-Deoxy-L-Ribo-D-Cha-Pro-NH-4-amb       12.   D-Fuco-D-Cha-Pro-NH-4-amb       13.   D-Cellobio-D-Cha-Pro-NH-4-amb       14.   D-Xylo-D-Cha-Pro-NH-4-amb       15.   L-Xylo-D-Cha-Pro-NH-4-amb       16.   Cellopentao-D-Cha-Pro-NH-4-amb       17.   D-Fructo-D-Cha-Pro-NH-4-amb       18.   Maltotrio-D-Cha-Pro-NH-4-amb       19.   Maltotetrao-D-Cha-Pro-NH-4-amb       20.   Glucohepto-D-Cha-Pro-NH-4-amb       21.   L-Allo-D-Cha-Pro-NH-4-amb       22.   D-Allio-D-Cha-Pro-NH-4-amb       23.   D-Gluco-D-Cha-Pro-NH-4-amb       24.   L-Gluco-D-Cha-Pro-NH-4-amb       25.   D-Manno-D-Cha-Pro-NH-4-amb       26.   L-Manno-D-Cha-Pro-NH-4-amb       27.   L-Galacto-D-Cha-Pro-NH-4-amb       28.   Dextro-D-Cha-Pro-NH-4-amb       29.   L-Lyxo-D-Cha-Pro-NH-4-amb       30.   D-Lyxo-D-Cha-Pro-NH-4-amb       31.   D-Lacto-D-Cha-Pro-NH-4-amb       32.   D-Talo-D-Cha-Pro-NH-4-amb       33.   L-Talo-D-Cha-Pro-NH-4-amb       34.   beta-Malto-D-Cha-Pro-NH-4-amb       35.   L-Fuco-D-Cha-Pro-NH-4-amb       36.   L-Gulo-D-Cha-Pro-NH-4-amb       37.   D-Gulo-D-Cha-Pro-NH-4-amb       38.   L-ldo-D-Cha-Pro-NH-4-amb       39.   D-ldo-D-Cha-Pro-NH-4-amb       40.   D-Cellotrio-D-Cha-Pro-NH-4-amb       41.   D-Galacturonic-D-Cha-Pro-NH-4-amb       42.   D-Glucuronic-D-Cha-Pro-NH-4-amb       43.   L-Rhamno-D-Cha-Pro-NH-4-amb       44.   D-Cellotetrao-D-Cha-Pro-NH-4-amb       45.   Maltohexao-D-Cha-Pro-NH-4-amb       46.   Maltopentao-D-Cha-Pro-NH-4-amb       47.   Xylobio-D-Cha-Pro-NH-4-amb       48.   D-Lacto-D-Cha-Pro-NH-4-amb       49.   D-Melibio-D-Cha-Pro-NH-4-amb       50.   Gentobio-D-Cha-Pro-NH-4-amb       51.   D-Rhamno-D-Cha-Pro-NH-4-amb       52.   L-Altro-D-Cha-Pro-NH-4-amb       53.   D-Galacto-D-Cha-Pro-NH-4-amb       54.   L-Glycer-D-Chg-Ace-NH-4-amb       55.   D-Glycer-D-Chg-Ace-NH-4-amb       56.   L-Erythro-D-Chg-Ace-NH-4-amb       57.   D-Erythro-D-Chg-Ace-NH-4-amb       58.   L-Threo-D-Chg-Ace-NH-4-amb       59.   D-Threo-D-Chg-Ace-NH-4-amb       60.   L-Arabino-D-Chg-Ace-NH-4-amb       61.   D-Arabino-D-Chg-Ace-NH-4-amb       62.   L-Ribo-D-Chg-Ace-NH-4-amb       63.   D-Ribo-D-Chg-Ace-NH-4-amb       64.   2-Deoxy-L-Ribo-D-Chg-Ace-NH-4-amb       65.   D-Fuco-D-Chg-Ace-NH-4-amb       66.   D-Cellobio-D-Chg-Ace-NH-4-amb       67.   D-Xylo-D-Chg-Ace-NH-4-amb       68.   L-Xylo-D-Chg-Ace-NH-4-amb       69.   Cellopentao-D-Chg-Ace-NH-4-amb       70.   D-Fructo-D-Chg-Ace-NH-4-amb       71.   Maltotrio-D-Chg-Ace-NH-4-amb       72.   Maltotetrao-D-Chg-Ace-NH-4-amb       73.   Glucohepto-D-Chg-Ace-NH-4-amb       74.   L-Allo-D-Chg-Ace-NH-4-amb       75.   D-Allo-D-Chg-Ace-NH-4-amb       76.   L-Gluco-D-Chg-Ace-NH-4-amb       77.   D-Manno-D-Chg-Ace-NH-4-amb       78.   L-Manno-D-Chg-Ace-NH-4-amb       79.   L-Galacto-D-Chg-Ace-NH-4-amb       80.   Dextro-D-Chg-Ace-NH-4-amb       81.   L-Lyxo-D-Chg-Ace-NH-4-amb       82.   D-Lyxo-D-Chg-Ace-NH-4-amb       83.   D-Lacto-D-Chg-Ace-NH-4-amb       84.   D-Talo-D-Chg-Ace-NH-4-amb       85.   L-Talo-D-Chg-Ace-NH-4-amb       86.   L-Fuco-D-Chg-Ace-NH-4-amb       87.   L-Gulo-D-Chg-Ace-NH-4-amb       88.   D-Gulo-D-Chg-Ace-NH-4-amb       89.   L-Ido-D-Chg-Ace-NH-4-amb       90.   D-Ido-D-Chg-Ace-NH-4-amb       91.   D-Cellotrio-D-Chg-Ace-NH-4-amb       92.   D-Galacturonic-D-Chg-Ace-NH-4-amb       93.   D-Glucuronic-D-Chg-Ace-NH-4-amb       94.   L-Rhamno-D-Chg-Ace-NH-4-amb       95.   D-Cellotetrao-D-Chg-Ace-NH-4-amb       96.   Maltohexao-D-Chg-Ace-NH-4-amb       97.   Maltopentao-D-Chg-Ace-NH-4-amb       98.   Xylobio-D-Chg-Ace-NH-4-amb       99.   D-Lacto-D-Chg-Ace-NH-4-amb       100.   D-Melibio-D-Chg-Ace-NH-4-amb       101.   Gentobio-D-Chg-Ace-NH-4-amb       102.   D-Rhamno-D-Chg-Ace-NH-4-amb       103.   L-Altro-D-Chg-Ace-NH-4-amb       104.   D-Galacto-D-Chg-Ace-NH-4-amb       105.   L-Glycer-D-Cha-Pyr-NH-3-(6-am)-pico       106.   D-Glycer-D-Cha-Pyr-NH-3-(6-am)-pico       107.   L-Erythro-D-Cha-Pyr-NH-3-(6-am)-pico       108.   D-Erythro-D-Cha-Pyr-NH-3-(6-am)-pico       109.   L-Threo-D-Cha-Pyr-NH-3-(6-am)-pico       110.   D-Threo-D-Cha-Pyr-NH-3-(6-am)-pico       111.   L-Arabino-D-Cha-Pyr-NH-3-(6-am)-pico       112.   D-Arabino-D-Cha-Pyr-NH-3-(6-am)-pico       113.   L-Ribo-D-Cha-Pyr-NH-3-(6-am)-pico       114.   D-Ribo-D-Cha-Pyr-NH-3-(6-am)-pico       115.   2-Deoxy-L-Ribo-D-Cha-Pyr-NH-3-(6-am)-pico       116.   D-Fuco-D-Cha-Pyr-NH-3-(6-am)-pico       117.   D-Cellobio-D-Cha-Pyr-NH-3-(6-am)-pico       118.   D-Xylo-D-Cha-Pyr-NH-3-(6-am)-pico       119.   L-Xylo-D-Cha-Pyr-NH-3-(6-am)-pico       120.   Cellopentao-D-Cha-Pyr-NH-3-(6-am)-pico       121.   D-Fructo-D-Cha-Pyr-NH-3-(6-am)-pico       122.   Maltotrio-D-Cha-Pyr-NH-3-(6-am)-pico       123.   Maltotetrao-D-Cha-Pyr-NH-3-(6-am)-pico       124.   Glucohepto-D-Cha-Pyr-NH-3-(6-am)-pico       125.   L-Allo-D-Cha-Pyr-NH-3-(6-am)-pico       126.   D-Allo-D-Cha-Pyr-NH-3-(6-am)-pico       127.   D-Gluco-D-Cha-Pyr-NH-3-(6-am)-pico       128.   L-Gluco-D-Cha-Pyr-NH-3-(6-am)-pico       129.   D-Manno-D-Cha-Pyr-NH-3-(6-am)-pico       130.   L-Manno-D-Cha-Pyr-NH-3-(6-am)-pico       131.   L-Galacto-D-Cha-Pyr-NH-3-(6-am)-pico       132.   Dextro-D-Cha-Pyr-NH-3-(6-am)-pico       133.   L-Lyxo-D-Cha-Pyr-NH-3-(6-am)-pico       134.   D-Lyxo-D-Cha-Pyr-NH-3-(6-am)-pico       135.   D-Lacto-D-Cha-Pyr-NH-3-(6-am)-pico       136.   D-Talo-D-Cha-Pyr-NH-3-(6-am)-pico       137.   L-Talo-D-Cha-Pyr-NH-3-(6-am)-pico       138.   beta-Malto-D-Cha-Pyr-NH-3-(6-am)-pico       139.   L-Fuco-D-Cha-Pyr-NH-3-(6-am)-pico       140.   L-Gulo-D-Cha-Pyr-NH-3-(6-am)-pico       141.   D-Gulo-D-Cha-Pyr-NH-3-(6-am)-pico       142.   L-ldo-D-Cha-Pyr-NH-3-(6-am)-pico       143.   D-Ido-D-Cha-Pyr-NH-3-(6-am)-pico       144.   D-Cellotrio-D-Cha-Pyr-NH-3-(6-am)-pico       145.   D-Galacturonic-D-Cha-Pyr-NH-3-(6-am)-pico       146.   D-Glucuronic-D-Cha-Pyr-NH-3-(6-am)-pico       147.   L-Rhamno-D-Cha-Pyr-NH-3-(6-am)-pico       148.   D-Cellotetrao-D-Cha-Pyr-NH-3-(6-am)-pico       149.   Maltohexao-D-Cha-Pyr-NH-3-(6-am)-pico       150.   Maltopentao-D-Cha-Pyr-NH-3-(6-am)-pico       151.   Xylobio-D-Cha-Pyr-NH-3-(6-am)-pico       152.   D-Lacto-D-Cha-Pyr-NH-3-(6-am)-pico       153.   D-Melibio-D-Cha-Pyr-NH-3-(6-am)-pico       154.   Gentobio-D-Cha-Pyr-NH-3-(6-am)-pico       155.   D-Rhamno-D-Cha-Pyr-NH-3-(6-am)-pico       156.   L-Altro-D-Cha-Pyr-NH-3-(6-am)-pico       157.   D-Galacto-D-Cha-Pyr-NH-3-(6-am)-pico       158.   L-Erythro-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       159.   D-Threo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       160.   L-Ribo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       161.   D-Ribo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       162.   2-Deoxy-L-Ribo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       163.   D-Fuco-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       164.   D-Cellobio-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       165.   D-Xylo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       166.   L-Xylo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       167.   Cellopentao-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       168.   D-Fructo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       169.   Maltotrio-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       170.   Maltotetrao-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       171.   Glucohepto-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       172.   L-Allo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       173.   D-Allo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       174.   D-Gluco-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       175.   L-Gluco-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       176.   D-Manno-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       177.   L-Manno-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       178.   L-Galacto-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       179.   Dextro-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       180.   L-Lyxo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       181.   D-Lyxo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       182.   D-Lacto-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       183.   D-Talo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       184.   L-Talo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       185.   beta-Maltro-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       186.   L-Fuco-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       187.   L-Gulo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       188.   D-Gulo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       189.   L-Ido-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       190.   D-ldo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       191.   D-Cellotrio-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       192.   D-Galacturonic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       193.   D-Glucuronic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       194.   D-Cellotetrao-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       195.   Maltohexao-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       196.   Maltopentao-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       197.   Xylobio-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       198.   D-Lacto-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       199.   Gentobio-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       200.   D-Rhamno-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       201.   L-Altro-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       202.   D-Galacto-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       203.   D-Galacturo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       205.   D-Glucohepto-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       206.   L-Allo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       207.   D-Allo-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       208.   D-Gluco-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       209.   D-Galacto-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       210.   L-Gluco-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       211.   L-Manno-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       212.   D-Manno-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       213.   D-Cellotrio-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       214.   D-Cellobio-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       215.   D-Glucuronic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       216.   Arabinic AC-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       217.   L-lduronic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       218.   Gluconlc-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       219.   Heptagluconic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       220.   Lactobionic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       221.   D-Xylonic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       222.   Arabic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       223.   Phenyl-beta-D-Glucuronic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       224.   Methyl-beta-D-Glucuronic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       225.   D-quinic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       226.   Phenyl-alpha-iduronic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       227.   Digalacturonlc-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       228.   Trigalacturonic-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       229.   3,4,5-Trihydroxy-6-hydroxymethy-tetrahydropyranyl(2)-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-           thiaz       230.   3-Acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyanyl(2)-CO-D-Cha-Pyr-NH-CH 2 -           2-(4-am)-thiaz       231.   D-Galacturo-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       232.   D-Glucohepto-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       233.   L-Allo-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       234.   D-Allo-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       235.   D-Gluco-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       236.   D-Galacto-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       237.   L-Gluco-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       238.   L-Manna-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       239.   D-Manno-NH-cyclohexyl-O-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       240.   D-Cellotrio-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       241.   D-Cellobio-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       242.   D-Glucuronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       243.   Arabinic AC-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       244.   L-Iduronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       245.   Gluconic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       246.   Heptagluconic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       247.   Lactoblonlc-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       248.   D-Xylonic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       249.   Arabic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       250.   Pheny-beta-D-Glucuronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       251.   Methyl-beta-D-Glucuronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       252.   D-quinic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       253.   Phenyl-alpha-iduronic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       254.   Digalacturonic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       255.   Trigalacturonic-NH-cyclohexyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       256.   3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-cyclohexyl-CO-D-Cha-Pyr-           NH-CH 2 -2-(4-am)-thiaz       257.   3-acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-cyclohexyl-CO-D-           Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       258.   D-Galacturo-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       259.   D-Glucohepto-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       260.   L-Allo-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       261.   D-Allo-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       262.   D-Gluco-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       263.   D-Galacto-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       264.   L-Gluco-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       265.   L-Manno-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       266.   D-Manno-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       267.   D-Cellotrio-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       268.   D-Cellobio-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       269.   D-Glucuronic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       270.   Arabinic AC-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       271.   L-lduronic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       272.   Gluconic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       273.   Heptagluconic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       274.   Lactobionic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       275.   D-Xylonic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       276.   Arabic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       277.   Phenyl-beta-D-Glucuronic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       278.   Methyl-beta-D-Glucuronic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       279.   D-quinic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       280.   Phenyl-alpha-iduronic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       281.   Digalacturonlc-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       282.   Trigalacturonic-NH-CH 2 -p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       283.   3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CONH-CH 2 -p-phenyl-CO-D-Cha-           Pyr-NH-CH 2 -2-(4-am)-thiaz       284.   3-Acetamldo-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CONH-CH 2 -p-phenyl-CO-           D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       285.   D-Galacturo-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       286.   D-Glucohepto-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       287.   L-Allo-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       288.   D-Allo-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       289.   D-Gluco-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       290.   D-Galacto-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       291.   L-Gluco-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       292.   L-Manno-NH-CH 2 -p-phenyl-CH 2 -D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       293.   D-Manno-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       294.   D-Cellotrio-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       295.   D-Cellobio-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       296.   D-Glucuronic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       297.   Arabinic AC-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       298.   L-lduronlc-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       299.   Gluconic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       300.   Heptagluconic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       301.   Lactobionic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       302.   D-Xylonic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       303.   Arabic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       304.   Phenyl-beta-D-Glucuronic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       305.   Methyl-beta-D-Glucuronic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       306.   D-quinic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       307.   Phenyl-alpha-Iduronic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       308.   Digalacturonic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       309.   Trigalacturonic-NH-CH 2 -p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       310.   3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-CH 2 -p-phenyl-CH 2 -CO-D-           Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       311.   3-Acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-CH 2 -p-phenyl-           CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       312.   D-Galacturo-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       313.   D-Glucohepto-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       314.   L-Allo-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       315.   D-Allo-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       316.   D-Gluco-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       317.   D-Galacto-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       318.   L-Gluco-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       319.   L-Manno-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       320.   D-Manno-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       321.   D-Cellotrio-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       322.   D-Cellobio-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       323.   D-Glucuronic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       324.   Arabinic AC-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       325.   L-lduronic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       326.   Gluconic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       327.   Heptagluconic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       328.   Lactobionlc-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       329.   D-Xylonic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       330.   Arabic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       331.   Phenyt-beta-D-Glucuronic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       332.   Methyl-beta-D-Glucuronlc-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       333.   D-quinic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       334.   Phenyl-alpha-Iduronic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       335.   Digalacturonlc-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       336.   Trigalacturonic-NH-p-phenyl-CH 2 -CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       337.   3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyrany[(2)-CO-NH-p-phenyl-CH 2 -CO-D-Cha-           Pyr-NH-CH 2 -2-(4-am)-thiaz       338.   3-Acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-p-phenyl-CH 2 -           CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       339.   D-Galacturo-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       340.   D-Glucohepto-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       341.   L-Allo-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       342.   D-Allo-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       343.   D Gluco-NH-p-henyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       344.   D-Galacto-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       345.   L-Gluco-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       346.   L-Manno-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       347.   D-Manno-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       348.   D-Cellotrio-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       349.   D-Cellobio-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       350.   D-Glucuronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       351.   Arabinic AC-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       352.   L-lduronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       353.   Gluconic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       354.   Heptagluconic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       355.   Lactobionic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       356.   D-Xylonic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       357.   Arabic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       358.   Phenyl-beta-D-Glucuronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       359.   Methyl-beta-D-Glucuronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       360.   D-quinlc-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       361.   Phenyl-alpha-iduronic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       362.   Digalacturonic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       363.   3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-p-phenyl-CO-D-Cha-Pyr-           NH-CH 2 -2-(4-am)-thiaz       364.   3-acetamido-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyranyl(2)-CO-NH-p-phenyl-CO-D-           Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       365.   Trlgalacturonic-NH-p-phenyl-CO-D-Cha-Pyr-NH-CH 2 -2-(4-am)-thiaz       366.   L-Glycer-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       367.   D-Glycer-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       368.   L-Erythro-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       369.   D-Erythro-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       370.   L-Threo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       371.   D-Threo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       372.   L-Arabino-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       373.   D-Arabino-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       374.   L-Ribo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       375.   D-Rlbo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       376.   2-Deoxy-L-Ribo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       377.   D-Fuco-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       378.   D-Xylo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       379.   L-Xylo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       380.   Cellopentao-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       381.   D-Fructo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       382.   Maltotrio-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       383.   Maltotetrao-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       384.   Glucohepto-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       385.   L-Allo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       386.   D-Allo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       387.   L-Gluco-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       388.   D-Manno-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       389.   L-Manno-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       390.   L-Galacto-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       391.   Dextro-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       392.   L-Lyxo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       393.   D-Lyxo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       394.   D-Lacto-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       395.   D-Talo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       396.   L-Talo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       397.   beta-Malto-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       398.   L-Fuco-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       399.   L-Gulo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       400.   D-Gulo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       401.   L-ldo-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       402.   D-Ido-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       403.   D-Celotrio-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       404.   D-Gatacturonic-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       405.   L-Rhamno-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       406.   D-Cellotetrao-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       407.   Maltopentao-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       408.   Xylobio-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       409.   D-Lacto-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       410.   D-Melibio-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       411.   Gentobio-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       412.   D-Rhamno-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       413.   L-Altro-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph       414.   D-Galacto-D-Chg-Pyr-NH-CH 2 -5-(3-am)-thioph                  
 
         [0465]    List of Abbreviations:  
                                       Abu:   2-aminobutyric acid       AIBN:   azobisisobutyronitrile       Ac:   acetyl       Acpc:   1-aminocyclopentane-1-carboxylic acid       Achc:   1-aminocyclohexane-1-carboxylic acid       Aib:   2-aminoisobutyric acid       Ala:   alanine       b-Ala:   beta-alanine (3-aminopropionic acid)       am:   amidino       amb:   amidinobenzyl       4-amb:   4-amidinobenzyl (p-amidinobenzyl)       Arg:   Arginine       Asp:   aspartic acid       Aze:   azetidine-2-carboxylic acid       Bn:   benzyl       Boc:   tert-butyloxycarbonyl       Bu:   butyl       Cbz:   carbobenzoxy       Cha:   cyclohexylalanine       Chea:   cycloheptylalanine       Cheg:   cycloheptylglycine       Chg:   cyclohexylglycine       Cpa:   cyclopentylalanine       Cpg:   cyclopentylglycine       d:   doublet       Dab:   2,4-diaminobutyric acid       Dap:   2,3-diaminopropionic acid       DC:   thin-layer chromatography       DCC:   dicyclohexylcarbodiimide       Dcha:   dicyclohexylamine       DCM:   dichloromethane       Dhi-1-COOH:   2,3-dihydro-1H-isoindole-1-carboxylic acid       DMF:   dimethylformamide       DIPEA:   diisopropylethylamine       EDC:   N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide       Et:   ethyl       Eq:   equivalent       Gly:   glycine       Glu:   glutamic acid       fur:   furan       guan:   guanidino       ham:   hydroxyamidino       HCha:   homocyclohexylalanine, 2-amino-4-cyclohexylbutyric           acid       His:   histidine       HOBT:   hydroxylbenzotriazol       HOSucc:   hydroxysuccinimide       HPLC:   high-performance liquid chromatography       Hyp:   hydroxyproline       Ind-2-COOH:   indoline-2-carboxylic acid       iPr:   isopropyl       Leu:   leucine       Lsg:   solution       Lys:   lysine       m:   multiplet       Me:   methyl       MPLC:   medium-performance liquid chromatography       MTBE:   methyl-tert-butyl ether       NBS:   N-bromosuccinimide       Nva:   norvaline       Ohi-2-COOH:   octahydroindole-2-carboxylic acid       Ohii-1-COOH:   octahydro-isoindole-1-carboxylic acid       Orn:   ornithine       Oxaz:   oxazole       p-amb:   p-amidinobenzyl       Ph:   phenyl       Phe:   phenylalanine       Phg:   phenylglycine       Pic:   pipecolic acid       pico:   picolyl       PPA:   propylphosphonic anhydride       Pro:   proline       Py:   pyridine       Pyr:   3,4-dehydroproline       q:   quartet       RP-18:   reversed phase C 18       RT:   room temperature       s:   singlet       Sar:   sarcosine (N-methylglycine)       sb:   singlet broad       t:   triplet       t:   tertiary (tert)       tBu:   tert-butyl       tert:   tertiary (tert)       TBAB:   tetrabutylammonium bromide       TEA:   triethylamine       TFA:   trifluoroacetic acid       TFAA:   trifluoroacetic anhydride       thiaz:   thiazole       Thz-2-COOH:   1,3-thiazolidine-2-carboxylic acid       Thz-4-COOH:   1,3-thiazolidine-4-carboxylic acid       thioph:   thiophene       1-Tic:   1-tetrahydro-isoquinoline carboxylic acid       3-Tic:   3-tetrahydro-isoquinoline carboxylic acid       TOTU:   O-(cyanoethoxycarbonylmethylene)amino-1-N,N,N′,N′-           tetramethyluronium tetra-fluoroboronate(?)       Z:   carbobenzoxy                  
 
         [0466]    Experimental Section  
         [0467]    The compounds of formula I can be represented by schemes I and II.  
         [0468]    The building blocks A—B, D, E, G and K are preferably made separately and used in a suitably protected form (cf scheme I, which illustrates the use of orthogonal protective groups (P or P*) compatible with the synthesis method used.  
                         
 
         [0469]    Scheme I describes the linear structure of the molecule I achieved by elimination of protective groups from P—K—L* (L* denotes CONH 2 , CSNH 2 , CN, C(═NH)NH—COOR*; R* denotes a protective group or polymeric carrier with spacer (solid phase synthesis)), coupling of the amine H—K—L* to the N-protected amino acid P—G—OH to form P—G—K—L*, cleavage of the N-terminal protective group to form H—G—K—L*, coupling to the N-protected amino acid P—E—OH to produce P—EG—K—L*, re-cleavage of the N-terminal protective group to form H—E—G—K—L* and optionally recoupling to the N-protected building block P—D—U (U=leaving group) to form P—D—E—G—K—L*, if the end product exhibits a building block D.  
         [0470]    If L* is an amide, thioamide or nitrile function at this synthesis stage, it will be converted to the corresponding amidine or hydroxyamidine function, depending on the end product desired. Amidine syntheses for the benzamidine, picolylamidine, thienylamidine, furylamidine, and thiazolylamidine compounds of the structure type I starting from the corresponding carboxylic acid amides, nitriles, carboxythioamides, and hydroxyamidines have been described in a number of patent applications (cf, for example, WO 95/35309, WO 96/178860, WO 96/24609, WO 96/25426, WO 98/06741, and WO 98/09950.  
         [0471]    After splitting-off the protective group P to form H—(D)—E—G—K—L* (L* denotes C(═NH)NH, C(═NOH)NH, or (═NH)NH—COOR*; R* denotes a protective group or a polymeric carrier with spacer (solid-phase synthesis), coupling is effected to the optionally protected (P)—A—B—U building block (U=leaving group) or by hydroalkylation with (P)—A—B′—U (U=aldehyde, ketone) to produce (P)—A—B—(D)—E—G—K—L*.  
         [0472]    Any protective groups still present are then eliminated. If L* denotes a C(═NH)NH spacer polymer support, these compounds are eliminated from the polymeric support in the final stage, and the active substance is thus liberated.  
                         
 
         [0473]    Scheme II describes an alternative route for the preparation of the compounds I by convergent synthesis. The appropriately protected building blocks P—D—E—OH and H—G—K—L* are linked to each other, the resulting intermediate product P—D—E—G—K—L* is converted to P—D—E—G—K—L* (L* denotes C(═NH)NH, C(═NOH)NH, or (═NH)NH—COOR*; R* denotes a protective group or a polymeric support with spacer (solid-phase synthesis), the N-terminal protective group is eliminated, and the resulting product H—D—E—G—K—L* is converted to the end product according to scheme I.  
         [0474]    The N-terminal protective groups used are Boc, Cbz, or Fmoc, and C-terminal protective groups are methyl, tert-butyl and benzyl esters. Amidine protective groups for the solid-phase synthesis are preferably Boc, Cbz, and derived groups. If the intermediate products contain olefinic double bonds, then protective groups that are eliminated by hydrogenolysis are unsuitable.  
         [0475]    The necessary coupling reactions and the conventional reactions for the provision and removal of protective groups are carried out under standardized conditions used in peptide chemistry (cf M. Bodanszky, A. Bodanszky, “The Practice of Peptide Synthesis”, 2nd Edition, Springer Verlag Heidelberg, 1994).  
         [0476]    Boc protective groups are eliminated by means of dioxane/HCl or TFA/DCM, Cbz protective groups by hydrogenolysis or with HF, and Fmoc protective groups with piperidine. Saponification of ester functions is carried out with LiOH in an alcoholic solvent or in dioxane/water. tert-Butyl esters are cleaved with TFA or dioxane/HCl.  
         [0477]    The reactions were monitored by DC, in which the following mobile solvents were usually employed:  
                                                       A. DCM/MeOH   95:5           B. DCM/MeOH    9:1           C. DCM/MeOH    8:2           D. DCM/MeOH/HOAc 50%   40:10:5           E. DCM/MeOH/HOAc 50%   35:15:5                      
 
         [0478]    If column separations are mentioned, these separations were carried out over silica gel, for which the aforementioned mobile solvents were used.  
         [0479]    Reversed phase HPLC separations were carried out with acetonitrile/water and HOAc buffer.  
         [0480]    The starting compounds can be produced by the following methods:  
         [0481]    Building Blocks A—B:  
         [0482]    The compounds used as building blocks A—B are for the most part commercially available sugar derivatives. If these compounds have several functional groups, protective groups are introduced at the required sites. If desired, functional groups are converted to reactive groups or leaving groups (eg, carboxylic acids to active esters, mixed anhydrides, etc.), in order to make it possible to effect appropriate chemical linking to the other building blocks. The aldehyde or keto function of sugar derivatives can be directly used for hydroalkylation with the terminal nitrogen of building block D or E.  
         [0483]    The Synthesis of Building Blocks D is Carried Out as Follows:  
         [0484]    The building blocks D—4-aminocyclohexanoic acid, 4-aminobenzoic acid, 4-aninomethylbenzoic acid, 4-aminomethylphenylacetic acid, and 4-aminophenylacetic acid—are commercially available.  
         [0485]    The Synthesis of the Building Blocks E Was Carried Out as Follows:  
         [0486]    The compounds used as building locks E-glycine, (D)- or (L)-alanine, (D)- or (L)-valine, (D)-phenylalanine, (D)-cyclohexylalanine, (D)-cycloheptylglycine, D-diphenylalanine, etc. are commercially available as free amino acids or as Boc-protected compounds or as the corresponding methyl esters.  
         [0487]    Preparation of cycloheptylglycine and cyclopentylglycine was carried out by reaction of cycloheptanone or cyclopentanone respectively with ethyl isocyanide acetate according to known instructions (H. -J. Prätorius, J. Flossdorf, M. Kula, Chem. Ber. 1985, 108, 3079, or U. Schöllkopf and R. Meyer, Liebigs Ann. Chem. 1977, 1174). Preparation of (D)-dicyclohexylalanine was carried out by hydrogenation after T. J. Tucker et al, J. Med. Chem. 1997, 40., 3687-3693.  
         [0488]    The said amino acids were provided by well-known methods with an N-terminal or C-terminal protective group depending on requirements.  
         [0489]    Synthesis of the Building Blocks G Was Carried Out as Follows:  
         [0490]    The compounds used as building blocks G—(L)-proline, (L)-pipecolinic acid, (L)-4,4-difluoroproline, (L)-3-methylproline, (L)-5-methylproline, (L)-3,4-dehydroproline, (L)-octahydroindole-2-carboxylic acid, (L)-thiazolidine-4-carboxylic acid, and (L)-azetidine carboxylic acid—are commercially available as free amino acids or as Boc-protected compounds or as corresponding methyl esters.  
         [0491]    (L)-Methyl thiazolidine-2-carboxylate was prepared after R. L. Johnson, E. E. Smissman, J. Med.Chem. 21, 165 (1978).  
         [0492]    Synthesis of the Building Blocks K Was Carried Out as Follows:  
         [0493]    p-Cyanobenzylamine  
         [0494]    Preparation of this building block was carried out as described in WO 95/35309.  
         [0495]    3-(6-Cyano)picolylamine  
         [0496]    Preparation of this building block was carried out as described in WO 96/25426 or WO 96/24609.  
         [0497]    5-Aminomethyl-2-cyanothiophen  
         [0498]    Preparation of this building block was carried out as described in WO 95/23609.  
         [0499]    5-Aminomethyl-3-cyanothiophen  
         [0500]    Preparation of this building block was carried out starting from 2-formyl-4-cyanothiophen in a manner similar to that described for 2-formyl-5-cyanothiophen (WO 95/23609).  
         [0501]    2-Aminomethylthiazole-4-thiocarboxamide  
         [0502]    Preparation was carried out according to G. Videnov, D. Kaier, C. Kempter and G. Jung, Angew. Chemie (1996) 108, 1604, where the N-Boc-protected compound described in said reference was deprotected with ethereal hydrochloric acid in dichloromethane.  
         [0503]    5-Aminomethy-2-cyanofuran  
         [0504]    Preparation of this building block was carried out as described in WO 96/17860.  
         [0505]    5-Aminomethyl-3-cyanofuran  
         [0506]    Preparation of this building block was carried out as described in WO 96/17860.  
         [0507]    5-Aminomethyl-3-methylthiophene-2-carbonitrile  
         [0508]    Preparation of this building block was carried out as described in WO 99/37668.  
         [0509]    5-Aminomethyl-3-chlorothiophene-2-carbonitrile  
         [0510]    Preparation of this building block was carried out as described in WO 99/37668.  
         [0511]    5-Aminomethyl-4-methylthiophene-3-thiocarboxamide  
         [0512]    Preparation of this building block was carried out as described in WO 99/37668.  
         [0513]    5-Aminomethyl-4-chlorothiophene-3-thiocarboxamide  
         [0514]    Preparation of this building block was carried out as described in WO 99/37668.  
         [0515]    2-Aminomethyl-4-cyanothiazole:  
         [0516]    a) Boc-2-aminomethylthiazole-4-carboxamide  
         [0517]    To a solution of Boc-glycinethioamide (370 g, 1.94 mol) in 3.9 liters of ethanol there was added ethyl bromopyruvate (386 g, 1.98 mol) dropwise at 10° C., and the mixture was stirred over a period of 5 h at from 20° to 25° C. Then 299 mL of 25% strength aqueous ammonia were added.  
         [0518]    940 mL of this mixture (equivalent to 19.9% of the total volume) were taken and 380 mL of ethanol were removed therefrom by distillation, after which 908 mL of 25% strength aqueous ammonia were added, and the mixture was stirred for 110 h at from 20° to 25° C. The mixture was cooled to 0° C., and the solids were filtered off and washed twice with water and dried. There were obtained 60.1 g of Boc-protected thiazole carboxamide having an HPLC purity of 97.9 areal %, corresponding to a yield for these two stages of 60.5%.  
         [0519]    [0519] 1 H-NMR (DMSO-d6, in ppm): 8.16 (s, 1H, Ar—H), 7.86 (t, broad, 1H, NH), 7.71 and 7.59 (2x s, broad, each 1H, NH 2 ), 4.42 (d, 2H, CH 2 ), 1.41 (s, 9H, tert-butyl).  
         [0520]    b) 2-Aminomethyl-4-cyanothiazole hydrochloride  
         [0521]    Boc-2-aminomethylthiazole 4-carboxamide (75.0 g, 0.29 mol) was suspended in 524 mL of dichloromethane and triethylamine (78.9 g, 0.78 mol) and 79.5 g (0.38 mol) of trifluoroacetic anhydride were added thereto at from −5° to 0° C. Stirring was continued over a period of 1 h, the mixture heated to from 20° to 25° C. and 1190 mL of water added, and the phases were separated. To the organic phase there were added 160 mL of from 5 to 6N isopropanolic hydrochloric acid, and the mixture was heated at boiling temperature over a period of 3 h and then at from 20° to 25° C. overnight with stirring, after which it was cooled to from −5° to 0° C. for 2.5 h prior to removal of the solids by filtering. This solid material was washed with dichloromethane and dried. There were obtained 48.1 g of 2-aminomethylcyanothiazole having an HPLC purity of 99.4 areal %, which is equivalent to a yield for these two stages of 94.3%.  
         [0522]    [0522] 1 H-NMR (DMSO-d6, in ppm): 8.98 (s, broad, 2H, NH 2 ), 8.95 (s, 1 h, Ar—H), 4.50 (s, 2H, CH 2 ).  
         [0523]    5-Aminomethyl-3-amidinothiophene bishydrochloride  
         [0524]    Synthesis of this compound was carried out starting from 5-aminomethyl-3-cyanothiophene by reaction with (Boc) 2 O to form 5-tert-butyl-oxycarbonylaminomethyl-3-cyanothiophene, conversion of the nitrile function to the corresponding thioamide by the addition of hydrogen sulfide, methylation of the thioamide function with iodomethane, reaction with ammonium acetate to produce the corresponding amidine followed by protective group elimination with hydrochloric acid in isopropanol to give 5-aminomethyl-3-amidinothiophene bishydrochloride.  
         [0525]    Building Blocks for Solid-Phase Synthesis:  
         [0526]    3-Amidino-5-[N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]aminomethylthiophene hydrochloride  
         [0527]    3-Amidino-5-aminomethylthiophene bishydrochloride (1.3 g, 5.7 mmol) was placed in DMF (15 mL), and N,N-diisopropylethylamine (0.884 g, 6.84 mmol) was added. Following stirring for 5 min at room temperature there were added acetyldimedone (1.25 g, 6.84 mmol) and trimethoxymethane (3.02 g, 28.49 mmol). Stirring was continued for 2.5 h at room temperature, after which the DMF was removed in high vacuum and the residue was stirred with DCM (5 mL) and petroleum ether (20 mL). The solvent was decanted from the pale yellow product and the solid matter was dried in vacuo at 40° C. Yield: 1.84 g (5.2 mmol, 91%).  
         [0528]    [0528] 1 H-NMR (400 MHz, [D6]DMSO, 25° C., TMS): delta=0.97 (s, 6H); 2.30 (s, 4H); 2.60 (s, 4H); 4.96 (d, J=7 Hz, 2H); 7.63 (s, 1H); 8.60 (s, 1H); 9.07 (sbr, 2H); 9.37 (sbr, 1H.  
         [0529]    Syntheses of Building Blocks H—G—K—CN:  
         [0530]    The synthesis of the H—G—K—CN building block is exemplarily described in WO 95/35309 for prolyl-4-cyanobenzylamide, in WO 98/06740 for 3,4-dehydroprolyl-4-cyanobenzylamide and in WO 98/06741 for 3,4-dehydroprolyl-5-(2-cyano)thienylmethylamide. The preparation of 3,4-dehydroprolyl-5-(3-cyano)thienylmethylamide is similarly carried out by coupling Boc-3,4-dehydroproline to 5-aminomethyl-3-cyanothiophen hydrochloride followed by protective group elimination.  
         [0531]    The synthesis of 3,4-dehydroprolyl-[2(4-cyano)thiazolmethyl]amide hydrochloride was carried out by coupling Boc-3,4-dehydroproline to 2-aminomethyl-4-cyanothiazole hydrochloride followed by protective group elimination.  
         [0532]    H—E—G—K—C(═NOH)NH 2 :  
         [0533]    The synthesis of the building block H—E—G—K—C(═NOH)NH 2  is exemplarily described for H—(D)-Cha-Pyr-NH—CH 2 -2-(4-ham)thiaz  
         [0534]    a) (Boc)-(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(4-cyano)thiazolyl]methylamide  
         [0535]    (Boc)-(D)-Cha-OH (21.3 g, 271.4 mmol) and H-Pyr-NH—CH 2 -2(4-CN)-thiaz hydrochloride (21.3 g, 270.7 mmol) were suspended in dichloromethane (750 mL) and to the suspension there was added ethyldiisopropylamine (50.84 g, 67.3 mL, 393.4 mmol), which gave a clear, slightly reddish solution. The reaction mixture was cooled to ca 10° C., and a 50% strength solution of propylphosphonic anhydride in ethyl acetate (78.6 mL, 102.3 mmol) was added dropwise. Following stirring overnight at RT, the mixture was concentrated in vacuo, the residue taken up in water and the mixture stirred for 30 min to effect hydrolysis of the excess propylphosphonic anhydride. The acid solution was then extracted 3 times with ethyl acetate and once with dichloromethane, the organic phases being washed with water, dried, and evaporated in vacuo in a rotary evaporator. The two residues were combined, dissolved in dichloromethane and precipitated with n-pentane. This procedure was repeated and 33.4 g of (Boc)-(D)-Cha-Pyr-NH—CH 2 -2(4CN)thiaz (yield 87%) were obtained as white solid.  
         [0536]    b) (Boc)-(D)yclohexylalanyl-3,4-dehydroprolyl-[2-(4-hydroxamidino)thiazolyl]methylamide  
         [0537]    (Boc)-(D)-Cha-Pyr-NH—CH 2 -2-(4-CN)-thiaz (26.3 g, 53.9 mmol) was dissolved in methanol (390 mL), to the solution there was added hydroxylamine hydrochloride (9.37 g, 134.8 mmol), and to this suspension diisopropylethylamine (69.7 g, 91.7 mL, 539.4 mmol) was slowly added dropwise, with cooling (water bath). Following agitation at room temperature over a period of 3 h, the reaction solution was evaporated in vacuo in a rotary evaporator, the residue taken up in ethyl acetate/water, and the aqueous phase was set to pH 3 with 2N hydrochloric acid and extracted 3 times with ethyl acetate and once with dichloromethane. The organic phases were washed a number of times with water, dried over magnesium sulphate and evaporated in vacuo in a rotary evaporator. The two residues were combined and stirred with n-pentane to give 26.8 g of (Boc)-(D)-Cha-Pyr-NH—CH 2 -2(4-ham)-thiaz (yield 95%) as a white solid.  
         [0538]    c) (D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(-4-hydroxamidino)thiazolyl]methylamide  
         [0539]    (Boc)-(D)-Cha-Pyr-NH—CH 2 -2(4-ham)-thiaz (5.0 g, 9.6 mmol) was dissolved in a mixture of isopropanol (50 mL) and dichloromethane (50 mL) and to the solution there was added HCl in dioxane (4M solution, 24 mL, 96 mmol) and stirring was continued for 3 h at room temperature. As starting material was still present, HCl in dioxane (4M solution, 12 mL, 48 mmol) was again added and the mixture stirred at room temperature overnight. The reaction mixture was evaporated in vacuo in a rotary evaporator, and co-distilled a number of times with ether and dichloromethane to remove adhering hydrochloric acid. The residue was dissolved in a little methanol and precipitated with a large quantity of ether. There were obtained 4.3 g of H—(D)-Cha-Pyr-NH—CH 2 -2(4-ham)thiaz hydrochloride (yield 98%).  
         [0540]    H—E—G—K—C(═NH)NH 2 :  
         [0541]    The synthesis of the H—E—G—K—C(═NH)NH 2  building block is exemplarily described for H—(D)-Cha-Pyr-NH—CH 2 -2(4-am)thiaz.  
         [0542]    a) (Boc)-(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(4-amidino)thiazolyl]methylamide  
         [0543]    (Boc)-(D)-Cha-Pyr-NH—CH 2 -2-(4-CN)-thiaz (27.0 g, 55.4 mmol) and N-acetyl-L-cysteine (9.9 g, 60.9 mmol) were dissolved in methanol (270 mL), heated under reflux, while ammonia was introduced over a period of 8 h. Since the reaction was still non-quantitative after DC checking, N-acetyl-L-cysteine (2.0 g, 12.0 mmol) was again added and the mixture heated under reflux for a further 8 h with introduction of ammonia. The reaction mixture was then concentrated in vacuo, and the residue was successively stirred in ether and dichloromethane/ether 9:1. The resulting crude product (Boc)-(D)-Cha-Pyr-NH—CH 2 -2(4-am)thiaz, which still contained N-acetyl-L-cysteine, was used without further purification in the next stage.  
         [0544]    b) (D)-cyclohexylalanyl-3,4-dehydroprolyl-[2(4-amidino)thiazolyl]methylamide  
         [0545]    (Boc)-(D)-Cha-Pyr-NH—CH 2 -2(4-am)thiaz (crude product, see above) was dissolved in a mixture of methanol (20 mL) and dichloromethane (400 mL), and to the solution there was added HCl in dioxane (4M solution, 205 mL, 822 mmol) and stirring was continued overnight at room temperature.  
         [0546]    As starting material was still present, HCl in dioxane was again added and stiring carried out overnight at room temperature. The reaction mixture was evaporated in vacuo in a rotary evaporator, and co-distilled a number of times with ether and dichloromethane to remove adhering hydrochloric acid. The residue was taken up in water and extracted 20 times with dichloromethane to remove N-acetyl-L-cysteine, and the aqueous phase was then lyophilized. The lyophilized matter was stirred out from ether to give 31.8 g of H(D)-Cha-Pyr-NH—CH 2 -2(4-am)thiaz dihydrochloride (yield over 2 stages: 81%).  
         [0547]    The preparation of the building block H—E—G—K—C(═NH)NH 2 H—(D)-Chg-Aze-NH 4-amb is described in WO 94/29336 Example 55. H—(D)-Chg-Pyr-NH—CH 2 5-(3-am)-thioph was synthesized in a similar manner to that used for H—(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz, the formation of amidine being effected using the corresponding nitrile precursor Boc-(D)-Chg-Pyr-NH—CH 2 -5-(3-CN)-thioph as described in WO 9806741 Example 1 via intermediate stages Boc-(D)-Chg-Pyr-NH—CH 2 -5-(3CSNH 2 )-thioph and Boc-(D)-Chg-Pyr-NH—CH 2 -5-(3-C(═NH)S—CH 3 )-thioph.  
       EXAMPLE 1  
       [0548]    (D)-Arabino-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xCH 3 COOH  
         [0549]    H—(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz dihydrochloride (2.0 g, 4.19 mmol) was dissolved in methanol (30 mL), and to the solution there were added D-(−)-arabinose (0.63 g, 4.19 mmol) and molecular sieve (4 Angstrom). The mixture was stirred over a period of 1 h at room temperature and sodium cyanoborohydride was then added portion wise, during which operation slight generation of gas occurred. Following stirring overnight at room temperature, the molecular sieve was filtered off in vacuo, the filtrate concentrated in vacuo and the residue stirred in acetone. The crude product filtered off in vacuo was purified by means of MPLC (RP-18 column, acetonitrile/watter/glacial acetic acid) and then lyophilized to give 840 mg of (D)-Arabino-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)thiaz xCH 2 COOH as a white solid (yield 34%).  
         [0550]    ESI-MS: M+H + : 539.  
       EXAMPLE 2  
       [0551]    (L)-Arabino-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xCH 3 COOH  
         [0552]    This compound was synthesized in a manner similar to that described in Example 1 but starting from L-(+)-arabinose.  
         [0553]    ESI-MS: M+H + : 539.  
       EXAMPLE 3  
       [0554]    (D)-Erythro-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-diaz xCH 3 COOH  
         [0555]    This compound was synthesized-in a manner similar to that described in Example 1 but starting from D-(+)-erythrose.  
         [0556]    ESI-MS: M+H + : 509.  
       EXAMPLE 4  
       [0557]    (L)-Erythro-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xCH 3 COOH  
         [0558]    This compound was synthesized in a manner similar to that described in Example 1 but starting from L-(+)-erythrose.  
         [0559]    ESI-MS: M+H + : 509.  
       EXAMPLE 5  
       [0560]    (D)-Glycer-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xCH 3 COOH  
         [0561]    This compound was synthesized in a manner similar to that described in Example 1 but starting from D-(+)-glycerinaldehyde.  
         [0562]    ESI-MS: M+H + : 479.  
       EXAMPLE 6  
       [0563]    (L)-Glycer-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xCI 3 COOH  
         [0564]    This compound was synthesized in a manner similar to that described in Example 1 but starting from L-(+)-glycerinaldehyde.  
         [0565]    ESI-MS: M+H + : 479.  
       EXAMPLE 7  
       [0566]    (L)-Rhamno-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xHCl  
         [0567]    This compound was synthesized in a manner similar to that described in Example 1 but starting from L-rhamnose.  
         [0568]    L-rhamnnose (0.82 g, 5 mmol) was dissolved in water (20 mL) at room temperature and H—(D)-Cha-Pyr-NH—CH 2 -2(4-am)thiaz dihydrochloride (2.4 g, 5 mmol) was stirred in. The clear solution became viscous after 20 min. Sodium cyanoborohydride was added portion wise in an equimolar amount over a period of 4 h to give a white precipitate, which dissolved on the addition of ethanol (2 mL). 5 mL of 1M HCl set the pH to 3 and solid was precipitated 3 times with 300 mL of acetone each time. The solid was removed by centrifugation and dissolved in water (100 mL). Following lyophilization there were obtained 2.6 g of (L)Rhamno-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xHCl as a white powder.  
       EXAMPLE 8  
       [0569]    (D)-Melibio-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xHCl  
         [0570]    This compound was synthesized in a manner similar to that described in Example 7 but starting from D-melibiose.  
         [0571]    D-melibiose (1.8 g, 5 mmol) was dissolved in water (20 mL) at room temperature and H—(D)-Cha-Pyr-NH—CH 2 -2-(4-am)thiaz dihydrochloride (2.4 g, 5 mmol) was stirred in. The clear pale yellow solution became viscous after 20 min. An equimolar amount of sodium cyanoborohydride was added portion wise over a period of 4 h. There was obtained a white solid precipitate, to which 2 mL of ethanol were added to give a clear solution. The pH was set to pH 5 with 5 mL of 1M HCl and precipitation was effected 3 times with 300 mL of acetone each time. Following centrifugation, the sediment obtained was taken up in 100 mL of water and the solution lyophilized.  
         [0572]    Yield: 3,2 g of (D)-Melibio-(D)-Cha-Pyr-NH—CH 2 -2-(4-am)-thiaz xHCl.  
       EXAMPLE 9  
       [0573]    (D)-Gluco-(D)-Chg-Pyr-NH—CH 2 -5-(3-am)-thioph xHCl  
         [0574]    This compound was synthesized in a manner similar to that described in Example 7 but starting from D-glucose.  
         [0575]    D-glucose (1.0 g, 5.6 mmol) was dissolved in 20 mL of water at room temperature and H—(D)-Chg-Pyr-NH—CH 2 -5-(3-am)thioph dihydrochloride (3.0 g, 6.5 mmol) was stirred in. The clear solution became viscous after 10 min. An equimolar amount of sodium cyanoborohydride was added portion wise over a period of 4 h to give a white precipitate. After cooling in an ice bath with 3×5 mL of H2O the mixture were shaken and the sediment was taken up in 20 mL of H 2 O and the pH set to pH 5.0 with ca 5 mL of 0.1 M NaOH. 1st precipitation using 300 mL of acetone. 2nd precipitation: the sediment was taken up in 30 mL of H 2 O and 300 mL of acetone were added. The sediment was dissolved in H 2 O and neutralized with 2 mL of 1M HCl; the solution was then lyophilized. Yield: 1,52 g (D)-Gluco-(D)-Chg-Pyr-NH—CH 2 -5-(3-am)-thioph xHCl als weiβes Pulver.  
       EXAMPLE 10  
       [0576]    Maltohexao-(D)-Chg-Pyr-NH—CH 2 -5-(3-am)-thioph xHCl  
         [0577]    This compound was synthesized in a manner similar to that described in Example 7 but starting from maltohexaose.  
         [0578]    Maltohexaose (2 g, 2 mmol) was dissolved in water (20 mL) at room temperature and H—(D)-Chg-Pyr-NH—CH 2 -5-(3-am)thioph dihydrochloride (0.92 g, 2 mmol) was stirred in. The clear solution became viscous after 10 min; an equimolar amount of sodium cyanoborohydride was added portion wise over a period of 4 h; after cooling in an ice bath, precipitation was effected with 8 volumes of ethanol. The sediment was reprecipitated with 300 mL of ethanol. The sediment was dissolved in water and the solution lyophilized.  
       EXAMPLE 11  
       [0579]    (D)-Cellobio-(D)-Chg-Pyr-NH—CH 2 -5-(3-am)-thioph xHCl  
         [0580]    This compound was synthesized in a manner similar to that described in Example 7 but starting from cellobiose.  
         [0581]    Cellobiose (2 g, 6 mmol) was stirred into water (20 mL) at 50° C. and H—(D)-Chg-Pyr-NH—CH 2 -5(3-am)thioph dihydrochloride (2.8 g, 6 mmol) added. The turbid solution became viscous as an equimolar amount of sodium cyanoborohydride was added portion wise over a period of 4 h. Stirring was continued for approximately one hour at 50° C. Approximately 10 mL of 1 M HCl were aded to set the pH to 3. Precipitation was then effected twice with 300 mL of acetone. Following cooling in an ice bath, the sediment was taken up in 60 mL of water and reprecipitated with 600 mL of acetone. The sediment was dissolved in water and the solution lyophilized. Yield: 4,4 g (D)-Cello-bio-(D)-Chg-Pyr-NE—CH 2 -5(3-am)-thioph xHCl.  
       EXAMPLE 12  
       [0582]    (D)-Glucuronic-(D)-Chg-Pyr-NH—CH 2 -5-(3-am)-thioph  
         [0583]    This compound was synthesized in a manner similar to that described in Example 7 but starting from the sodium salt of D-glucuronic acid.  
         [0584]    The sodium salt of D-glucuronic acid xH2O (1.4 g, 6 mmol) was dissolved in water (20 mL) at room temperature and H—(D)-Chg-Pyr-NH—CH 2 -5-(3-am)thioph dihydrochloride (2.8 g, 6 mmol) was stirred in at room temperature. The clear solution turned pale yellow after 10 min. An equimolar amount of 330 mg of sodium cyanoborohydride was added portion wise over a period of 4 h to give a solid, compact precipitate. 4 mL of 0.1 M NaOH were added and the supernatant was decanted off and the precipitate stirred up in acetone. The sediment was taken up in 40 mL of H 2 O and 3 mL of 1M HCl were added to give a pH of 4. The compound passed into solution. Precipitation was effected with 400 mL of acetone. The sediment was then dissolved in water and the solution lyophilized. Yield: 3,1 g (D)-Glucuronic-(D)-Chg-Pyr-NH—CH 2 -5(3-am)-thioph.  
       EXAMPLE 13  
       [0585]    (D)-Gluco-(D)-Chg-Aze-NH-4-amb xHCl  
         [0586]    This compound was synthesized in a manner similar to that described in Example 7 but starting from D-glucose.  
         [0587]    D-glucose (2.5 g, 14 mmol) was dissolved in water (40 mL) at room temperature and H—(D)-Chg-Aze-NH-4-amb (WO 94/29336 Example 55; 6.8 g; 15.4 mmol) was stirred in. An equimolar amount of sodium cyanoborohydride was added portion wise over a period of 4 h and the mixture was then stirred overnight. There was obtained a greasy, viscous emulsion. 50 mL of water were added, after which ethanol was added until the solution became clear.  
         [0588]    The pH was adjusted to 4.0 with ca 15 mL of 0.1M HCl. 1st precipitation using 600 mL of acetone. 2nd precipitation: the sediment was taken up in 50 mL of water and 600 mL of acetone were added; the sediment was redissolved in water and the solution lyophilized. Yield: 7,8 g (D)-Gluco-(D)-Chg-Aze-NH4-amb xHCl.  
       EXAMPLE 14  
       [0589]    Malto-(D)-Chg-Aze-NH-4-amb xHCl  
         [0590]    This compound was synthesized in a manner similar to that described in Example 7 but starting from maltose.  
         [0591]    Maltose xH 2 O (5 g, 14 mmol) was dissolved in 40 mL of water at room temperature and H-Chg-Aze-NH-4-amb (6.8 g; 15.4 mmol) was stirred in. There followed a portion wise addition of an equimolar amount of sodium cyanoborohydride over a period of 4 h. The initially clear, viscous solution slowly changed to a greasy, viscous emulsion. 50 mL of water were added followed by ca 15 mL 0.1 M HCl to give a pH of 4.0. 1st precipitation using 600 mL of acetone. 2nd precipitation: the sediment was taken up in 50 mL of water and 600 mL of acetone were added; the sediment was redissolved in water and the solution lyophilized. Yield: 10,1 g Malto-(D)-Chg-Aze-NH-4-amb xHCl.  
       EXAMPLE 15  
       [0592]    (L)-Erythro-(D)-Cha-Pyr-NH—CH 2 -2-(4-ham)-thiaz xCH 3 COOH  
         [0593]    This compound was synthesized in a manner similar to that described in Example 1 but starting from L-(+)-erythrose and H—(D)-Cha-Pyr-NH—CH 2 -2-(4-ham)thiaz.  
         [0594]    ESI-MS: M+H + : 525.  
       EXAMPLE 16  
       [0595]    (L)-Arabino-(D)-Cha-Pyr-NH—CH 2 -2-(4-ham)-thiaz xCH 3 COOH  
         [0596]    This compound was synthesized in a manner similar to that described in Example 1 but starting from L-(+)-arabinose and H—(D)-Cha-Pyr-NH—CH 2 -2-(4-ham)thiaz.  
         [0597]    ESI-MS: M+H + : 555.  
       Example 17  
       [0598]    Malto-(D)-Cha-Pyr-NH—CH 2 -2-(4-ham)-thiaz  
         [0599]    This compound was synthesized in a manner similar to that described in Example 1 but starting from maltose.  
         [0600]    H—(D)-Cha-Pyr-NH—CH 2 -2-(4-ham)-thiaz Maltose xH2O(2.2 g, 6 mmol) was dissolved in 40 mL of water and 60 mL of ethanol at room temperature and H—(D)-Cha-Pyr-NH—CH 2 -2-(4ham)-thiaz (2.8 g, 6.6 mmol) was stirred in. The portion wise addition of an equimolar amount of sodium cyanoborohydride over a period of 8 h gave a highly viscous, clear, brownish solution. 1st precipitation using 500 mL of acetone. The sediment was dissolved in 50 mL of water and set to pH 7.5 with 0.1 M of HCl followed by precipitation with 500 mL of acetone. The sediment was dissolved in 100 mL of water and the solution lyophilized. Yield: 3,6 g Malto-(D)-Cha-Pyr-NH—CH 2 -4-ham)thiaz.  
         [0601]    For the following compounds, the thrombin time was determined according to Example A:  
                                                                 Example No.   Thrombin time EC 100  [mol/L]                                        10    2.4E−08           12    1.4E−08           9    1.5E−08           11    2.1E−08           14    2.1E−08           13    2.1E−08           8   1.64E−08           7   9.68E−09           2    1.4E−08