DE10124041A1 - New peptide-type compounds, useful as protease, especially thrombin, inhibitors for treating e.g. thrombosis and cardiac infarct - Google Patents

Abstract

Peptide derivatives (I), their tautomers, stereoisomers (or mixtures) and salts. Peptide derivatives of formula (I), their tautomers, stereoisomers (or mixtures) and salts are new. A = aryl, 3-8C cycloalkyl or cycloalkenyl, optionally fused to phenyl (all optionally substituted by 1-5 halo, OH, SH, CN, CF3, formyl, 1-8C alkylcarbonyl, carboxy, 1-4C alkoxycarbonyl, COOH, 1-4C alkylcarbonyloxy, 1-16C alkyl, 1-8C alkoxy (optionally substituted by 1-8C alkyl), 1-8C alkyl (substituted by 1-8C alkoxy), formyl, or 1-8C alkylcarbonyl), NO2, amino or carboxamido (both optionally substituted by 1-2 1-4C alkyl), 1-4C alkylcarbonylamino, also, for at least partly saturated rings, oxo, and all substituents other than oxo may be present on fused phenyl; D = O or S(O)x; x = 0-2; X = O, S or NR3; R1-R3 = H, 1-16C alkyl, 1-8C alkoxy, 1-8C alkylcarbonyl, 1-4C alkoxycarbonyl, 1-4C alkylcarbonyloxy, 1-8C alkoxy optionally substituted by 1-8C alkyl, 1-8C alkyl substituted by 1-8C alkoxy, formyl, or 1-8C alkylcarbonyl, NO2, amino or carboxamido (both optionally substituted by 1-2 1-4C alkyl), 3-5C cycloalkyl, aryl or benzyl; Y = aryl, 3-8C cycloalkyl or cycloalkenyl, (all of which may be substituents on 1-8C alkyl, alkoxy or 1-8C alkylcarbonyl), all optionally fused to phenyl and optionally substituted as specified for A; E, Z = H, halo, OH, SH, CF3, CN, formyl, 1-8C alkylcarbonyl, carboxy, 1-4C alkoxycarbonyl, COOH, 1-4C alkylcarbonyloxy, 1-16C alkyl, 1-8C alkoxy optionally substituted by 1-8C alkyl, 1-8C alkyl substituted by 1-8C alkoxy, formyl, or 1-8C alkylcarbonyl, NO2, amino or carboxamido (both optionally substituted by 1-2 1-4C alkyl), 1-4C alkylcarbonylamino, aryl, 3-8C cycloalkyl or cycloalkenyl, or 8-12C bicycloalkyl (the last four groups may be linked through CO, 1-8C alkyl, alkoxy, or alkylcarbonyl, aminocarbonyl or 1-8C alkylaminocarbonyl), where all rings may be fused to phenyl and optionally substituted as for A.

Description

The invention relates to pharmacologically active compounds which Are protease inhibitors, such as serine proteases (in particular thrombin), their manufacture and their use as medicines.

Proteases are enzymes that selectively bind proteins to specific peptide bonds columns. They can be divided into four main classes: serine, cysteine, Aspartyl and metalloproteases. Proteases regulate many physiological Processes such as digestion, immune defense, wound healing, differentiation and Apoptosis. Faulty proteolysis leads to diseases such as Arthritis and emphysema. Protease inhibitors are therefore often promising Starting materials in drug development.

Serine proteases include enzymes such as cathepsin G, elastase, trypsin, Chymotrypsin, Thrombin and Factor Xa. Cathepsin G and Elastase are from Leukocytes released in inflamed areas. Inhibitors of these two Enzymes often have an anti-inflammatory effect and are therefore potential active ingredients for the treatment of gout, arthritis or others inflammatory diseases. Digestive enzyme inhibitors Chymotrypsin and trypsin are e.g. B. in disease of the pancreas used.

The serine protease thrombin is a multifunctional protein that Platelets, leukocytes, endothelial and smooth muscle cells and neurons influenced in many ways (Taparelli et al., Trends in Pharmacological  Sciences (1993) 14: 366-376). Thrombin plays through its influence on the Blood coagulation plays a central role in hemostasis (preventing an blood loss caused by injured blood vessels) and thrombosis (the pathological occlusion of a blood vessel) by a blood clot (Thrombus).

The activation of thrombin is the result of a complex series enzymatic reactions by an intrinsic and an extrinsic Signal path can be triggered (Wiley M. R. & Fisher M. J., Exp. Opin. Ther. Patents (1997), 7: 1265-1282). The intrinsic system is triggered when the blood comes into contact with a surface other than that Inside of the vessels. The extrinsic system is activated when a Injury various factors can be released from the tissue.

Thrombin catalyzes several reactions: by proteolytic cleavage of Fibrinopeptides it converts fibrinogen into fibrin monomers, which too Filaments aggregate and become insoluble by the action of factor XIII Cross-linked fibrin (formation of a blood clot). Also activated Thrombin other enzymes in the blood coagulation cascade, such as factors V, VII, VIII and XIII. Thrombin is also stimulated via the thrombin receptor Platelets, this process may result in a. for adhesion and aggregation of Platelets on the injured vascular endothelium.

Because insoluble fibrin and stimulated platelets are the main components of Are blood clots, are substances that inhibit the activity of thrombin, potential active ingredients for diseases such as thrombosis, heart attack, Stroke and arthritis. Thrombin inhibitors are called anticoagulants also applied to materials used to make instruments  and blood collection and transfusion devices such as Catheters and blood dialysis machines can be used.

The need for protease inhibitors, especially thrombin inhibitors, is therefore very large.

Different approaches are particularly potent in developing low molecular weight thrombin inhibitors (Wiley M. R. & Fisher M. J., Exp. Opin. Ther. Patents (1997), 7: 1265-1282). The main approach is based on Tripeptides and peptide mimetics that determine the structure of fibrinogen Mimicking the binding site, one of the natural thrombin substrates. On another approach uses modified arginine tertiary amide derivatives. A number of small organic thrombin inhibitors have also been found through structure-based drug design and through the screening of Natural product libraries or developed from synthetic compounds.

Synthetic thrombin inhibitors are interesting because the Commonly used heparin therapy is often undesirable Shows side effects (e.g. risk of bleeding). The only one currently approved Thrombin inhibitor argatroban has been induced in patients with heparin Thrombocytopenia (HIT) successfully applied (Lewis B.E. et al., Semin. Thromb. Hemost. (1997) 23: 197-202).

The introduction of synthetic thrombin inhibitors as drugs Treatment for cardiovascular disease has come from several Founded as a relatively lengthy process: Although the use of synthetic thrombin inhibitors as anticoagulants since the mid-1970s Years of research, became the first synthetic thrombin inhibitor (Argatroban) only approved as a medicine in 1990. Most synthetic  However, thrombin inhibitors are still experimental or preclinical Development phase (Hauptmann J. & Sturzbecher J., Thrombosis Research (1999) 93: 203-241). This is often due to the very low oral Bioavailability of the substances.

There is therefore a constant need for new chemical substances that represent potent and selective protease inhibitors and which are an improved one Have bioavailability and fewer side effects.

The aim of the invention is to provide such chemical substances.

The invention relates to compounds of the formula I.

where A, D, R ¹ , R ² , X, Y, E and Z have the following meaning:
A: aryl, C _3-8 -cycloalkyl, C _3-8 -cycloalkenyl, it being possible for a phenyl ring to be fused onto each ring and all the radicals mentioned optionally having up to five identical or different radicals selected from -F, -Cl, -Br, -I, -OH, -SH, - CF ₃ -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, -OCHO, -OC (O) - C _1-4 alkyl, C _1-16 alkyl, C _1-8 alkyloxy, C _1-8 alkyloxy C _1-8 alkyl, C _1-8 alkyl C _1-8 -Alkyloxy-, HC (O) -C _1-8 alkyl-, C _1-8 alkyl-C (O) -C _1-8 -alkyl-, -NO ₂ , -NH ₂ , - NH-C _1-4 -Alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) -N (C _1-4 -Alkyl) ₂ , -NHC (O) -C _1-4 -alkyl or, if the rings are at least partially saturated, can carry oxo (= O), these residues (with the exception of = O) also being fused on Phenyl ring can be located;
D: -O-, -S-, -S (O) -, -S (O ₂ ) -;
R ¹ and R ² : independently of one another -H, C ₁ -C ₁₆ -alkyl-, C _1-8 -alkoxy-, -C (O) - C _1-8 -alkyl, -COOC _1-4 -alkyl, - OC (O) -C _1-4 alkyl, C _1-8 alkyloxy-C _1-8 alkyl, C _1-8 alkyl C _1-8 alkyloxy, HC (O) -C _{1- 8} alkyl-, C _1-8 alkyl-C (O) -C _1-8 alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) - N (C _1-4 -alkyl) ₂ , -NHC (O) -C _{1 -4} alkyl, C _3-5 cycloalkyl, aryl, benzyl;
X: -O-, -S-, -N (R ³ ) -, wherein
R ³ : -H, C ₁ -C ₁₆ alkyl, C _1-8 alkoxy, -C (O) -C _1-8 alkyl, -COOC _1-4 alkyl, -OC (O) - C _1-4 alkyl, C _1-8 alkyloxy-C _1-8 alkyl, C _1-8 alkyl C _1-8 alkyloxy, HC (O) -C _1-8 alkyl, C _1-8 alkyl-C (O) -C _1-8 alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C ( O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) -N (C _1-4 -alkyl) ₂ , -NHC (O) -C _1-4 -alkyl, C _3-5 cycloalkyl, aryl, benzyl;
Y: aryl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, aryl C _1-8 alkyl, C _3-8 cycloalkyl C _1-8 alkyl, C _3-8 -Cycloalkenyl-C _1-8 -alkyl-, aryl-C _1-8 -alkoxy-, C _3-8 - cycloalkyl-C _1-8 -alkoxy-, C _3-8 -cycloalkenyl-C _1-8 -alkoxy- , Aryl-C _1-8 alkyl-C (O) -, C _3-8 -cycloalkyl-CigAlkyl-C (O) -, C _3-8 -cycloalkenyl-C _1-8 alkyl-C (O) -, whereby a phenyl ring can be fused onto each ring and all the radicals mentioned optionally have up to five identical or different radicals selected from -F, -Cl, -Br, -I, -OH, -SH, -CF ₃ -CN, -CHO, - C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, -OCHO, -OC (O) -C _1-4 alkyl, C _1-16 alkyl, C _{1- 8} -alkyloxy, C _1-8 -alkyloxy-C _1-8 - alkyl, C _1-8 alkyl-C _1-8 alkyloxy-, HC (O) -C _1-8 alkyl, C _{1- 8} alkyl-C (O) -C _1-8 -alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O ) NH ₂ , -C (O) -NH- C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or if so it is at least partially saturated rings Oxo (= O) can carry, the se residues (with the exception of = O) may also be on the fused phenyl ring;
E and Z together or independently of one another -H, -F, -Cl, -Br, -I, hydroxyl, thio, trifluoromethyl, cyano, formyl, -C (O) -C _1-8 -alkyl, carboxyl, -COOC _{1 -4} - alkyl, -OCHO, -OC (O) -C _1-4 alkyl, C _1-16 alkyl, C _1-8 alkyloxy, C _1-8 alkyloxy C _1-8 alkyl -, C _1-8 alkyl-C _1-8 alkyloxy-, HC (O) -C _1-8 alkyl-, C _1-8 alkyl-C (O) -C _1-8 - alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 alkyl , -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl aryl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _8-12 bicycloalkenyl, aryl C (O), C _3-8 cycloalkyl C (O), C _3-8 cycloalkenyl C (O), C _8-12 bicycloalkenyl C ( O) -, aryl-C _1-8 alkyl, C _3-8 cycloalkyl-C _1-8 alkyl, C _3-8 cycloalkenyl-C _1-8 alkyl, C _8-12 bicycloalkenyl -C _1-8 - alkyl-, aryl-C _1-8 -alkoxy-, C _3-8 -cycloalkyl-C _1-8 -alkoxy-, C _3-8 -cycloalkenyl- C _1-8 -alkoxy-, C _8-12 bicycloalkenyl-C _1-8 alkoxy-, aryl-C _1-8 alkyl-C (O) -, C _3-8 - cycloalkyl-C _1-8 alkyl-C (O) -, C _{3- 8-} cycloalkenyl-C _1-8 alky l-C (O) -, C _8-12 - bicycloalkenyl-C _1-8 -alkyl-C (O) -, aryl-NH-C (O) -, C _3-8 -cycloalkyl-NH-C (O) - , C _3-8 -cycloalkenyl-NH-C (O) -, C _8-12 -bicycloalkenyl-NH-C (O) -, aryl-C _1-8 -alkyl-NH-C (O) -, C _{3 -8-} Cycloalkyl-C _1-8 -alkyl-NH-C (O) -, C _3-8 -cycloalkenyl-C _1-8 -alkyl-NH-C (O) -, C _8-12 -bicycloalkenyl-C _1-8 -Alkyl-NH-C (O) -, where a phenyl ring can be fused to each ring and all the mentioned radicals of the ring (s) optionally up to five identical or different radicals selected from -F, -Cl, -Br, -I, -OH, -CF ₃ -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, -OCHO, -OC (O) -C _{1 -4} -alkyl, C _1-16 -alkyl-, C _1-8 -alkyloxy-, C _1-8 -alkyloxy-C _1-8 -alkyl-, C _1-8 - alkyl-C _1-8 -alkyloxy- , HC (O) -C _1-8 alkyl, C _1-8 alkyl-C (O) -C _1-8 alkyl, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl , -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 alkyl, -C (O) - N (C _1-4 alkyl) ) ₂ , -NHC (O) -C _1-4 alkyl or, if the rings are at least partially saturated rings, can carry oxo (= O), these being Residues (with the exception of = O) may also be on the fused phenyl ring, or
if E is -C (O) - then Z can be a primary or secondary amine, its tautomers, stereoisomers, mixtures and salts.

Compounds of the formula I in which A, D, R ¹ , R ² , X, Y, E and Z have the following meanings are preferred:
A: phenyl, optionally up to five identical or different radicals selected from -F, -Cl, -Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-4 -alkyl, -COOH, -COOC _1-4 -alkyl, C _1-4 -alkyl-, C _1-4 -alkyloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, - N (C _{1 -4-} alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) -N (C _1-4 -alkyl) ₂ , -NHC ( Can carry O) -C _1-4 alkyl;
D: -S-;
R ¹ and R ² : independently of one another -H, C _1-4 -alkyl-, C _1-4 -alkyloxy-, -C (O) -C _1-4 -alkyl;
X: -N (R ³ ) -, wherein
R ³ : -H, C _1-4 alkyl, C _1-4 alkyloxy, -C (O) -C _1-4 alkyl;
Y: - (CH ₂ ) _n -R ⁴ , where
n: 0, 1, 2, 3 or 4 and
R ⁴ : aziridine, oxirane, acetidine, oxetane, thiethan, pyrrolidine, tetrahydrofuran, thiolan, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepan, pyrrole, furazole , Pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, azepine, each residue optionally being up to five identical or different substituents selected from -F, -Cl, Br , -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 -Alkyloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or, if the rings are at least partially saturated, oxo (= O) can wear;
E: -C (O) -;
Z: primary or secondary amine, -OH, OC _1-4 alkyl, -NR ⁵ R ⁶ , wherein
R ⁵ , R ⁶ independently of one another: -H, - (CH ₂ ) _m -R ¹² , - (C ₂ H ₄ O) _o -CH ₂ -R ¹² , where
m, o is independently 0, 1, 2, 3 or 4 and
R ¹² : -H, -F, -Cl, -Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 - Alkyl, C _1-4 alkyl, C _1-4 alkyloxy, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or
Phenyl, aziridine, oxirane, acetidine, oxetane, thiethan, pyrrolidine, tetrahydrofuran, thiolan, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyridine Is imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, azepine, where a phenyl ring can be fused to each ring and each residue optionally having up to five identical or different substituents selected from -F, -Cl, Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _{1- 4} -alkyl-, C _1-4 -alkyloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or if it is at least partially saturated rings acts oxo (= O); or
Z: a radical of formula II

wherein
G: a bond or -O-, -S-, -NR ⁷ -, -CR ⁷ R ^{7 '} -, -CH ₂ -O-, -CH ₂ -S-, -CH ₂ - NR ⁷ -, -CH ₂ -CR ⁷ R ^{7 '} - and
R ⁷ , R ⁸ together form a ring selected from pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, pyrrole, furan, dihydrofuran, thiophene, pyolazole, pyrazole, pyrazole , Isoxazole, thiazole, isothiazole, triazole, thiadiazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, where a phenyl ring may be fused to each ring and R ^{7 '} , R ⁹ , R ¹⁰ , R ¹¹ independently of one another have the following meaning have or
R ⁷ , R ^{7 '} , R ⁸ , R ⁹ R ¹⁰ , R ¹¹ independently of one another: -H, -F, -Cl, -Br, -OH, -CF ₃ , - CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 alkyloxy, -NO ₂ , -NH ₂ , -NH-C _1-4 -Alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 -alkyl, -C (O) -N (C _1-4 -Alkyl) ₂ , -NHC (O) -C _1-4 -alkyl or
Phenyl, aziridine, oxirane, acetidine, oxetane, thiethan, pyrrolidine, tetrahydrofuran, thiolan, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyridine Imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, azepine, each residue optionally being up to five identical or different substituents selected from -F, -Cl, -Br , -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 - Alkyloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or, if the rings are at least partially saturated, oxo (= O ) can carry, their tautomers, stereoisomers, mixtures and salts.

Compounds of the formula I in which A, D, R ¹ , R ² , X, Y, E and Z have the following meanings are particularly preferred:
A: phenyl, optionally up to five identical or different radicals selected from -F, -Cl, -Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-4 -alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 alkyloxy, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _{1 -4-} alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) -N (C _1-4 -alkyl) ₂ , -NHC ( Can carry O) -C _1-4 alkyl;
D: -S-;
R ¹ and R ² : independently of one another -H, C _1-4 alkyl-, C _1-4 -alkyloxy-, -C (O) -C _1-4 -alkyl;
X: -NH- or -N (CH ₃ ) -
Y: - (CH ₂ ) _n -R ⁴ , where
n: 0, 1, 2, 3 or 4 and
R ⁴ : furanyl (preferably furan-2-yl) or thiazolyl (preferably thiazol-4-yl);
E: -C (O) -;
Z: -OH, -OCH ₃ , -NR ⁵ R ⁶ , wherein
R ⁵ : H;
R ⁶ : -H, - (CH ₂ ) _m -R ¹² , - (C ₂ H ₄ O) _o -CH ₂ -R ¹² , where
m, o is independently 0, 1, 2, 3 or 4 and
R ¹² : -H, -OH, -OCH ₃ -CN, -CHO, -C (O) CH ₃ , -COOH, -COOCH ₃ , -NH ₂ , -NH- CH ₃ , -N (CH ₃ ) ₂ , -C (O) NH ₂ , -C (O) -NH-CH ₃ , -C (O) -N (CH ₃ ) ₂ , -NHC (O) -CH ₃ or
Phenyl, pyridine (preferably -2-yl), imidazole (preferably linked via N, -2-yl or -4-yl), indole (preferably -3-yl), thiazole (preferably -2-yl), thiadiazole (preferred 1,3,4-thiadiazol-5-yl), morpholine (preferably linked via N), pyrrolidine (preferably -2-yl), piperazine (preferably linked via N), furan (preferably -2-yl), pyrazole (preferred -3-yl), where each radical can optionally contain up to three identical or different substituents selected from chloro, cyano, methoxy, methyl, ethyl or
Z: a radical of formula II

wherein
G: a bond or -O-, -S-, -NR ⁷ -, -CR ⁷ R ^{7 '} -, -CH ₂ -O-, -CH ₂ -S-, -CH ₂ - NR ⁷ -, -CH ₂ -CR ⁷ R ^{7 '} - and
R ⁷ , R ^{7 '} , R ⁸ , R ⁹ R ¹⁰ , R ¹¹ independently of one another: -H, -OH, -C (O) -CH ₃ , methyl, ethyl, hydroxymethyl, hydroxyethyl, -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NR ¹³ R ¹⁴ , wherein
R ¹³ , R ¹⁴ independently of one another are H, methyl, ethyl or
Phenyl (preferably 4-chlorophenyl or 4-acetylphenyl), 2-keto-benzimidazoline (preferably -1-yl), their tautomers, stereoisomers, mixtures and salts.

The following compounds according to formula III are also

the tautomers, stereoisomers, mixtures and salts of the invention:

In the description and the claims apply to the individual Substituents / residues have the following definitions:

The term "cycloalkyl" by itself or as part of another substituent includes saturated, cyclic hydrocarbon groups which contain the stated number of carbon atoms and in which up to three CH ₂ groups can be replaced by oxygen, sulfur or nitrogen atoms. C _3-8 - Cycloalkyl refers to saturated rings with 3 to 8 carbon atoms such as. B. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl-cyclohexyl, cyclohexylmethylene, cycloheptyl or cyclooctyl, aziridine, oxirane, acetidine, oxetane, thiethan, pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, imidazolidine, oxazolidine, oxazolidine, oxazolidine, oxazolidine, oxazolidine Piperidine, piperazine, morpholine, thiomorpholine, azepan.

The term "cycloalkenyl" by itself or as part of another substituent includes cyclic radicals which contain the stated number of carbon atoms and contain at least one double bond, in which up to three ring carbons can be replaced by oxygen, sulfur or nitrogen atoms. C _3-8 cycloalkenyl refers to unsaturated rings with 3 to 8 carbon atoms such as. B. cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 4-methylcyclohexenyl, cyclohexenylmethylene, cycloheptenyl, cyclooctenyl, pyrrole, furan, dihydrofuran, thiophene, pyrazole, imidazole, oxazole, isoxazol, thiazoliazole, thiazole, thiazole, thiazole , Pyran, pyridazine, pyrimidine, pyrazine, triazine, azepine.

The term "bicycloalkenyl" by itself or as part of another substituent includes bicyclic radicals which contain the stated number of carbon atoms and contain at least one double bond, in which up to four ring carbons can be replaced by oxygen, sulfur or nitrogen atoms. C _8-12 bicycloalkenyl refers to unsaturated rings with 8 to 10 ring atoms such as. B. pteridine, purine.

The term "alkyl" by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case, which may be saturated or unsaturated and in which up to five CH ₂ groups are replaced by oxygen, sulfur or nitrogen atoms could be. The heteroatoms are separated from one another by at least two carbon atoms. So C _1-4 alkyl means z. B. methyl, hydoxymethyl, ethyl, hydroxyethyl, vinyl, 1-propyl, 2-propyl, allyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 1-but-2-enyl, 2-butyl, C _1-6 alkyl e.g. B. C _1-4 alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3,3-dimethyl-butyl , C _1-8 alkyl means, in addition to the radicals specified for C _1-4 alkyl, for. B. C _1-6 alkyl, heptyl, 2- (2-methoxyethoxy) ethyl or octyl.

The term "alkoxy" by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case, which may be saturated or unsaturated and is bonded to the parent compound in question via an oxygen atom, with up to four CH ₂ - Groups can be exchanged for oxygen atoms, there being at least two carbon atoms between two oxygen atoms. So C _1-4 - alkoxy means z. B. methoxy, ethoxy, 2-hydroxyethoxy, 1-propoxy, 2-propoxy, allyloxy, 2-methyl-2-propoxy, 2-methyl-1-propoxy, 1-butoxy, 2-butoxy.

The term "aryl" by itself or as part of another substituent includes mono-, bi- or tricyclic aromatic hydrocarbons, such as phenyl, Naphthyl, tetralinyl, indenyl, fluorenyl, indanyl, anthracenyl, phenanthrenyl.

The new compounds can be used to combat or prevent thromboembolic events such as venous and arterial thrombosis, Pulmonary embolism, unstable angina, cerebrovascular diseases, Atrial fibrillation and heart attack are used.

They can also be used to treat atherosclerosis, osteoporosis and Disseminated intravascular coagulation (DIC) can be used.

In particular, they are suitable in combination therapy with thrombolytics Shortening the reperfusion time and lengthening the reocclusion time and They can help prevent reocclusions after bypass surgery or percutaneous transluminal coronary angioplasty (PTCA) can be used.  

Furthermore, these compounds have an effect on and prevent tumor cells the formation of metastases. Thus, they can be used as anti-tumor agents become.

In addition, they can be genetically determined or acquired for therapy Disorders of cell interactions with each other or with solid ones Structures are used.

Other areas of application are inflammatory diseases such as asthma, Arthritis, pancreatitis, rhinitis, and urticaria.

The invention further relates to a process for the preparation of preferred compounds III

in which
A: phenyl, which can optionally carry up to five identical or different radicals selected from -Cl, -Br, -OCH ₃ , -CF ₃ ;
Y: - (CH ₂ ) _n -R ⁴ , where
n: 0, 1, 2, 3 or 4 and
R ⁴ : furanyl (preferably furan-2-yl) or thiazolyl (preferably thiazol-4-yl);
and Z is a primary or secondary amine,
the steps comprehensively

• a) Implementation of amino-terminated tetagel synthetic resin with Rinklinker with 4-carboxybenzenesulfonamide;
• b) reaction of the immobilized sulfonamide with an appropriately protected amino acid H ₂ N-CH (Y) -COOH;
• c) implementation of the deblocked amino function with the acid AS-CH ₂ - COOH;
• d) activation of the sulfonamide with iodoacetonitrile;
• e) insertion of a primary or secondary amine Z with simultaneous Cleavage from synthetic resin.

For example, the 9-fluorenylmethoxycarbonyl (Fmoc) protecting group can be used. The amino acid can be in the D, L or racemate form. This results in the following reaction scheme:

An alternative process for the production of preferred compounds III comprises the steps:

• a) coupling of an appropriately protected amino acid H ₂ N-CH (Y) - COOH to Wang resin;
• b) reaction of the deblocked amino function with the acid AS-CH ₂ - COOH;
• c) cleavage from the solid phase using trifluoroacetic acid;  
• d) reaction of the free carboxylic acid with a primary or secondary amine Z in solution.

For example, the 9-fluorenylmethoxycarbonyl (Fmoc) protecting group can be used. The amino acid can be in the D, L or racemate form. This results in the following reaction scheme:

EXAMPLES

In the examples, the following numbering is used for the connections:

example 1 Synthesis of compounds 1-46 a) Preparation of the compounds (1-4, 10, 14-15, 17, 29-34, 36, 39, 40)

In all subsequent experiments, a disposable PP syringe was used as the reaction vessel PP frit. The appropriate resin was weighed directly into the syringe and pre Start the test with the respective solvent for 10 min. pre-swollen.

Coupling between tentagel resin and Fmoc-Rink linker

The Fmoc-Rink linker was dissolved with the HATU in 0.5 ml DMF, the base was added and added the solution to the resin. The suspension was shaken for 1.5 hours and the Reaction solution separated from the resin. The resin was then applied several times with DMF washed. To remove the Fmoc protective group, the resin was mixed with a solution for 30 minutes incubated by 25% piperidine in DMF. The resin was then washed five times with DMF.

Coupling with 4-carboxybenzenesulfonamide

The chemicals were dissolved in 0.3 ml DMF and added to the resin. The suspension was shaken for 3 hours. The reaction solution was separated from the resin and that Resin thoroughly washed with DMF.

Coupling of Fmoc-L-4-thiazolylalanine or Fmoc-L-2-furylalanine

The respective amino acids were dissolved in 0.3 ml DMF with HATU and the base Resin added and the suspension shaken for 2 hours. The reaction solution was dated Resin separated and the resin washed several times with DMF. Then the Remove the Fmoc protective group as described above and the resin again thoroughly with DMF washed.

Coupling of 4-chlorophenylthioacetic acid

The chemicals mentioned were dissolved in 0.3 ml DMF, added to the resin and the Shaken suspension for 1 hour. The reaction solution was separated from the resin and this washed several times with DMF.

Activation step with iodoacetonitrile

The resin was first washed several times with NMP. Then that was Iodine acetonitrile dissolved in 0.3 ml of NMP and the base added. The reaction solution was added to the resin and the suspension shaken for 12 hours. The deep brown colored Reaction solution was separated from the resin and this was repeated several times with NMP and THF washed.  

Substitution with amines

chemicals
various amines: 0.323 mmol

The respective amine was dissolved in 0.3 ml of THF and added to the resin. The suspension was shaken overnight, the reaction solution was separated from the resin and the resin washed several times with a little THF. The combined washing solutions were with Acidified with a mixture of 3/2 (v / v) acetonitrile / water + 0.1% Trifluoroacetic acid diluted and purified using preparative LC-MS.

The overall yield of the synthesis fluctuated depending on the amine used between 10-70%.

Characterization of the compounds produced using LC-MS 1

2- (4-chlorophenylsulfanyl) -N- [1-furan-2-ylmethyl-2-oxo-2- (1,3,4,9-tetra-hydro-beta-carbolin-2-yl) ethyl] - acetamide
LC-MS: m / z (M +) = 494
Ber. MW = 494.01

2

2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-furan-2-yl-N- (3,4,5-trimethoxybenzyl) propionamide
LC-MS: m / z (M +) = 519
Ber. MW = 519.01

3

2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-furan-2-yl-N- (2-pyridin-2-yl-ethyl) propionamide
LC-MS: m / z (M +) = 444
Ber. MW = 443.95

4

2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-furan-2-yl-N- (3-imidazol-1-yl-propyl) propionamide
LC-MS: m / z (M +) = 447
Ber. MW = 446.96

10

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (3-imidazol-1-yl-propyl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 464
Ber. MW = 464.01

29

N-benzyl-2- [2- (4-chlorophenylsulfanyl) -acetylamino] -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 446
Ber. MW = 445.99

30

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (2,4-dichlorobenzyl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 515
Ber. MW = 514.88

32

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- [2- (1H-imidazol-4-yl) ethyl] -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 450
Ber. MW = 449.99

33

2- [2- (4-chloro-phenylsulfanyl) -acetylamino] -N-propyl-3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 398
Ber. MW = 397.95

40

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (2-piperazin-1-yl-ethyl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 467
Ber. MW = 468.04

14

2- (4-chloro-phenylsulfanyl) -N- (1-furan-2-ylmethyl-2-oxo-2-piperidin-1-yl-ethyl) -acetamide
LC-MS: m / z (M +) = 407
Ber. MW = 406.93

15

N- {2- [4- (4-chlorophenyl) -4-hydroxy-piperidin-1-yl] -1-furan-2-ylmethyl-2-oxo-ethyl} -2- (4-chlorophenylsulfanyl) - acetamide
LC-MS: m / z (M +) = 533
Ber. MW = 533.47

17

2- (4-chloro-phenylsulfanyl) -N- (1-furan-2-ylmethyl-2-oxo-2-piperazin-1-yl-ethyl) -acetamide
LC-MS: m / z (M +) = 408
Ber. MW = 407.92

31

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (2,4-dichlorobenzyl) -3-furan-3-yl-propionamide
LC-MS: m / z (M +) = 498
Ber. MW = 497.83

34

2- [2- (4-chloro-phenylsulfanyl) -acetylamino] -3-furan-3-yl-N- (3-methoxy-propyl) -propionamide
LC-MS: m / z (M +) = 411
Ber. MW = 410.92

36

2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-furan-3-yl-N- (3-morpholin-4-yl-propyl) propionamide
LC-MS: m / z (M +) = 466
Ber. MW = 466.00

39

2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-furan-3-yl-N- [2- (1-methyl-pyrrolidin-2-yl) ethyl] propionamide
LC-MS: m / z (M +) = 450
Ber. MW = 450.00

b) Preparation of the compounds (5-9, 11-13, 18-28, 35, 37-38, 41-44)

Coupling of Fmoc-L-4-thiazolylalanine or Fmoc-L-2-furylalanine to Wang resin

The amino acid was dissolved together with the HATU in 0.3 ml DMF and the base added. The reaction solution was added to the resin and the suspension for 1.5  Shaken for hours. The solution was separated from the resin and the resin was used several times DMF washed. The Fmoc protecting group was split off as above.

Coupling with 4-chlorophenylthioacetic acid

The acid was dissolved in 1 ml of DMF together with the HATU and the base was added. The solution was added to the resin and the suspension shaken for 1 hour. After that the solution was separated from the resin and the remaining resin thoroughly with DMF and then washed with dichloromethane.

Separation from the Wang resin

The compounds were treated with 50/45/5 (v / v / v) trifluoroacetic acid / DCM / triethylsilane from Split off resin. The solution was added to the resin and the suspension for 30 min. shaken. The solution was separated from the resin and this with smaller amounts of DCM washed. The combined solutions were made by passing a stream of nitrogen concentrated. The respective crude product was either prepared using preparative LC-MS purified, the yields of product being about 50% or in small amounts Acetonitrile / water was taken up and lyophilized overnight.

Coupling with different amines

The corresponding carboxylic acids were mixed with the TBTU and the base in 0.3 ml DMF dissolved, shaken briefly and then added the corresponding amine. The Reaction solutions were shaken overnight. The reaction solutions were with Acetic acidified, with THF and a mixture of Acetonitrile / water / trifluoroacetic acid (60 / 39.9 / 0.1) added and by means of preparative LC-MS purified.

The overall yield of the synthesis was between 20-80 depending on the one used %.  

Characterization of the compounds produced using LC-MS 5

N- {2- [4- (4-Acetylphenyl) piperazin-1-yl] -1-furan-2-ylmethyl-2-oxo-ethyl} -2- (4-chlorophenylsulfanyl) acetamide
LC-MS: m / z (M +) = 526
Ber. MW = 526.05

6

2- (4-Chlorophenylsulfanyl) -N- {1-furan-2-ylmethyl-2-oxo-2- [4- (2-oxo-2,3-dihydrobenzoimidazol-1-yl) piperidin-1-yl ] ethyl} acetamide
LC-MS: m / z (M +) = 539
Ber. MW = 539.05

7

2- (4-chloro-phenylsulfanyl) -N- (2-oxo-2-piperidin-1-yl-1-thiazol-4-ylmethyl-ethyl) -acetamide
LC-MS: m / z (M +) = 424
Ber. MW = 423.99

8th

2- (4-chlorophenylsulfanyl) -N- (2-oxo-1-thiazol-4-ylmethyl-2-thiomorpholin-4-yl-ethyl) acetamide
LC-MS: m / z (M +) = 442
Ber. MW = 442.03

9

N- [2- (4-acetylpiperazin-1-yl) -2-oxo-1-thiazol-4-ylmethylethyl] -2- (4-chlorophenylsulfanyl) acetamide
LC-MS: m / z (M +) = 467
Ber. MW = 467.01

11

N- [2- (4-Acetylpiperazin-1-yl) -1-furan-2-ylmethyl-2-oxo-ethyl] -2- (4-chlorophenyl sulfanyl) acetamide
LC-MS: m / z (M +) = 450
Ber. MW = 449.96

12

2- (4-chlorophenylsulfanyl) -N- (1-furan-2-ylmethyl-2-oxo-2-thiomorpholin-4-yl-ethyl) acetamide
LC-MS: m / z (M +) = 425
Ber. MW = 424.97

13

2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-furan-2-yl-N- [2- (1H-indol-3-yl) ethyl] propionamide
LC-MS: m / z (M +) = 482
Ber. MW = 482.00

18

2- (4-chlorophenylsulfanyl) -N- [2- (2-hydroxymethylpiperidin-1-yl) -2-oxo-1-thiazol-4-ylmethylethyl] acetamide
LC-MS: m / z (M +) = 454
Ber. MW = 454.01

19

2- (4-chlorophenylsulfanyl) -N- [2- (3,5-dimethyl-piperidin-1-yl) -1-furan-3-ylmethyl-2-oxoethyl] acetamide
LC-MS: m / z (M +) = 435
Ber. MW = 434.99

20

2- (4-chlorophenylsulfanyl) -N- [1-furan-3-ylmethyl-2- (4-methyl-piperidin-1-yl) -2-oxo-ethyl] acetamide
LC-MS: m / z (M +) = 421
Ber. MW = 420.96

21

2- (4-chlorophenylsulfanyl) -N- [1-furan-3-ylmethyl-2- (2-methyl-piperidin-1-yl) -2-oxo-ethyl] acetamide
LC-MS: m / z (M +) = 421
Ber. MW = 420.96

22

2- (4-chlorophenylsulfanyl) -N- [2- (3,5-dimethyl-piperidin-1-yl) -2-oxo-1-thiazol-4-ylmethylethyl] acetamide
LC-MS: m / z (M +) = 452
Ber. MW = 452.04

23

2- (4-Chlorophenylsulfanyl) -N- {2- [2- (2-hydroxyethyl) piperidin-1-yl] -2-oxo-1-thiazol-4-ylmethylethyl} acetamide
LC-MS: m / z (M +) = 452
Ber. MW = 452.04

24

2- (4-Chlorophenylsulfanyl) -N- [2- (4-hydroxy-piperidin-1-yl) -2-oxo-1-thiazol-4-ylmethylethyl] acetamide
LC-MS: m / z (M +) = 440
Ber. MW = 439.99

25

1- {2- [2- (4-Chlorophenylsulfanyl) acetylamino] -3-furan-3-yl-propionyl} piperidine-3-carboxylic acid diethylamide
LC-MS: m / z (M +) = 506
Ber. MW = 506.06

26

2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-furan-3-yl-N- (4-methylthiazol-2-yl) propionamide
LC-MS: m / z (M +) = 436
Ber. MW = 435.95

27

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (5-ethyl- [1,3,4] thiadiazol-2-yl) -3-furan-3-yl-propionamide
LC-MS: m / z (M +) = 451
Ber. MW = 450.97

28

2- [2- (4-Chlorophenylsulfanyl) acetylamino] -N- (5-ethyl- [1,3,4] thiadiazol-2-yl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 468 ,,
Ber. MW = 468.02

35

N- (2-azepan-1-yl-2-oxo-1-thiazol-4-ylmethyl-ethyl) -2- (4-chlorophenylsulfanyl) -acetamide
LC-MS: m / z (M +) = 438
Ber. MW = 438.01

37

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (3-methyl-pyridin2-yl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 447
Ber. MW = 446.98

38

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (3-methyl-pyridin-2-yl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 444
Ber. MW = 443.96

41

2- [2- (4-chloro-phenylsulfanyl) -acetylamino] -N-furan-2-ylmethyl-3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 436
Ber. MW = 435.95

42

2- [2- (4-chlorophenylsulfanyl) acetylamino] -N- (4-cyano-1H-pyrazol-3-yl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 447
Ber. MW = 446.94

43

2- [2- (4-Chlorophenylsulfanyl) acetylamino] -N- (4,5-dicyano-1H-imidazol-2-yl) -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 472
Ber. MW = 471.95

44

1- {2- [2- (4-Chlorophenylsulfanyl) acetylamino] -3-thiazol-4-yl-propionyl} piperidine-3-carboxylic acid diethylamide
LC-MS: m / z (M +) = 523
Ber. MW = 523.12

c) Amines used in a) -b) (for compounds 1-15, 17-44)

d) Preparation of compound 16

Coupling the Fmoc-Rink linker to the tentagel

The Fmoc-Rink linker was coupled to the resin as described above and the Fmoc- Protective group split off.  

Coupling of Fmoc-8-Amino-3,6-Dioxaoctanoic Acid

The acid was dissolved together with the HATU in 0.3 ml DMF, shaken briefly and then added the base. The reaction solution was added to the resin and the Shaken suspension for 1.5 hours. The solution was separated and the resin several times washed with DMF. The Fmoc protecting group was split off as described above.

Coupling of Fmoc-4-L-thiazolylalanine

The amino acid was dissolved in a little DMF together with the HATU, briefly shaken and then added the base. The reaction solution was added to the resin and shaken the suspension for 1.5 hours. The solution was separated and the resin washed several times with DMF. The Fmoc protecting group was as described above cleaved.

The coupling of 4-chlorophenylthioacetic acid was carried out as described above.

The connection was split off analogously to the split-off of those described above Separation from the Wang resin.

The remaining oil was in a mixture of acetonitrile / water and trifluoroacetic acid (3: 2; 0.1%) and purified by preparative LC-MS.

Characterization of compound 16 16

N- [2- (2-Carbamoylmethoxyethoxy) ethyl] -2- [2- (4-chlorophenylsulfanyl) acetylamino] -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 501
Ber. MW = 501.03

e) Preparation of compounds 45 and 46

The coupling of the Fmoc-Rink linker to the tentagel, the coupling of Fmoc-4-L- Thiazolylalanine or Fmoc-2-L-furylalanine and 4-chlorophenylthioacetic acid were carried out as described above.

The cleavage and processing took place as described above under compound 16.

Characterization of compounds 45 and 46 46

2- [2- (4-chloro-phenylsulfanyl) -acetylamino] -3-furan-2-yl-propionamide
LC-MS: m / z (M +) = 339
Ber. MW = 338.81

45

2- [2- (4-chloro-phenylsulfanyl) -acetylamino] -3-thiazol-4-yl-propionamide
LC-MS: m / z (M +) = 356
Ber. MW = 355.87

f) Reagents used with the corresponding abbreviations

Tentagel HL-NH2
Load: 0.43 mmol / g rapp polymers
Wang resin
100-200 mesh load: 1.20 mmol / g
HOBt
1-hydroxy-1H-benzotriazole, Aldrich
DCM
dichloromethane
DMF
N, N-dimethylformamide, 99.9% for HPLC, Aldrich
TBTU
O- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, Aldrich
HATU
(O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) perseptives
Biosystems
Fmoc Rink linker
NovaBiochem

Trial 2 Thrombin competition assay

The inhibitory properties of compounds 1 to 46 were investigated in a thrombin competition assay (determination of the inhibitor constant K _i ).

Thrombin activity is determined at 20 ° C and pH 7.4 with the fluorogenic substrate Tos-GPR-AMC (Bachem, I 1365, λexc. = 370 nm, λem. = 450 nm). The test mixture contains 20 μM substrate, 0.1-100 μM inhibitor and 100 pM human thrombin in a total volume of 200 μl HBS (10 mM Hepes, 150 mM NaCl, 0.005% Tween 20). The reaction is started after 5 minutes of preincubation of the enzyme with the inhibitor by adding substrate, and the fluorescence intensity is measured for 10 minutes at 1 minute intervals. With competitive inhibition, the Ki value is calculated as follows:

v ₀ / v _i = 1 + I / Ki

v ₀ = initial speed of the reaction
v _i = initial rate of reaction in the presence of the inhibitor
I = inhibitor concentration

Trial 3 Determination of the inhibitory effect on factor Xa

The determinations were carried out at 25 ° C. in Tris buffer (0.05 mol / l, pH 8.0, contains 0.154 mol / l NaCl and 5% ethanol). The substrates (Pentapharm AG, Basel, CH) were dissolved in H ₂ O, the inhibitor in the corresponding measuring buffer (dissolving in ethanol, filling with buffer). The absorbance was measured at 405 nm using a microplate reader (MR 5000, Dynatech, Denkendorf, D).

The evaluation was carried out according to the Dixon method. The regulations were carried out three times.

The enzyme factor Xa (bovine) was from Diagnostic Reagents Ltd. (Thame, Oxon, England). The enzyme solution (in H ₂ O) contained 0.625 U / ml enzyme; CH ₃ OCO-D-Nle-Gly-Arg-pNA (Chromozym X) was used as the substrate in concentrations of 4, 2 and 1 mmol / l.

the mixture for measurement

200 µl buffer or inhibitor,
25 µl substrate,
50 µl enzyme,
Response time 3.5 min.
25 µl acetic acid (50%).

Compound 32 showed a K _i value of 26 µM.

Claims (10)

1. Compounds of formula I.
where A, D, R ¹ , R ² , X, Y, E and Z have the following meaning:
Aryl, C _3-8 -cycloalkyl, C _3-8 -cycloalkenyl, it being possible for a phenyl ring to be fused onto each ring and all the radicals mentioned optionally having up to five identical or different radicals selected from -F, -Cl, -Br, -I , -OH, -SH, -CF ₃ -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, -OCHO, -OC (O) - C _1-4 alkyl, C _1-16 alkyl, C _1-8 alkyloxy, C _1-8 alkyloxy C _1-8 alkyl, C _1-8 alkyl, C _1-8 alkyloxy -, HC (O) -C _1-8 alkyl-, C _1-8 alkyl-C (O) -C _1-8 -alkyl-, -NO ₂ , -NH ₂ , - NH-C _1-4 -alkyl , -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ) ₂ , -NHC (O) -C _1-4 alkyl or, if the rings are at least partially saturated, can carry oxo (= O), these residues (with the exception of = O) also being present on the fused-on phenyl ring can;
D: -O-, -S-, -S (O) -, -S (O ₂ ) -;
R ¹ and R ² : independently of one another -H, C ₁ -C ₁₆ -alkyl-, C _1-8 -alkoxy-, -C (O) - C _1-8 -alkyl, -COOC _1-4 -alkyl, - OC (O) -C _1-4 alkyl, C _1-8 alkyloxy-C _1-8 alkyl, C _1-8 alkyl C _1-8 alkyloxy, HC (O) -C _{1- 8} alkyl-, C _1-8 alkyl-C (O) -C _1-8 alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) - N (C _1-4 -alkyl) ₂ , -NHC (O) -C _{1 -4} alkyl, C _3-5 cycloalkyl, aryl, benzyl;
X: -O-, -S-, -N (R ³ ) -, wherein
R ³ : -H, C ₁ -C ₁₆ alkyl, C _1-8 alkoxy, -C (O) -C _1-8 alkyl, -COOC _1-4 alkyl, -OC (O) - C _1-4 alkyl, C _1-8 alkyloxy-C _1-8 alkyl, C _1-8 alkyl C _1-8 alkyloxy, HC (O) -C _1-8 alkyl, C _1-8 alkyl-C (O) -C _1-8 alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C ( O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) -N (C _1-4 -alkyl) ₂ , -NHC (O) -C _1-4 -alkyl, C _3-5 cycloalkyl, aryl, benzyl;
Y: aryl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, aryl C _1-8 alkyl, C _3-8 cycloalkyl C _1-8 alkyl, C _3-8 -Cycloalkenyl-C _1-8 -alkyl-, aryl-C _1-8 -alkoxy-, C _3-8 - cycloalkyl-C _1-8 -alkoxy-, C _3-8 -cycloalkenyl-C _1-8 -alkoxy- , Aryl-C _1-8 alkyl-C (O) -, C _3-8 -cycloalkyl-CigAlkyl-C (O) -, C _3-8 -cycloalkenyl-C _1-8 alkyl-C (O) -, whereby a phenyl ring can be fused onto each ring and all the radicals mentioned optionally have up to five identical or different radicals selected from -F, -Cl, -Br, -I, -OH, -SH, -CF ₃ -CN, -CHO, - C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, -OCHO, -OC (O) -C _1-4 alkyl, C _1-16 alkyl, C _{1- 8} -alkyloxy, C _1-8 -alkyloxy-C _1-8 - alkyl, C _1-8 alkyl-C _1-8 alkyloxy-, HC (O) -C _1-8 alkyl, C _{1- 8} alkyl-C (O) -C _1-8 -alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O ) NH ₂ , -C (O) -NH- C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or if so it is at least partially saturated rings Oxo (= O) can carry, the se residues (with the exception of = O) may also be on the fused phenyl ring;
E and Z together or independently of one another -H, -F, -Cl, -Br, -I, hydroxyl, thio, trifluoromethyl, cyano, formyl, -C (O) -C _1-8 -alkyl, carboxyl, -COOC _{1 -4} - alkyl, -OCHO, -OC (O) -C _1-4 alkyl, C _1-16 alkyl, C _1-8 alkyloxy, C _1-8 alkyloxy C _1-8 alkyl -, C _1-8 alkyl-C _1-8 alkyloxy-, HC (O) -C _1-8 alkyl-, C _1-8 alkyl-C (O) -C _1-8 - alkyl-, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 alkyl , -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl aryl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _8-12 bicycloalkenyl, aryl C (O), C _3-8 cycloalkyl C (O), C _3-8 cycloalkenyl C (O), C _8-12 bicycloalkenyl C ( O) -, aryl-C _1-8 alkyl, C _3-8 cycloalkyl-C _1-8 alkyl, C _3-8 cycloalkenyl-C _1-8 alkyl, C _8-12 bicycloalkenyl -C _1-8 - alkyl-, aryl-C _1-8 -alkoxy-, C _3-8 -cycloalkyl-C _1-8 -alkoxy-, C _3-8 -cycloalkenyl- C _1-8 -alkoxy-, C _8-12 bicycloalkenyl-C _1-8 alkoxy-, aryl-C _1-8 alkyl-C (O) -, C _3-8 - cycloalkyl-C _1-8 alkyl-C (O) -, C _{3- 8-} cycloalkenyl-C _1-8 alky l-C (O) -, C _8-12 - bicycloalkenyl-C _1-8 -alkyl-C (O) -, aryl-NH-C (O) -, C _3-8 -cycloalkyl-NH-C (O) - , C _3-8 -cycloalkenyl-NH-C (O) -, C _8-12 -bicycloalkenyl-NH-C (O) -, aryl-C _1-8 -alkyl-NH-C (O) -, C _{3 -8-} Cycloalkyl-C _1-8 -alkyl-NH-C (O) -, C _3-8 -cycloalkenyl-C _1-8 -alkyl-NH-C (O) -, C _8-12 -bicycloalkenyl-C _1-8 -Alkyl-NH-C (O) -, where a phenyl ring can be fused to each ring and all the mentioned radicals of the ring (s) optionally up to five identical or different radicals selected from -F, -Cl, -Br, -I, -OH, -CF ₃ -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, -OCHO, -OC (O) -C _{1 -4} -alkyl, C _1-16 -alkyl-, C _1-8 -alkyloxy-, C _1-8 -alkyloxy-C _1-8 -alkyl-, C _1-8 - alkyl-C _1-8 -alkyloxy- , HC (O) -C _1-8 alkyl, C _1-8 alkyl-C (O) -C _1-8 alkyl, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl , -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 alkyl, -C (O) - N (C _1-4 alkyl) ) ₂ , -NHC (O) -C _1-4 alkyl or, if the rings are at least partially saturated rings, can carry oxo (= O), these being Residues (with the exception of = O) may also be on the fused phenyl ring, or
if E is -C (O) - then Z can be a primary or secondary amine, its tautomers, stereoisomers, mixtures and salts. 2. Compounds of formula I according to claim 1, wherein A, D, R ¹ , R ² , X, Y, E and Z have the following meaning:
A: phenyl, optionally up to five identical or different radicals selected from -F, -Cl, -Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-4 -alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 alkyloxy, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _{1 -4-} alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) -N (C _1-4 -alkyl) ₂ , -NHC ( Can carry O) -C _1-4 alkyl;
D: -S-;
R ¹ and R ² : independently of one another -H, C _1-4 -alkyl-, C _1-4 -alkyloxy-, -C (O) -C _1-4 -alkyl;
X: -N (R ³ ) -, wherein
R ³ : -H, C _1-4 alkyl, C _1-4 alkyloxy, -C (O) -C _1-4 alkyl;
Y: - (CH ₂ ) _n -R ⁴ , where
n: 0, 1, 2, 3 or 4 and
R ⁴ : aziridine, oxirane, acetidine, oxetane, thiethan, pyrrolidine, tetrahydrofuran, thiolan, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepan, pyrrole, furazole , Pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, azepine, each residue optionally being up to five identical or different substituents selected from -F, -Cl, Br , -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 -Alkyloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or, if the rings are at least partially saturated, oxo (= O) can wear;
E: -C (O) -;
Z: primary or secondary amine, -OH, OC _1-4 alkyl, -NR ⁵ R ⁶ , wherein
R ⁵ , R ⁶ independently of one another: -H, - (CH ₂ ) _m -R ¹² , - (C ₂ H ₄ O) _o -CH ₂ -R ¹² , where
m, o is independently 0, 1, 2, 3 or 4 and
R ¹² : -H, -F, -Cl, -Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 - Alkyl, C _1-4 alkyl, C _1-4 alkyloxy, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or
Phenyl, aziridine, oxirane, acetidine, oxetane, thiethan, pyrrolidine, tetrahydrofuran, thiolan, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyridine Is imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, azepine, where a phenyl ring can be fused to each ring and each residue optionally having up to five identical or different substituents selected from -F, -Cl, Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _{1- 4} -alkyl-, C _1-4 -alkyloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or if it is at least partially saturated rings acts oxo (= O); or
Z: a radical of formula II
wherein
G: a bond or -O-, -S-, -NR ⁷ -, -CR ⁷ R ^{7 '} -, -CH ₂ -O-, -CH ₂ -S-, -CH ₂ - NR ⁷ -, -CH ₂ -CR ⁷ R ^{7 '} - and
R ⁷ , R ⁸ together form a ring selected from pyrrolidine, tetrahydrofuran, thiolane, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, pyrrole, furan, dihydrofuran, thiophene, pyolazole, pyrazole, pyrazole , Isoxazole, thiazole, isothiazole, triazole, thiadiazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, where a phenyl ring may be fused to each ring and R ^{7 '} , R ⁹ , R ¹⁰ , R ¹¹ independently of one another have the following meaning have or
R ⁷ , R ^{7 '} , R ⁸ , R ⁹ R ¹⁰ , R ¹¹ independently of one another: -H, -F, -Cl, -Br, -OH, -CF ₃ , - CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 alkyloxy, -NO ₂ , -NH ₂ , -NH-C _1-4 -Alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 -alkyl, -C (O) -N (C _1-4 -Alkyl) ₂ , -NHC (O) -C _1-4 -alkyl or
Phenyl, aziridine, oxirane, acetidine, oxetane, thiethan, pyrrolidine, tetrahydrofuran, thiolan, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyrrole, furzole, pyrrole, pyrrole, pyridine Imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole, pyridine, pyran, pyridazine, pyrimidine, pyrazine, triazine, azepine, each residue optionally being up to five identical or different substituents selected from -F, -Cl, -Br , -OH, - CF ₃ , -CN, -CHO, -C (O) -C _1-8 alkyl, -COOH, -COOC _1-4 alkyl, C _1-4 alkyl, C _1-4 - Alkyloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 -alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH- C _1-4 alkyl, -C (O) -N (C _1-4 alkyl) ₂ , -NHC (O) -C _1-4 alkyl or, if the rings are at least partially saturated, oxo (= O ) can carry, their tautomers, stereoisomers, mixtures and salts. 3. Compounds of formula I according to claim 1, wherein A, D, R ¹ , R ² , X, Y, E and Z have the following meaning:
A: phenyl, optionally up to five identical or different radicals selected from -F, -Cl, -Br, -OH, -CF ₃ , -CN, -CHO, -C (O) -C _1-4 -alkyl, -COOH, -COOC _1-4 -alkyl, C _1-4 -alkyl-, C _1-4 -aloxy-, -NO ₂ , -NH ₂ , -NH-C _1-4 -alkyl, -N (C _{1 -4-} alkyl) ₂ , -C (O) NH ₂ , -C (O) -NH-C _1-4 -alkyl, -C (O) -N (C _1-4 -alkyl) ₂ , - NHC ( Can carry O) -C _1-4 alkyl;
D: -S-;
R ¹ and R ² : independently of one another -H, C _1-4 -alkyl-, C _1-4 -alkyloxy-, -C (O) -C _1-4 -alkyl;
X: -NH- or -N (CH ₃ ) -
Y: - (CH ₂ ) _n -R ⁴ , where
n: 0, 1, 2, 3 or 4 and
R ⁴ : furanyl (preferably furan-2-yl) or thiazolyl (preferably thiazol-4-yl);
E: -C (O) -;
Z: -OH, -OCH ₃ , -NR ⁵ R ⁶ , wherein
R ⁵ : H;
R ⁶ : -H, - (CH ₂ ) _m -R ¹² , - (C ₂ H ₄ O) _o -CH ₂ -R ¹² , where
m, o is independently 0, 1, 2, 3 or 4 and
R ¹² : -H, -OH, -OCH ₃ -CN, -CHO, -C (O) CH ₃ , -COOH, -COOCH ₃ , -NH ₂ , -NH- CH ₃ , -N (CH ₃ ) ₂ , -C (O) NH ₂ , -C (O) -NH-CH ₃ , -C (O) -N (CH ₃ ) ₂ , -NHC (O) -CH ₃ or
Phenyl, pyridine (preferably -2-yl), imidazole (preferably linked via N, -2-yl or -4-yl), indole (preferably -3-yl), thiazole (preferably -2-yl), thiadiazole (preferred 1,3,4-thiadiazol-5-yl), morpholine (preferably linked via N), pyrrolidine (preferably -2-yl), piperazine (preferably linked via N), furan (preferably -2-yl), pyrazole (preferred -3-yl), where each radical can optionally contain up to three identical or different substituents selected from chloro, cyano, methoxy, methyl and ethyl
Z: a radical of formula II
wherein
G: a bond or -O-, -S-, -NR ⁷ -, -CR ⁷ R ^{7 '} -, -CH ₂ -O-, -CH ₂ -S-, -CH ₂ - NR ⁷ -, -CH ₂ -CR ⁷ R ^{7 '} - and
R ⁷ , R ^{7 '} , R ⁸ , R ⁹ R ¹⁰ , R ¹¹ independently of one another: -H, -OH, -C (O) -CH ₃ , methyl, ethyl, hydroxymethyl, hydroxyethyl, -NH ₂ , -NH-C _1-4 alkyl, -N (C _1-4 alkyl) ₂ , -C (O) NH ₂ , -C (O) -NR ¹³ R ¹⁴ , wherein
R ¹³ , R ¹⁴ independently of one another are H, methyl, ethyl or phenyl (preferably 4-chlorophenyl or 4-acetylphenyl), 2-keto-benzimidazoline (preferably -1-yl), their tautomers, stereoisomers, mixtures and salts. 4. Selected compounds according to formula III
their tautomers, stereoisomers, mixtures and salts:
5. Process for the preparation of compounds of formula III
in which
A: phenyl, which can optionally carry up to five identical or different radicals selected from -Cl, -Br, -OCH ₃ , -CF ₃ ;
Y: - (CH ₂ ) _n -R ⁴ , where
n: 0, 1, 2, 3 or 4 and
R ⁴ : furanyl (preferably furan-2-yl) or thiazolyl (preferably thiazol-4-yl);
and Z is a primary or secondary amine,
the steps comprehensively

• a) reaction of amino-terminated tetagel synthetic resin with Rinklinker with 4-carboxybenzenesulfonamide;
• b) reaction of the immobilized sulfonamide with an appropriately protected amino acid H ₂ N-CH (Y) -COOH;
• c) implementation of the deblocked amino function with the acid AS-CH ₂ - COOH;
• d) activation of the sulfonamide with iodoacetonitrile;
• e) insertion of a primary or secondary amine Z with simultaneous cleavage from the synthetic resin.

6. A process for the preparation of compounds III according to claim 5, comprising the steps of:

• a) coupling of an appropriately protected amino acid H ₂ N-CH (Y) - COOH to Wang resin;
• b) reaction of the deblocked amino function with the acid AS-CH ₂ - COOH;
• c) cleavage from the solid phase using trifluoroacetic acid;
• d) reaction of the free carboxylic acid with a primary or secondary amine Z in solution.

7. Compounds obtainable from one of the production processes according to claim 5 or 6.   8. Medicines containing, in addition to conventional carriers and auxiliaries Compounds of the formulas I or III according to at least one of the Claims 1 to 4 or 7. 9. Use of a compound according to at least one of claims 1 to 4 or 7 for the manufacture of a medicament with a protease inhibitory, especially thrombin-inhibiting effect. 10. Use of compounds according to at least one of claims 1 to 4 or 7 for the manufacture of a medicament for combating or Prevention of venous and arterial thrombosis, pulmonary embolism, unstable angina, cerebrovascular diseases, atrial fibrillation, Heart attack, arteriosclerosis, osteoporosis, disseminated intravascular Coagulation (DIC) or in combination therapy with thrombolytics for Shortening the reperfusion time and lengthening the reocclusion time or to prevent reocclusions after bypass surgery or percutaneous transluminal coronary angioplasty (PTCA) or the Formation of metastases, asthma, arthritis, pancreatitis, rhinitis, and Urticaria.