JP2005525336A - Use of sodium / hydrogen exchanger inhibitors for the treatment of thrombotic and inflammatory disorders - Google Patents

Abstract

Inhibitors of cellular sodium / hydrogen exchangers have an inhibitory effect on the secretion of von Willebrand factor and increased expression of P-selectin. Said inhibitors can therefore be used for the treatment of thrombotic and inflammatory diseases.

Description

  The present invention relates to the use of cellular sodium / hydrogen exchanger inhibitors in human and veterinary medicine for the prevention and treatment of acute or chronic diseases caused by elevated levels of von Willebrand factor in the blood. Inhibitors can therefore be used for the treatment of thrombotic and inflammatory disorders.

  In recent years, inhibitors of sodium / hydrogen exchanger (NHE) protect heart tissue that is at risk of death by the onset of rapid ischemic events when the heart is hypoperfused in many preclinical studies. It is characterized as a material suitable for an excellent method. The protection of heart tissue with NHE inhibitors includes all degrees of hypoperfusion resulting from cardiac arrhythmia and temporary loss of function due to myocardial hyperconstriction to cardiac tissue death and associated permanent damage. Damage included.

  The mechanism of action of NHE inhibitors important in acute ischemic events is due to the reduced influx of sodium ions that occurs in acute hypoperfused tissues due to NHE activation as a result of intracellular acidification. Become. This delays the tissue sodium overload situation. This prevents fatal calcium overload of heart cells, as there is a coupling of sodium and calcium ion transport in heart tissue.

  NHE inhibitors are also known to protect the central nervous system (CNS), and such agents protect the CNS in a similar manner to the heart against acute ischemic conditions. These conditions are caused by rapid hypoperfusion and thereby a lack of nutrient, oxygen or mineral supply. Such ischemic harm to the CNS appears especially in the case of central nervous system infarcts such as stroke. Thus, as expected, the protective effect of NHE inhibitors against these acute events is not observed when blood flow is normal and healthy, since ischemic harm to heart tissue or CNS tissue is not initiated rapidly. It is.

  Many types of substances that intervene in the interaction of clotting factors and thereby stop the clotting cascade have been described in the prior art. Similarly, many principles of action have been developed to break down (dissolve) previously formed thrombi without inhibiting thrombus formation. Some of these principles of action intervening at various junctions in the cascade, such as derivatives of the vitamin K group (phylloquinone), factor VIII and factor IX products, platelet aggregation inhibitors such as acetylsalicylic acid, dipyridamole and ticlopidine Anticoagulants, such as heparin or heparinoids, have been introduced into therapy to prevent thrombus formation.

The blood coagulation cascade can be mechanically divided into two pathways as shown in the diagram below: intrinsic and extrinsic pathways, which eventually merge to activate factor X Resulting in the production of thrombin followed by fibrin.

  In the therapeutic use of such blood clotting inhibitors, it is important that the clotting inhibition achieved is not too strong or not complete, or the frequent microtraumas necessary for life support. The formation of microthrombi and microcoagulants that should occur in is inhibited. The degree of clotting inhibition can only be adjusted indefinitely as a result of differences in a particular individual's response at a particular time and must be carefully monitored when possible. Inhibiting these many ongoing clotting processes increases the risk of extensive bleeding (hemophilia).

  Thus, a drawback of known therapeutic agents available on the market that intervene as inhibitors of clotting is the high risk of bleeding complications. There is a risk of fatal bleeding, especially during the treatment of high dose thrombolysis, for example in the treatment of acute myocardial infarction or pulmonary embolism. Therefore, there is an urgent need for a therapeutic agent that does not involve the risk of increased bleeding tendency even when administered in excess.

  Many of the known anticoagulants exert their effects on platelets, plugs and act by inhibiting their function or inhibiting their activation. It is also clear that the endothelium plays a central role in the clotting phenomenon. Thus, for example, von Willebrand factor (vWF), which is necessary for clotting, is produced in most parts of the endothelial cells and is constantly (constituted) into the circulating blood by the endothelial cells to ensure the necessary clotting process in the blood. Is secreted). A significant portion of the vWF produced is stored in cytoplasmic granules termed the Weibull-Parade body and released as needed upon stimulation of endothelial cells. If endothelial cells produce vWF and cannot supply it to the blood, the result is a well-known genetic vWF-dependent disease, von Willebrand-Jurgens syndrome; this almost stops bleeding It is characterized by not being able to. In recent years, vWF concentrations in the blood have risen, leading to known diseases that, for example, induce a tendency to increase blood clotting and inflammatory processes. Kamphuisen et al., Therefore, based on a number of studies in their publication “Elevated factor VIII levels and the risk of thrombosis” (Arterioscler. Thromb. Vasc. Biol. 21 (5): 731-738 (2001)). It shows that there is a dominant link between elevated levels of vWF in the medium and the rate of increase in thrombotic disorders. Factor VIII forms a complex with vWF as a prerequisite for blood clotting. It has become possible to establish that high levels of von Willebrand factor (vWF) in blood and factor VIII associated with vWF are clear risk factors for thrombosis. However, antithrombotic agents that antagonize the stabilization of binding of vWF to factor VIII are disadvantageous when overdosed because blood coagulation is substantially inhibited and the risk of bleeding tendency must be expected. I must.

  Here, in an attempt to find effective compounds for the treatment of acute or chronic diseases caused by elevated levels of von Willebrand factor in the blood, the compounds used in the present invention release von Willebrand factor from endothelial cells. Was found to inhibit. The compounds of the present invention inhibit the pH-dependent mass release of vWF accumulated during ischemia.

  Now, secretion is normally done constitutively at normal blood pH, which is known to be about 7.4, and a portion of vWF is stored in the Weibel-Parade body. It was found that there was a delay and decrease in vWF release as the pH decreased. The exocytosis of Weibull-Parade bodies containing vWF increases as pH decreases. Thus, under acidosis conditions, there is a significant increase in the Weibel-Parade body, which results in extensive accumulation of vWF in endothelial cells and reduced constitutive and stimulated secretion of vWF. This is visualized by the staining method and can be shown by quantitative measurement of vWF in the supernatant. Such acidosis conditions with a significant pH decrease below 7 occur, for example, in the case of tissue ischemia. When re-alkalined and the endothelial cells are stimulated, this corresponds to a reperfusion condition, and exocytosis takes place within a few seconds, thereby emptying the Weibel-Parade body (WPB) and pre-thrombosis. Risk factors are released in large quantities.

  In addition to vWF, the Wiebel-Parade body also stores the transmembrane protein P-selectin (Wagner, D.D. 1993, Thromb. Haemost., 70: 105-110). P-selectin is in the vesicle membrane and is taken up into the plasma membrane of endothelial cells after vesicle fusion (exocytosis). This means that all Weibel-Parade body exocytosis not only increases vWF release, but also increases P-selectin expression in endothelial cell membranes. The examples show vWF secretion (quantitative measurement by ELISA) during acidosis and subsequent reperfusion. In parallel, these quantitative measurements were confirmed by immunofluorescence data on the Weibel-Parade body. Thus, the measured vWF is not only a marker of an increased thrombotic tendency (via increased platelet aggregation) (increased in vWF secretion) or decreased (decreased in vWF secretion), but also P-selectin in the endothelial cell membrane It is also a direct marker of increased or decreased expression. P-selectin serves as an anchor for leukocytes and hence the early inflammatory response (Vestweber, D., Blanks, JE 1999, Physiol. Rev., 79: 181-213; Issekutz, AC, Issekutz, TB 2002, J. Immunol. 168: 1934-1939). Pathophysiological significance is extensive and has been confirmed for ischemia / reperfusion injury, thrombosis and arteriosclerosis (Massberg, S., et al., 1998, Blood ;. 92: 507-515; Kita, T. , Et al., 2001, Ann. NY Acad. Sci., 947: 199-205). In addition to the significance of P-selectin as a marker of inflammation and as an initiator of inflammation, it is a cancer metastasis process (Varki, A., Varki, NM 2001, Braz. J. Med. Biol. Res. 34: 711-717 ) And during various inflammations (arthritis) of the joint (Veihelmann, A. et al., 1999, Microcirculation, 6: 281-290; Mclnnes, IB, et al., 2001, J. Immunol., 167: 4075-4082) Plays an essential role. Thus, the mode of action of the substances described herein can also find use as a therapeutic for all the above-mentioned P-selectin related disorders.

Accordingly, the present invention relates to the use of sodium / hydrogen exchanger inhibitors for the manufacture of a medicament for the prevention and treatment of acute and chronic diseases caused by elevated levels of von Willebrand factor in the blood.

Furthermore, the present invention provides at least one of the following for producing a medicament for preventing or treating acute and chronic diseases caused by elevated von Willebrand factor levels in blood and / or increased expression of P-selectin:

の化合物および／または上記化合物のすべての立体異性体形態および／またはこれらの形態のあらゆる比率における混合物、および／または上記化合物の生理学上許容しうる塩の使用に関する。

And / or all stereoisomeric forms of the compounds and / or mixtures in any proportions of these forms and / or the use of physiologically acceptable salts of the compounds.

の使用に関する。 Furthermore, the present invention relates to cariporide for producing a medicament for the prevention and treatment of acute or chronic diseases caused by elevated von Willebrand factor levels in blood and / or increased expression of P-selectin.

About the use of.

  The above compounds are known, for example EP 0416 499, EP 0 556 673, EP 0 589 336, EP 0 622 356, EP 0 699 666, EP 0 708 088, EP 0 719 766, EP 0726 254, EP 0 787. 728, EP 0 972 767, DE19529612, DE19601303, WO 9900379 or T. Kawamoto et al., Potent and selective Inhibition of the human Na + / H + exchanger isoform NHE1 by a novel aminoguanidine derivative T-162559 Eur. J. Pharmacol. 420 (2001 ), 1-8.

  When the above compounds can take the form of diastereoisomers or enantiomers and are produced as mixtures thereof in the chosen synthesis, separation into the pure stereoisomers is optionally carried out on the chiral support material. Or by fractional crystallization of diastereomeric salts formed using optically active bases or acids as auxiliaries if the racemate of the compound can form a salt. Examples of chiral stationary phases suitable for the separation of enantiomers by thin layer or column chromatography are improved silica gel carriers (so-called Pirkle phases) and high molecular weight carbohydrates such as triacetylcellulose. Alternatively, gas chromatographic methods on chiral stationary phases can be used for analytical purposes after appropriate derivatization known to those skilled in the art. Optically active, usually commercially available bases such as (−)-nicotine, (+) and (−)-phenylethylamine, quinine base, L-lysine or optically active bases for separating enantiomers of racemic carboxylic acids L- and D-arginine are used to form diastereomeric salts with different solubilities, the less soluble components are isolated as solids, and the more soluble diastereomers are precipitated from the mother liquor. The pure enantiomer is obtained from the stereomeric salt. In principle, in the same way amino groups with optically active acids such as (+)-camphor-10-sulfonic acid, D and L-tartaric acid, D and L-lactic acid and (+) and (-)-mandelic acid are used. Racemic compounds of formula I containing basic groups such as can be converted to pure enantiomers. Alternatively, a chiral compound containing an alcohol or amine functional group can be converted to the corresponding ester or amide using an appropriately activated or optionally N-protected enantiopure amino acid, or Conversely, chiral carboxylic acids can be converted to amides using carboxyl-protected enantiopure amino acids or to the corresponding chiral esters using enantiopure hydroxycarboxylic acids such as lactic acid. The chirality of the amino acid or alcohol residue prepared in enantiopure form is then subjected to separation of the existing diastereomers by crystallization or chromatography in an appropriate stationary phase, and the contained chiral moiety is then converted by an appropriate method. By removing it, it can be used for separation of isomers.

  The acidic or basic product of the compound can exist in its salt form or in free form. Preferably, pharmacologically suitable salts, such as alkali metal or alkaline earth metal salts, or hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates, and amino acids, natural Or a salt of a carboxylic acid.

  Physiologically acceptable salts are prepared in a manner known per se from the above compounds, including the salt-forming stereoisomeric forms. Carboxylic acids and hydroxamic acids are basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia, or organic bases such as trimethyl or triethylamine, ethanolamine or triethanolamine, or basic amino acids such as lysine. Forms stable alkali metal salts, alkaline earth metal salts or optionally substituted ammonium salts with ornithine or arginine. Moreover, when the said compound has a basic group, a stable acid addition salt can be manufactured using a strong acid. Inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylsulfamic acid, trifluoromethylsulfonic acid, Acetic acid, oxalic acid, tartaric acid, succinic acid or trifluoroacetic acid are all suitable for this purpose. Methane sulfonates of the above compounds are particularly preferred.

  Due to their pharmacological properties, the compounds are suitable for the prevention and treatment of acute or chronic diseases caused by elevated levels of von Willebrand factor in the blood and / or increased expression of P-selectin.

  This includes thrombotic disorders subsequently induced by ischemic conditions with reperfusion; thrombosis in acute myocardium, mesentery or cerebral infarction; thrombotic disorders occurring during or after surgery; pulmonary embolism; Deep vein thrombosis and vasculitis (eg associated with autoimmune disease or connective tissue disease) that often occur after long-term blood flow restriction, particularly in the lower limbs, eg after lying or sitting for a long time In particular, inflammatory disorders that occur during ischemia and subsequent reperfusion are included. This also includes disorders caused by increased expression of P-selectin, such as early inflammatory response; as well as prevention and treatment of arteriosclerosis; and prevention and treatment of cancer; and disorders of joint inflammation and arthritis, such as chronic joints Contains rheumatism.

  Administration of the medicament of the present invention can be carried out by oral, inhalation, rectal or transdermal administration, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred.

  The invention also converts at least one of the above compounds into a suitable dosage form together with a pharmaceutically suitable physiologically acceptable carrier and optionally another suitable active ingredient, additive or excipient. The manufacturing method of the pharmaceutical which consists of.

  The above compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and appropriate dosage forms such as tablets, coating tablets, two-piece capsules, hydroalcoholic or Converts to an oily suspension or aqueous or oily solution. Examples of inert carriers that can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Furthermore, the production can be carried out as dry and wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.

  For subcutaneous, intraperitoneal or intravenous administration, the active compound is converted into a solution, suspension or emulsion, if desired, using substances suitable for this purpose, such as solubilizers, emulsifiers or other excipients. . Examples of suitable solvents are not only saline or alcohols such as ethanol, propanol, glycerol, but also sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned above.

  Conventional auxiliaries such as carriers, disintegrants, binders, coating agents, swelling agents, lubricants or lubricants, flavoring agents, sweetening agents and solubilizing agents are also used. Frequently used and listed excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils such as fish liver oil, sunflower oil, Peanut oil or sesame oil, polyethylene glycol and solvents such as sterile water and mono- and polyhydric alcohols such as glycerol.

  The compound is preferably prepared and administered as a dose unit of pharmaceutical product, wherein one unit contains a defined dose of the compound of formula I as the active ingredient. This medicament is orally administered at a dose of 0.01 mg / kg / day to 25.0 mg / kg / day, preferably 0.01 mg / kg / day to 5.0 mg / kg / day, or Parenterally, it can be administered at a dose of 0.001 mg / kg / day to 5 mg / kg / day, preferably 0.001 mg / kg / day to 2.5 mg / kg / day. In severe cases, the dose can be increased. In many cases, however, lower doses are sufficient. These data are for an adult weighing approximately 75 kg.

  The above compounds can be used alone or in combination with anticoagulants, platelet aggregation inhibitors or fibrinolytic agents. Administration in combination includes, for example, factor Xa inhibitor, standard heparin, low molecular weight heparin such as enoxaparin, dalteparin, sertropaline, parnaparin or tinzaparin, direct thrombin inhibitors such as hirudin, aspirin, fibrinogen receptor antagonist, streptokinase, urokinase and / or Alternatively, it can be performed with tissue plasminogen activator (tPA).

  Sodium / hydrogen exchanger inhibitors are known to affect platelet aggregation and have an adhesion-inhibiting effect (Rosskopf, Dieter, J. Thromb. Thrombolysis (1999), 8 (1), 15-23; Or Nieuwland, Rienk; Akkerman, Jan-Willem Nicolaas, Adv. Mol. Cell Biol. (1997), 18 (Platelet), 353-366).

Also, in contrast to the previously described effect on platelet aggregation, the compounds show inhibition of excessive release of von Willebrand factor. This novel antithrombotic action principle differs from the previously disclosed antithrombotic action principle in a very important and convenient way, a) it acts only on ischemic tissue during the subsequent reperfusion phase and is Other cells not affected by blood (before ischemia) remain completely unaffected and b) do not have to worry about any dangerous bleeding complications during lytic treatment.
The invention is illustrated in more detail by the following examples.

The following examples show the effect of extracellular acidosis (pH _ex = 6.4) and the effect of the above compounds of the invention on intracellular pH (pH _i ) and von Willebrand factor (vWF) release. All examples were performed with human umbilical vein endothelial cells (HUVEC). This consists of a primary cell culture isolated from the umbilical vein.

  In the following examples, after the first passage, on gelatin-coated glass plates (measurement of intracellular proton concentration) or cell culture plates (12-well culture plate, Falcon, New Jersey, USA; measurement of vWF release) Cells were cultured in any of the above.

Example 1:
Measurement of intracellular pH To measure intracellular proton concentration (pH _i ), HUVEC was loaded with pH sensitive fluorescent dye BCECF-AM (2 ′, 7′-bis (carboxyethyl) -5 (6) -carboxyfluorescein) did. A Deltascan fluorescence spectrophotometer (PTI, Hamburg) was used for subsequent fluorescence measurements. The measurement system consists essentially of a UV source, a monochromator, a photon detector and a Felix and Oscar software package (PTI, Hamburg) for controlling the system with a computer. After alternating excitation at wavelengths of 439.5 nm (pH independent) and 490 nm (pH sensitive), the measured BCECF release rate (ratio) was recorded and after calibration the pH was examined. The cell measurements were designed so that the temperature and carbon dioxide partial pressure parameters in the system were controlled during continuous perfusion. In the reperfusion simulation, the experimental conditions were 37 ° C., and the partial pressure of carbon dioxide was set to 5% or 10% by supplying gas to the system and perfusate.

In the experiment, a 60-minute preincubation was first used with sodium bicarbonate buffer pH _ex 6.4 to simulate respiratory metabolic acidosis. The starting perfusion was then changed to pH 7.4 sodium bicarbonate buffer with 10 μM histamine as a reperfusion simulation. These control experiments were compared to experiments in which the NHE inhibitor cariporide was added to the reperfusion buffer at a concentration of 10 μM.

The results of several experiments are summarized in Tables 1 and 2.
Table 1: Intracellular pH during extracellular acidosis (pH _i (acidosis)) and under control conditions (Co) for at least 15 minutes.

Extracellular acidosis leads to intracellular acidification, which persists during acidosis. The pH of intracellular acidosis is substantially the same as the extracellular pH (applied extracellular acidosis pH _ex = 6.4).

Table 2: Reperfusion with experimental buffer (HOE) comprising cariporide and control buffer (Co). After 60 minutes of acidosis, the initial rate of increase in pHi values was determined from measurements during the first 30 seconds after reperfusion.

  When the extracellular pH changed from 6.4 to 7.4, the increase rate of intracellular pH decreased 3.6 times compared to the control. Therefore, the use of cariporide during reperfusion can significantly reduce the realkalization rate.

Example 2
Measurement of vWF release after reperfusion
Measurements were performed in a Heraeus Heracell incubator. This makes it possible to calculate umbilical vein endothelial cells under controlled physiological conditions (temperature 37 ° C., relative humidity 100%, pCO ₂ constant 5%) and ensure rapid changes in different cell culture media. .

The cells are first treated with acidosis medium (pH 6.4, ingredient: medium M199w / Earle's
& Amino acid, w / L-glutamine, w / o NaHCO ₃ , w / o Hepes + NaHCO ₃ 0.084 g / l) or pH standard medium (pH 7.4, component: medium M199)
and w / Earle's & amino acids, w / L-glutamine, w / o NaHCO ₃ , w / o Hepes + NaHCO ₃ 2.200 g / l). Before beginning reperfusion, a sample of the supernatant was taken and the vWF concentration was measured under acidosis conditions (vWF acidosis) and control conditions (vWF _co ). In order to simulate reperfusion, the medium is changed to that of pH 7.4 (components: medium M199w / Earle's and amino acids, w / L-glutamine, w / o NaHCO ₃ , w / o Hepes + NaHCO ₃ 2.200 g / l + 10 μM histamine). To this, the NHE inhibitor cariporide was added at a concentration of 10 μM. Changes to similar media without the corresponding inhibitor added serve as controls. The vWF concentration was measured using a sample collected from the supernatant. This was done by ELISA method (enzyme linked antibody immunosorbent assay) using specific antibodies. The vWF content of standard human plasma (Behring, Marburg) was calculated using international standards (2nd International Standard 87/718; National Institute for Biological Standards and Control, London).

Table 3: vWF concentration in cell supernatant under acidosis (vWF acidosis) and control conditions (vWF _co ) measured after 15 minutes incubation. The vWF concentration under control conditions was set at 100%.

In acidosis, the decrease was different in vWF secretion, both constitutive and stimulated Weibel-Parade body secretions. vWF secretion decreased 2-fold compared to control cells during acidosis (pH _ex = 6.4).

Table 4: vWF secretion was measured by stimulation during a 10 minute reperfusion period. Control cell (vWF _co ) vWF secretion was set at 100%. The vWF concentration during reperfusion of preacidosis cells (vWF acidosis) and the vWF concentration during reperfusion of preacidosis cells in the presence of 10 μM cariporide (vWF _HOE ) were shown as values compared to control values. Control cells were incubated with cariporide (vWF _{CO + HOE} ).

  There was a large increase in vWF secretion that doubled during reperfusion. Blocking NHE with cariporide reduced the increase in vWF secretion to almost 60%, thereby approaching the control value. Control cells incubated with cariporide (10 μM) showed no increase or decrease in vWF secretion.

The examples show that extracellular acidosis present, for example during ischemia, leads to intracellular acidosis, resulting in decreased (constitutive and stimulated) vWF secretion and decreased P-selectin expression. Subsequent reperfusion and endothelial cell stimulation resulted in rapid intracellular realkalization. The increase in vWF secretion and the increase in p-selectin expression were simultaneously greatly increased. Delayed realkalization with cariporide reduced increased vWF secretion and P-selectin expression, which alleviated possible thrombosis and inflammatory responses. The examples show that the intracellular pH depends on the extracellular pH. Second, secretion by endothelial cells depends on intracellular pH. Thus, inhibiting realkalization can greatly reduce known endothelial cell activation during the reperfusion phase and greatly reduce concerns regarding rethrombosis (vWF secretion) and inflammation. Incubation of healthy non-acidosis control cells with cariporide had no effect. This indicates that the possibility of side effects is low and excessive bleeding tendency is prevented. The drug acts only where ischemia is present.

Claims (7)

  Use of a sodium / hydrogen exchanger inhibitor for the manufacture of a medicament for preventing and treating acute or chronic diseases caused by elevated levels of von Willebrand factor in blood and / or increased expression of P-selectin. following,

Sodium / hydrogen exchanger inhibitors of at least one of the compounds and / or stereoisomeric forms of the compounds and / or mixtures of any ratios of these forms and / or pharmacologically acceptable salts of the compounds Use according to claim 1, used as   Use according to claim 1 or 2, wherein cariporide is used as an inhibitor of sodium / hydrogen exchanger.   Thrombotic disorders that are later induced by ischemic conditions with reperfusion; thrombosis in acute myocardium, mesentery or cerebral infarction; thrombotic disorders that occur during or after surgery; pulmonary embolism; Deep vein thrombosis, which often occurs after long-term blood flow restriction in the lower limbs, for example after lying or sitting for a long time, and ischemia during vasculitis associated with autoimmune or connective tissue disease And an inflammatory disorder that occurs during and subsequent reperfusion, or an early inflammatory response, prevention and treatment of arteriosclerosis, prevention and treatment of cancer or treatment of arthritic disorders such as joint inflammation and rheumatoid arthritis. Use of any one of -3.   The use according to any one of claims 1 to 4, wherein the compound according to any one of claims 1 to 3 is used in combination with an anticoagulant, a platelet aggregation inhibitor or a fibrinolytic agent.   Additional agents include factor Xa inhibitors, standard heparins, low molecular weight heparins such as enoxaparin, dalteparin, sertropaline, parnaparin or tinzaparin, direct thrombin inhibitors such as hirudin, aspirin, fibrinogen receptor antagonists, streptokinase, urokinase and / or Or the use according to claim 5, selected from the group of tissue plasminogen activators.   Use according to any one of claims 1 to 6, wherein the medicament is administered by oral, inhalation, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection.