CZ2003452A3 - Data processing system, with an Internet connection facility has a structured program loaded in memory for use in assigning predetermined data from a multiplicity of data to hierarchical memory addresses - Google Patents

Abstract

Data processing system with processor and memory units, input and output and a bi-directional interface for connection to the Internet, whereby a program is stored in memory for execution of the following steps: assignment of predetermined data from a multiplicity of data contained in a data pool to hierarchical memory addresses; selection of data from the data pool; and bi-directional transfer of data between hierarchical planes.

Description

Technical field

The present invention relates to novel compounds with an anti-clotting action (so-called anticoagulants), as well as to their pharmacologically acceptable salts and / or salts. solvates and hydrates, pharmaceutical compositions containing them as an active ingredient, a process for the preparation of such compounds, salts and compositions, as well as their use for the prevention and / or treatment of thromboembolic diseases. These compounds, salts and compositions are very potent Factor Xa inhibitors. The present invention also relates to prodrugs, optically active forms, racemates and diastereoisomers of these compounds and salts.

BACKGROUND OF THE INVENTION

Thromboembolic diseases are based on an increased propensity for blood to clot in persons at risk factors such as major surgery, prolonged immobilisation, lower extremity bone fractures, obesity, disorders of blood fat metabolism, Gram-negative organism infections, cancer and older age.

Venous thrombosis may result in edema or inflammation in tissue provided by the affected vein. Deep vein thrombosis (so-called deep vein thrombosis) can lead to serious complications such as pulmonary embolism. Arterial thrombosis can lead to ischemic necrosis of tissue supplied by the affected artery, such as in the case of coronary artery disease to myocardial infarction. Other thromboembolic diseases are eg arteriosclerosis, apoplexy (stroke), angina pectoris, claudicatio intermittens.

Under normal physiological conditions, natural blood coagulation protects against greater blood loss from the blood vessels. During blood coagulation, liquid blood is converted to a blood cake, a jelly-like mass which, by forming a stopper, acts to seal the blood vessels. In a multistage process, the so-called blood coagulation cascade, the conversion of the soluble fibrinogen present in the plasma takes place into a fibrous jelly clot, fibrin.

A distinction is made between two different ways of activating blood coagulation. The intrinsic path of blood clotting occurs when blood comes into contact with non-physiological surfaces.

The external route of blood clotting occurs when the blood vessels are injured. Both blood coagulation routes result in a common pathway in which blood clotting factor X, serine proteinase, is converted to its active form (factor Xa). Factor Xa, together with Factor Va and Ca ²⁺ , causes in the so-called prothrombinase complex that prothrombin is converted to thrombin, which by its cleavage of peptides from fibrinogen releases fibrin monomers that are able to coagulate into fibrin fibers. Factor XIII finally crosslinks and thus stabilizes fibrin fibers.

Anticoagulants are applied in both prevention and treatment of thromboembolic diseases. In a narrower sense, in anticoagulants, immediate-acting heparin, which directly inhibits certain blood clotting factors, is different from vitamin K antagonists (eg coumarin derivatives). The latter inhibit the production of certain clotting factors in the liver, dependent on the presence of vitamin K, and they are only slow in their action. Other blood coagulation suppressants are fibrinolytics which induce direct or indirect activation of the fibrinolytic system and platelet aggregation inhibitors such as acetylsalicylic acid. A more commonly applied procedure is the reduction of blood fibrinogen levels by the ancrod enzyme. The aim of using blood coagulation suppressants is to prevent the formation of a blood clot closing the blood vessel or, once formed, to dissolve it again.

The aforementioned anticoagulants in the narrower sense, ie heparin and vitamin K antagonists, have disadvantages. Heparin distinguishes between unfractionated heparin (UFH) and low molecular weight heparin (LMWH). In UFH, the disadvantage is that it generally has to be administered intravenously, exhibits a fluctuating effect on blood coagulation suppression, making frequent patient monitoring and dose adjustment necessary. Although LMWH can be used subcutaneously in constant dosing without supervision, due to its short chain length it has a reduced effect against UFH.

Vitamin K antagonists, such as warfarin, exhibit different efficacy from patient to patient, possibly genetically determined. In addition to the aforementioned slow-starting effect, this is associated with the disadvantage that patients must be controlled and individual dose adjustment is necessary.

Other known anticoagulants belong to the class of thrombin inhibitors. Current reviews relating to research activities in this field are found, for example, in Jules A. Shafer, Current Opinion in Chemical Biology 2, 458-485 (1988), Joseph P. Vacca, Current Opinion in Chemical Biology 4, 394-400 ( 2000) as well as Fahad AlObeidi and James A. Ostrém, DDT, Volume 3, No. 5, May 223-231 (1998). The decisive disadvantage of thrombin inhibitors is that in order to achieve the desired effect in vivo, a strong suppression of thrombin activity is required in such a way that the tendency to bleed can increase and this makes dosing difficult.

Factor Xa inhibitors, on the other hand, suppress new thrombin production from prothrombin, while not interfering with the existing thrombin activity required for primary hemostasis.

In addition to the aforementioned review articles, the following may be cited for example: DE 197 43 435, DE 197 55 268, DE 198 19 548, DE 198 39 499, and WO 0031068.

The spectra of activity and side effects of these factor Xa inhibitors have not yet been fully investigated.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel compounds with useful properties, in particular a blood coagulation-inhibiting effect.

More specifically, it was an object of the present invention to provide novel Factor Xa inhibitors with improved efficacy, reduced side effect and / or increased selectivity. In addition, suitable pharmaceutical compositions should be made available. These compounds respectively. the compositions should in particular be applicable orally.

Another object of the present invention was to provide a process for the preparation of these novel compounds.

Furthermore, these novel compounds should be useful in the prevention and / or treatment of thromboembolic diseases.

The present invention describes blood clotting compounds, pharmacologically acceptable salts thereof, and the like. solvates and hydrates as well as formulations that are novel, show high activity and selectivity, and can be administered orally. In another aspect, the present invention relates to prodrugs, optically active forms, racemates and diastereoisomers of these compounds and salts. For their part, said compounds and salts can also be prodrugs which are only activated by metabolism. Disclosed are also pharmaceutical compositions, wherein said compounds, respectively, are incorporated herein by reference. salts, etc., contain as active ingredient. In addition, a number of direct and simple syntheses of the compounds of the invention, prodrugs, salts are described

4 as well as compositions and intermediates useful in such syntheses. The use of these compounds for the prevention and / or treatment of thromboembolic diseases is described below.

The present invention provides a compound of formula (I):

in which

X is equal to Cl, Br, or R ¹ -N = C (-NH ₂ ) -, wherein R ¹ is H, OH, -C (= O) OR ² , alkyl, aralkyl, aralkyloxy or heteroalkyl group such as alkyloxy, acyl or acyloxy wherein R ² is alkyl such as methyl, ethyl or tert-butyl, heteroalkyl, carbocyclic, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl such as benzyl;

Ar is equal to arylene, heteroarylene, heteroarylalkylene or aralkylene, wherein X is directly attached to the aromatic ring system;

R ³ is equal to H, alkyl such as C 1 -C 4 alkyl, heteroalkyl or aralkyl;

R ⁴ groups are independent alkyl groups which may be substituted by one or more -OH or -NH ₂ radicals, or heteroalkyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups or aralkyl groups, which groups may be substituted by one or more unsubstituted groups selected alkyl, heteroalkyl such as alkyloxy, acyl or acyloxy, carbocyclic groups, heterocycioalkyl, aryl, heteroaryl or aralkyl, or hydroxy or glycosyloxy groups.

n is an integer from 0 to 5, in particular 0, 1 or 2 (according to a preferred embodiment, n = 0);

R ⁵ is equal to H, alkyl, heteroalkyl, carbocyclic group, heterocycioalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl;

R ⁶ and R ⁷ independently of one another are H, alkyl, heteroalkyl, carbocyclic group, heterocycloalkyl such as aryl-heterocycloalkyl, aryl, heteroaryl, aralkyl or.

Heteroarylalkyl, which groups may be substituted by one or more particularly unsubstituted groups selected from alkyl, heteroalkyl such as alkoxy, acyl or acyloxy, carbocyclic groups, heterocycloalkyl , aryl, heteroaryl, aralkyl, -OH or -NH 2, or together are part of a beterocycloalkyl ring system, especially an arylheterocycloalkyl ring system such as an aryl or heteroaryl-piperazinyl, or a heteroaryl ring system, which systems may be substituted with one or more particularly unsubstituted groups selected from alkyl, heteroalkyl such as alkoxy, acyl or acyloxy, carbocyclic groups, heterocycloalkyl, aryl, heteroaryl, aralkyl, -OH or -NH ₂ ; and

R ⁸ is H, alkyl, heteroalkyl, carbocyclic, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl, or together with R ⁵ is part of a heterocycloalkyl ring system;

or a pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable formulation thereof.

The compounds of formula (I) contain one or more chiral centers due to their substitution. The present invention therefore encompasses both all pure enantiomers and all pure diastereoisomers, as well as mixtures thereof in each mixing ratio.

The term alkyl refers to a straight or branched chain saturated or at least partially unsaturated hydrocarbon group having, for example, 1 to 12 carbon atoms, in particular 1 to 6 carbon atoms such as methyl, ethyl, η-propyl-, isopropyl, η -butyl-, isobutyl-, tert -butyl- n -hexyl-, 2,2-dimethylbutyl-, η-octyl-, allyl-isoprenyl- or hexa-2-enyl.

The term heteroalkyl refers to an alkyl group in which one or more carbon atoms are replaced by at least one oxygen, nitrogen, phosphorus or sulfur atom, with an oxygen and nitrogen atom, such as an alkoxy group such as methoxy or ethoxy, or methoxymethyl, cyano or 2,3-dioxyethyl. Further, the term heteroalkyl refers to a carboxylic acid or a carboxylic acid derived group such as acyl, acyloxy, carboxyalkyl, carboxyalkyl ester such as methyl carboxyalkyl ester, carboxyalkylamide, alkoxycarbonyl or alkoxycarbonyloxy.

The term carbocyclic group refers to a saturated or partially unsaturated cyclic group having one or more scaffold rings comprising, for example, 3 to 14 carbon atoms, in particular 5 or 6 to 10 carbon atoms, such as cyclopropyl, cyclohexyl , tetralin or cyclohex-2-enyl. The heterocycloalkyl group may be further substituted with unsubstituted alkyl, heteroalkyl, heteroaryl or aryl.

The term heterocycloalkyl refers to a carbocyclic group in which one or more carbon atoms are independently replaced by an oxygen, nitrogen, phosphorus or sulfur atom. The heterocycloalkyl group may be further substituted by an unsubstituted alkyl, heteroalkyl, heteroaryl or aryl group and, for example, may be a piperidine, morpholine, N-methylpiperazine or N-phenylpiperazine group.

The term aryl refers to an aromatic cyclic group having one or more rings and consisting of a backbone containing, for example, 5 to 14 carbon atoms, in particular 5 or 6 to 10 carbon atoms. The aryl group may additionally be substituted by unsaturated alkyl or heteroalkyl groups, -OH, -CN, -NO2 or -NH2 and may be, for example, phenyl, naphthyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxyphenyl.

The term heteroaryl refers to an aryl group in which one or more carbon atoms are independently replaced by an oxygen, nitrogen, phosphorus or sulfur atom. In particular, only 1 or 2 carbon atoms are replaced. Examples of such groups are 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl.

The term aralkyl refers to groups which, according to the above definitions, include both aryl and alkyl and / or carbocyclic groups, such as benzyl or tetrahydronaphthalene. The term heteroarylalkyl refers to aralkyl groups in which one or more carbon atoms are independently replaced by an oxygen, nitrogen, phosphorus or sulfur atom, e.g., tetrahydroisoquinolinyl, 2- or 3-ethylindolyl, or 4-methylpyridino.

The terms alkyl, heteroalkyl, carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl and aralkyl refer to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or by -OH, -NH ₂ or -SH . These terms further refer to the corresponding groups which are substituted by unsubstituted alkyl, heteroalkyl, aralkyl or aralkyloxy groups.

The terms arylene, heteroarylene, heteroarylalkylene and aralkylene refer to double substituted aryl, heteroaryl, heteroarylalkyl, and aralkyl groups, i.e., groups bearing at least two substituents other than H.

The term glycosyloxy group in the context of the present invention refers to an α- or β-O-glycosyl bonded saccharide, in particular a monosaccharide, in particular glucose or fructose.

Preferred are compounds of formula (I) or (II) wherein X = R ¹ -N = C (-NH ₂ ) -.

Further preferred are compounds of formula (I) wherein R ¹ = H, OH or C 1 -C 4 -alkyloxy such as methoxy or ethoxy.

Further preferred are compounds of formula (I) wherein Ar is substituted or unsubstituted m-phenylene.

Particularly preferred are compounds of formula (I) wherein Ar is mphenylene in para position to X substituted by -OH, -NH 2, C 1 -C 4 -alkyloxy (e.g. methoxy-), C 1 -C 4 -alkylamino, C 2 -C 6 - dialkylamino or a halogen atom (e.g. chlorine or fluorine).

Further preferred are compounds of formula (I) wherein R ³ = H.

Further preferred are compounds of formula (I) wherein R ⁴ are independently -OH, -OCH 2 COOH, -COOH, C 1 -C 4 -alkyloxy, glycosyloxy or a halogen atom such as F or Cl. A particularly preferred R ⁴ group is -OCH 2 COOH, -COOH or β-D-glucosyloxy.

Further preferred are compounds of formula (I) wherein R ⁵ is H, C 1 -C 6 -alkyl, C 1 -C 6 -heteroalkyl or a natural amino acid chain. Particularly preferred R ⁵ is H or methyl.

Further preferred are compounds of formula (1) wherein R ⁶ and R ⁷ together are part of an aryl- or heteroaryl-piperazinyl ring (especially a 4-aryl- or 4-heteroaryl-piperazinyl ring is preferred).

Further preferred are compounds of formula (I) wherein R ⁸ is H or C 1 -C 6 -alkyl, such as methyl.

Further preferred are compounds of formula (I) having the following structure (II):

where

R ¹ is H, OH or C 1 -C 4 -alkyloxy, such as methoxy or ethoxy;

R ⁴ independently of one another is -OH, -OCH 2 COOH, -COOH, C 1 -C 4 alkyloxy, glycosyloxy (preferably β-D-glucosyloxy) or a halogen atom such as F or Cl; n is equal to 0,1 or 2, in particular 0 or 1;

R ⁵ is H or C 1 -C 4 -alkyl such as methyl;

R ⁹ is H, OH, F or C 1 -C 4 -alkyloxy (particularly preferably methoxy);

R ¹⁰ is equal to H, a halogen atom (F is particularly preferred), CN, NO 2, or C 1 -C 4 -alkyloxy (especially methoxy is preferred);

Y is equal to N or CR ¹¹ a

R ¹¹ is equal to H, a halogen atom (F is particularly preferred), CN, NO 2, or C 1 -C 4 -alkyloxy (particularly preferably methoxy).

Examples of pharmaceutically acceptable salts of the compounds of formulas (I) and (II) are salts of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. The compounds of formulas (I) and (II) may be solvated, in particular hydrated. Hydration can occur, for example, during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formulas (I) and (II).

The pharmaceutical compositions of the present invention contain as active ingredient at least one compound of formulas (I) and (II) and optionally carriers and / or adjuvants.

The prodrugs of the present invention also consist of a compound of formulas (I) or (II) and at least one pharmacologically acceptable protecting group that is cleaved under physiological conditions, e.g., alkoxy, aralkyloxy acyl, or acyloxy groups such as ethoxy, benzyloxy, acetyl or acetyloxy groups.

The compounds of formulas (I) or (II) in which the cyano group is used serve as starting materials for the synthesis of said biologically active compounds. These compounds can be synthesized by methods generally known for amide bond formation. Thus, the acid compound of formula (III) and the amine compound of formula (IV) may be

in a solvent such as dimethylformamide, reacted with a condensing agent such as carbonyldiimidazole or dicyclohexylcarbodiimide and 1-hydroxybenztriazole.

Compounds of formula (III) in which X is a cyano group can be synthesized when the amine of formula (V) is a keto acid of formula (VI)

H (v) wherein X is cyano, reacts with a-

(VI) eg in a solvent such as ethanol or methanol, eg using sodium cyanoborohydride and a catalytic amount of acetic acid.

Alternatively, compounds of formula (III) may be synthesized when the abromacid has reacted with a base such as sodium hydroxide, the solvent is evaporated and excess amine of formula (V) is added and the resulting mixture is stirred for several hours at a preferred temperature of 80 ° to 120 ° C. warms up.

Alternatively, the compounds of formula (III) may be synthesized by reacting an aldehyde such as 3-cyanobenzaldehyde with an amino acid in an aqueous solution of a base such as sodium hydroxide and adding, e.g., sodium cyanoborohydride, preferably below 5 ° C.

In one preferred route of stereoselective synthesis of compounds of formulas (I) and (II), compounds of formula (III) are synthesized when an aryl bromide such as 3-bromobenzonitrile is reacted with a phenylglycine derivative such as (S) -phenylglycine. This synthesis can be carried out, for example, analogously to vMaD. et al., J. Am. Chem. Soc. 120, 12459-12647 (1998) as described above. The compounds of formula (I) and (II) with the (R) configuration on the phenylglycine unit, as well as the corresponding compounds with the (S) configuration, have been found to be very potent inhibitors of Factor Xa with compounds having (S) configurations at the same substitution have slightly better inhibitory properties. In the second amino acid unit of formula (I) or (II), compounds with the (S) configuration are also somewhat better factor Xa inhibitors, whereas the corresponding compounds with the (R) -configuration are also very effective factor Xa inhibitors. Also preferred according to the invention are compounds of formulas (I) or (II) having the S, S-configuration, wherein the compounds with R, S-, SR- and R, R-configuration also have very good inhibitory properties and are included in the invention.

Compounds of formula (IV) can be synthesized by reacting an N-Boc protected amino acid with an amine of formula (XI) using standard coupling methods using a coupling reagent such as carbonyldiimidazole or dicyclohexylcarbodiimide and 1-hydroxybenztriazole. Compounds of formula (IV) may also be synthesized by using mixed anhydrides or 4-nitrophenyl esters of the corresponding N-Boc protected amino acids. Removal of the protecting group on the amine group by treatment with an acid such as hydrochloric acid, trifluoroacetic acid or formic acid in water or dichloromethane leads to the final compounds of formula (IV).

Compounds of formula (I) in which X equals -CN or -C (= NH) NH 2 and R ⁸ is H may also be synthesized according to the invention in one step when the amine of formula (VII), the aldehyde of formula (VIIIa) and the isonitrile of formula (IX) is reacted together in a solvent such as methanol, isopropyl alcohol, ethanol, chloroform, acetonitrile, dichloromethane or in a solvent mixture such as methanol / water, isopropyl alcohol / water, acetonitrile / water or chloroform / water.

·· * ·· «

• · · · ©

The described reaction can be catalyzed by the addition of Bransted acids, such as p-toluenesulfonic acid or 2,4-dinitrobenzenesulfonic acid, or Lewis acids, such as zinc chloride, ferric chloride, boron trifluoroetherate or ytterbium triflate.

Compounds of formula (IX) may be synthesized by reacting an isonitrile of formula (X) with

(XI) in a solvent such as methanol, dichloromethane or dimethylformamide, or also without a solvent, e.g. at room temperature or up to 80 ° C (cf. Matsumoto K. et al., Synthesis 1997, 249-250).

The abovementioned starting compounds, in particular compounds (VII), (VIII), (XI), (V) and (VI) are commercially available and can be prepared from the literature by known methods. Compounds of formula (X) may be synthesized according to the known method of I. Ugi (Publisher of I. Ugi, Isonitrile Chemistry in Organic Chemistry, Volume 20, Academic Press 1971, New York and London).

To convert -CN to -C (= NH) NH 2, the starting nitrile may be dissolved in a solvent such as ethanol or methanol, or a mixture of solvents such as chloroform and methanol or chloroform and ethanol, and this solution is exposed to a stream of anhydrous hydrogen chloride below 10 °. C. After an reaction time of several hours to days, the intermediate is precipitated with ether and filtered off. This intermediate can be dissolved in water and, after neutralization with a base such as sodium carbonate or sodium hydroxide, extracted with a solvent such as dichloromethane, chloroform or acetic acid ester. The material is then treated with anhydrous ammonia

9 · 9 · 9

9999 or an ammonium salt such as ammonium chloride in a solvent such as methanol or ethanol, especially at a temperature of up to 80 ° C. Alternatively, the filtered intermediate can be reacted immediately with anhydrous ammonia or an ammonium salt such as ammonium chloride in a solvent such as methanol or ethanol.

To convert -CN to -C (= NH) NH 2, the starting nitrile may be dissolved in a solvent such as dimethylformamide or ethanol, and a solution such as sodium, sodium hydride or triethylamine and hydroxylamine or salt may be added to the reaction mixture, particularly below 5 ° C. hydroxylamine such as hydroxylamine hydrochloride in a solvent such as dimethylformamide or ethanol. To convert -CN to -C (= NR ¹ ) NH 2 _, where R ¹ = alkoxy, the corresponding alkylhydroxylamine is used instead of hydroxylamine.

To convert -CN to -C (= NH) NH 2, the starting nitrile can first be converted to a compound (I) in which X is -C (= N-OH) NH 2 according to the above procedure. In a second step, the compound is hydrogenated under a hydrogen atmosphere over a catalyst such as palladium or palladium on carbon or platinum or Raney nickel by dissolving it in a solvent such as ethanol or acetic acid.

Compounds of formula (I) wherein R ¹ is -C (= O) OR ² can be synthesized in a solvent such as dimethylformamide or dichloromethane by reacting a compound of formula (I) wherein R ¹ is H with a chloroformic acid ester of formula cic ( = 0) or ² .

Compounds of formula (I), prepared according to any of the above described procedures, can be separated into individual stereoisomers by HPLC.

After synthesis, compounds of formula (I) with X = -C (= NR ¹ ) NH 2 may be converted optionally to a physiologically acceptable salt, solvate or hydrate.

To list only some of the indications, the compound or pharmaceutical composition of the present invention can be used to inhibit factor Xa activity, prevent and / or treat thromboembolic diseases, arterial restenosis, blood poisoning, cancer, acute inflammation, or other diseases that are mediated by factor activity Xa and in particular in venous thromboses, edema or inflammation, deep vein thrombosis, pulmonary embolism, thromboembolic complications after major surgery, vascular surgery, prolonged immobilisation, bone fractures of the lower limbs, etc., in arterial myocardial thrombosis, particularly heart myocardial thrombosis as well as arteriosclerosis, apoplexy, tonsillitis and Claudicatio intermittens.

·· · β * · · β ·· «·

As mentioned at the outset, in general, the active compounds according to the invention should have the highest inhibitory effect against factor Xa with the highest selectivity. In this case, selectivity was appreciated by comparing the inhibitory effect against factor Xa as well as tryptase and thrombin (two other serine proteinases).

As mentioned above, the therapeutic application of the compounds of formulas (I) or (II), their pharmacologically acceptable salts, and the like, is to be understood. solvates and hydrates, as well as formulations and pharmaceutical compositions within the scope of the present invention.

The use of these active substances for the manufacture of medicaments for the prevention and / or treatment of thromboembolic diseases is also an object of the present invention. Generally, the compounds of formulas (I) or (II) are administered using known and acceptable methods either singly or in combination with any therapeutic agent. Such therapeutically useful compositions may be administered by any of the following routes: orally, e.g. as coated tablets, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, eg as injectable solutions; rectally as suppositories; by inhalation, eg as a powder formulation or spray, transdermally or intranasally. For the manufacture of such tablets, pills, semisolids, coated tablets, dragees and hard gelatine capsules, the therapeutically useful product may be admixed with pharmacologically inert, inorganic or organic drug carrier substances, e.g., lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, skimmed milk powder and the like. Drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols can be used to make soft capsules. Drug carriers such as water, alcohols, aqueous salt solutions, aqueous dextrose, polyols, glycerol, vegetable oils, petroleum, animal or synthetic oils can be used to produce liquid solutions and syrups. Drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used for suppositories. Compressed gases suitable for this purpose, such as oxygen, nitrogen and carbon dioxide, are used for aerosol formulations. Pharmaceutically usable compositions may also contain preservatives, stabilizers, emulsifiers, sweeteners, flavoring agents, salts for varying the osmotic pressure, buffers, coating additives and antioxidants.

Combinations with other therapeutic agents may contain other active agents which are usually employed to prevent and / or treat thromboembolic diseases such as warfarin, etc.

For the prevention and / or treatment of the above-described diseases, the dose of the biologically active compound of the invention may vary within a wide range and may be adjusted according to the individual need. Generally, a daily dose is from 0.1 µg to 10 mg / kg body weight, with a preferred dose per day being 0.5 mg to 4 mg / kg. In appropriate cases, the dosage may lie below or above the above values.

The following examples are intended to illustrate the invention. The stereochemistry of 3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy corresponds to the stereochemistry of β-D-glucose.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 0.05 mol of 2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) benzaldehyde (helicin), a solution of 0,05 mol of 3-aminobenzamidine dihydrochloride and a solution of 0,05 mol of 2-isocyanate The 1- [4- (2-methoxyphenyl) piperazin-1-yl] ethanone in methanol was reacted in a sealed vessel for 24 hours at room temperature. After evaporation of the solvent, the product was subjected to liquid chromatography and mass spectroscopy to demonstrate the structure of the final product. Product, 2- {3-Carbamimidoyl-phenylamino) -N- {2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -2-oxo-ethyl} -2- [2- (3,4,5-trihydroxy-6-ol)] -hydroxymethyl-tetrahydropyran-2-yloxy) phenyl] -acetamide can be purified by reverse phase liquid chromatography using water-acetonitrile gradients as eluent.

C ₃₄ H ₄₂ N ₆ O ₉ (678.7486)

ESI-TOF-MS: 679 [M + H] < + > ^.

Example 2

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (4-methoxyphenyl) piperazin-1-yl] 2-oxoethyl} -2- [ 2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) phenyl] acetamide.

C ₃ 4H ₄ 2N ₆ O ₉ (678.7486)

ESI-TOF-MS: 679 [M + H] +

Example 3

Analogously to Example 1, 2-biphenyl-4-yl-2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] was obtained using the appropriate corresponding starting materials. -2-oxoethyl} acetamide.

CíwHseNeOa (576.7044)

ESI-TOF-MS: 577 [M + H] < + > ^.

Example 4

In analogy to Example 1, 2-biphenyl-4-yl-2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (4-methoxyphenyl) piperazin-1-yl] -2- was obtained using the appropriate starting materials. oxoethyl} acetamide.

C34H ₃₆ N ₆ O ₃ (576.7044)

ESI-TOF-MS: 577 [M + H] < + > ^.

Example 5

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -2- (3,4-dimethoxyphenyl) -N- {2- [4- (2-methoxyphenyl) piperazine-1-] was obtained using the appropriate corresponding starting materials. yl] -2-oxoethyl} acetamide.

CsoHssNeOs (560,6586)

ESI-TOF-MS: 561 [M + H] +

Example 6

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -2- (3,4-dimethoxyphenyl) -N- {2- [4- (4-methoxyphenyl) piperazine-1-] was obtained using the appropriate corresponding starting materials. yl] -2-oxoethyl} acetamide.

CaoHaeNeOs (560,6586)

ESI-TOF-MS: 561 [M + H] < + > ^.

I /

/

Example 7 * ·· ♦ ·

Analogously to Example 1, 2 - [(3-cyanophenylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethyl} -2- [ 2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -phenyl] -acetamide.

CmH2N5O5 (661.72)

ESI-TOF-MS: 662 [M + H] +

Example 8

0.8 mol of the product of Example 7 was added to a methanol solution containing an equimolar amount of hydroxylamine hydrochloride and a suitable base such as triethylamine or sodium methoxide and stirred at room temperature for 24 hours. After evaporation of all volatile components, the compound was analogous to Example 1 by liquid chromatography. 2- [3- (N-hydroxycarbamimidoyl) phenylamino] -N {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethyl} -2- [2- (3,4,5,5)] was obtained. trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) phenyl] acetamide as a slightly yellow powder.

C ^ FLzNeOio (694.7480)

ESI-TOF-MS: 695 [M + H] +

Example 9

Analogously to Example 1, 2- (5-carbamimidoyl-2-hydroxyphenylamino) -N- {2- [4- (2,4-difluorophenyl) piperazin-1-yl] -2-oxoethyl was obtained using the appropriate corresponding starting materials. } -2- [2- (3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-yloxy) -phenyl] -acetamide.

C33H3eF ₂ N ₆ O ₉ (700.7024)

ESI-TOF-MS: 701 [M + H] +

Example 10

[3 - {(3-Carbamimidoyl-phenylamino) - {2- [4- (2,4-difluorophenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} was obtained in analogy to Example 1 using the appropriate corresponding starting materials. methyl) phenoxy] -acetic acid.

C ₂₉ H ₃₀ F ₂ N ₆ 0 ₅ (580.5965)

ESI-TOF-MS, 581 (M + H +)

Example 11

In analogy to Example 1, 2- (5-carbamimidoyl-2-hydroxyphenylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethyl} -2-oxoethyl} was obtained using the appropriate starting materials. 2- [2- (3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-yloxy) -phenyl] -acetamide.

C34H4 ₂ N ₆ O ₁₀ (694.7480)

ESI-TOF-MS: 695 [M + H] +

Example 12

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2-cyanophenyl) piperazin-1-yl] -2-oxo-ethyl} -2- was obtained using the appropriate corresponding starting materials. 2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -phenyl] -acetamide.

C34H ₃₉ N ₇ O _e (673.7320)

ESI-TOF-MS: 674 [M + H] +

Example 13

Analogously to Example 1, 2- (5-carbamimidoylpyridin-2-ylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethyl} -2 was obtained using the appropriate corresponding starting materials. [2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -phenyl] -acetamide.

C33H41N ₇ O ₈ (679.7362)

ESI-TOF-MS. 680 [M + H] +

Example 14

{2 - [{2- [4- (4-Bromophenyl) -4-hydroxypiperidin-1-yl] -2-oxoethylcarbamoyl} - (3-carbamimidoyl-phenylamino) "was obtained analogously to Example 1 using the appropriate corresponding starting materials. methyl] phenoxy) acetic acid.

CaoHasBrNsOe (638.5234)

ESI-TOF-MS: 639 (M + H +)

Example 15

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {1- [4- (2-methoxyphenyl) piperazine-1-carbonyl] -2-methylpropyl} -2 was obtained using the appropriate starting materials. -phenyl-acetamide.

CaiHseNeCh (542.6869)

ESI-TOF-MS: 543 [M + H] +

Example 16

[3 - ((3-Carbamimidoyl-phenylamino) - {2- [4- (2-nitrophenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) phenoxy] -acetic acid was obtained analogously to Example 1 using the appropriate corresponding starting materials. acid,

C29H31N7O7 (589.6131)

ESI-TOF-MS: 590 [M + H] +

Example 17

[5 - ((3-Carbamimidoyl-phenylamino) - {2- [4- (2,4-difluorophenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) was obtained analogously to Example 1 using the appropriate corresponding starting materials. -2-methoxyphenoxy] -acetic acid.

CaoHaaFaNeOe (610,6229)

ESI-TOF-MS: 611 [M + H] +

Example 18

Analogously to Example 1, [3 - ((3-carbamimidoyl-phenylamino) - {2- [4- (2,4-dimethoxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl was obtained using the appropriate corresponding starting materials. (phenoxy) -acetic acid.

CaiHaeNeOy (604.6686)

ESI-TOF-MS: 605 [M + H] +

Example 19

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- [2-oxo-2- (4-pyridin-4-ylmethylpiperazin-1-yl) ethyl] -2- was obtained using the appropriate starting materials. phenyl acetamide.

C ₂ 7H ₃₁ N ₇ O ₂ (485.5938)

ESI-TOF-MS: 486 [M + H] +

Example 20

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2-nitrophenyl) piperazin-1-yl] -2-oxo-ethyl} -2- was obtained using the appropriate corresponding starting materials. phenyl acetamide.

C27H29N7O4 (515.5767)

ESI-TOF-MS: 516 [M + H] +

Example 21

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- {4- (2,4-difluorophenyl) piperazin-1-yl] -2-oxoethyl} -2-phenyl was obtained using the appropriate corresponding starting materials. -acetamide.

C ₂ 7H28F ₂ N ₆ O2 (506.5600)

ESI-TOF-MS. 507 [M + H] +

Example 22

In analogy to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2,4-difluorophenyl) piperazin-1-yl] 2-oxoethyl} -2-oxoethyl} -2 was obtained using the appropriate corresponding starting materials. [2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -phenyl] -acetamide.

C ₃₃ H38F ₂ N ₆ O ₆ (684.7030)

ESI-TOF-MS: 685 [M + H] +

Example 23

In analogy to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- [2-oxo-2- (4-pyridin-4-yl-piperazin-1-yl) -ethyl] - was obtained using the appropriate starting materials. 2-phenyl-acetamide.

C26H29N7O2 (471.5667)

ESI-TOF-MS: 472 (MH < + ^>)

Example 24

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2,4-dimethoxyphenyl) piperazin-1-yl] -2-oxoethyl} -2 was obtained using the appropriate starting materials. [2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -phenyl] -acetamide.

C35H44N6O10 (708.7751)

ESI-TOF-MS: 709 [M + H] < + > ^.

Example 25

In analogy to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- [2-oxo-2- [4- (pyridin-4-yl-piperazin-1-yl) -ethyl] -ethyl] was obtained using the appropriate corresponding starting materials. 2- [2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -phenyl] -acetamide.

C ₃ 2H ₃₉ N ₇ O (649.7097) ESI-TOF-MS: 650 [Μ + H]

Example 26

Analogously to Example 1, 2- (3-carbamimidoyl-phenylainino) -N- {2- [4- (2-nitrophenyl) piperazin-1-yl] -2-oxoethyl} -2- [2] was obtained using the appropriate corresponding starting materials. - (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) phenyl] acetamide,

C ₃₃ H ₃₉ N ₇ Oio (693.7197)

ESI-TOF-MS: 694 [M + H] < + > ^.

Example 27

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2 ₎ 4-dimethoxyphenyl) piperazin-1-yl] -2-oxoethyl} -2 was obtained using the appropriate corresponding starting materials. -phenyl-acetamide.

θ29Η34Νβθ4 (530.6321)

ESI-TOF-MS: 531 [M + H] +

Example 28

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] 2-oxoethyl} -2-phenyl was obtained using the appropriate corresponding starting materials. acetamide.

C ₂ 8H ₃ 2N ₆ O ₃ (500.6056)

ESI-TOF-MS: 501 [M + H] < + > ^.

Example 29

[2 - ((3-Carbamimidoyl-phenylamino) - {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) phenoxy] was obtained in analogy to Example 1 using the appropriate corresponding starting materials. -acetic.

C ₃ oH ₃ N ₆ 0 ₆ (574.6421)

ESI-TOF-MS: 575 [M + H] < + > ^.

Example 29a

[3 - ((3-Carbamimidoyl-phenylamino) - {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) was obtained analogously to Example 1 using the appropriate corresponding starting materials. phenoxy] -acetic.

CaoH 4 NeOe (574.6421)

ESI-TOF-MS: 575 [M + H] +

Example 30

[2 - ((3-Carbamimidoyl-phenylamino) - {2- [4- (2-hydroxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) was obtained analogously to Example 1 using the appropriate corresponding starting materials. phenoxy] -acetic.

C29H32N6O6 (560.6150)

ESI-TOF-MS: 561 [M + H] +

Example 31

[2 - ((3-Carbamimidoyl-phenylamino) - {2- [4- (3-cyanophenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) was obtained analogously to Example 1 using the appropriate corresponding starting materials. phenoxy] -acetic.

C30H31N7O5 (569.6255)

ESI-TOF-MS: 570 [M + H] +

Example 32

Analogously to Example 1, 4 - ((3-carbamimidoyl-phenylamino) - {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) benzoic acid was obtained using the appropriate corresponding starting materials. .

C ^ HaaNeOs (544.6156)

ESI-TOF-MS: 545 [M + H] +

Example 33

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- [2- (4-hydroxy-4-phenylpiperidin-1-yl) -2-oxoethyl] -2-phenyl was obtained using the appropriate corresponding starting materials. I-acetam id.

C ₂₈ H ₃ iN ₅ O ₃ (485.5910)

ESI-TOF-MS; 486 [M + H] < + > ^.

Example 34

[4 - {(3-Carbamimidoyl-phenylamino) - {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl] was obtained analogously to Example 1 using the appropriate corresponding starting materials. phenoxy] -acetic.

C ^ H ^ NeOs (574.6421)

ESI-TOF-MS: 575 [M + H] +

Example 35

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (4-methoxyphenyl) piperazin-1-yl] 2-oxoethyl} -2-phenyl was obtained using the appropriate corresponding starting materials. -acetamide.

C ₂₈ H ₃₂ N ₆ O ₃ (500.6056)

ESI-TOF-MS: 501 [M + H] +

Example 36

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -2- (2-hydroxyphenyl) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] was obtained using the appropriate corresponding starting materials. -2-oxoethyl} acetamide.

C ₂₈ H ₃ 2N ₆ O4 (516.6050)

ESI-TOF-MS. 517 [M + H] +

Example 37

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N - {[(pyridin-3-ylmethyl) carbamoyl] methyl} -2- (2- (3,4,5,5) was obtained using the appropriate starting materials. - trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) phenyl acetamide.

C29H ₃ 4N ₆ O ₈ (594.6297)

ESI-TOF-MS: 595 [M + H] +

Example 38

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] 2-oxoethyl} -2-oxoethyl} -2- (3-carbamimidoyl-phenylamino) was obtained using appropriate corresponding starting materials. 3- (3-Trifluoromethylphenoxy) phenyl] acetamide.

C35H35F3N6O4 (660.7022)

ESI-TOF-MS: 661 [M + H] +

Example 39

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -2- (3,4-dimethoxyphenyl) -N- {2- [4- (4-methoxyphenyl) piperazine-1-] was obtained using the appropriate corresponding starting materials. yl] -2-oxoethyl} acetamide.

CsoHseNeOs (560,6586)

ESI-TOF-MS: 561 [M + H] +

Example 40

[2-Benzyloxy-5 - ((3-carbamimidoyl-phenylamino) - {2- [4 (2-methoxy-phenyl) -piperazin-1-yl] -2] - was obtained analogously to Example 1 using the appropriate corresponding starting materials. (oxoethylcarbamoyl} methyl) phenoxy] -acetic acid.

C ₃₇ H4oN ₆ 07 (680.7674)

ESI-TOF-MS: 681 (M + H < + >)

• · * ··· · ·

Example 41 mmol of 3-bromobenzonitrile, 40 mmol of (S) -phenylglycine, 60 mmol of potassium carbonate and 4 mmol of cuprous iodide were stirred in 50 ml of dry dimethylacetamide under inert gas (N ₂ ) for 24 h at 100 ° C. After solvent removal, fragment I was purified by liquid chromatography. At room temperature (RT) overnight, 20 mmol of Boc-sarcosine, HOBt, diisopropylcarbodiimide (DIC), piperazine and triethylamine were stirred in 110 ml of dimethylformamide (DMF). After removal of the solvent in vacuo, the resulting crude product was purified by column chromatography. The resulting product was stirred in a mixture of 20 ml of trifluoroacetic acid and 20 ml of dichloromethane at room temperature for 5 h. After removal of the solvent, fragment II was purified by liquid chromatography.

After 2 mmol of fragment I, fragment II, DIC, HOBt and triethylamine in 14 ml DMF were stirred at RT overnight. After removal of the solvent, the crude product was purified by liquid chromatography. To convert the cyanide to amidine, 1 mmol of cyanide was dissolved in 10 mL of chloroform, to which was added 5 mL of a saturated solution of hydrogen chloride in dry methanol and left to stand at 4'C for two days. After removal of the solvent in vacuo, 20 ml of anhydrous ammonia in methanol solution were added thereto and stirred for 4 h at RT. The desired product, 2- (3-carbamimidoyl-phenylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethyl} -N-methyl-2-phenyl-acetamide was purified by HPLC.

C29H34N ₆ O3 (514.6327)

ESI-TOF-MS: 515 [M + H] +

Example 42

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- {2- | 4- (2-methoxyphenyl) piperazin-1-yl] 1-methyl-2-oxoethyl} was obtained using the appropriate corresponding starting materials. -2-phenyl-acetamide.

In addition, analogous to Example 41, four diastereoisomers were selectively synthesized using the appropriate corresponding starting compounds.

C29H ₃ 4N ₆ O ₃ (514.6327)

ESI-TOF-MS: 515 [M + H] +

Example 43

[2-Benzyloxy-5 - ((3-carbamimidoyl-phenylamino) - {244 (2-hydroxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) was obtained in analogy to Example 1 using the appropriate corresponding starting materials. phenoxy] -acetic.

C36H38N6O7 (666.7403)

ESI-TOF-MS: 667 [M + H] < + > ^.

Example 44

Analogously to Example 1, 4 - ((3-carbamimidoyl-phenylamino) - {2- [4- (2-nitrophenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) was obtained using the appropriate corresponding starting materials - benzoová.

C ₂ 8H29N ₇ O ₆ (559.5866)

ESI-TOF-MS: 560 [M + H] < + > ^.

Example 45

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N - {[(pyridin-3-ylmethyl) carbamoyl] methyl} -2-quinolin-4-yl-acetamide was obtained using the appropriate corresponding starting materials.

C26H ₂ 5N ₇ O ₂ (467.5349)

ESI-TOF-MS: 468 [M + H] +

Example 46

Analogously to Example 1, 2- (3-carbamimidoyl-phenylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1-Hisoquinolin-2-yl) -2] was obtained using appropriate appropriate starting materials. oxoethyl] -2- [2- (3 ₎ 4,5-thhydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) phenyl] acetamide.

C34H ₄ iN ₅ Oio (679.7334)

ESI-TOF-MS: 680 [M + H] < + > ^.

Example 47

Analogously to Example 1, N- [2- (4-acetyl-4-phenylpiperidin-1-yl) -2-oxoethyl] -2- (3-carbamimidoylphenylamino) -2- [2- (3,4 ₍ 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) phenyl) acetamide.

C36H43N5O9 (689.7722)

ESI-TOF-MS: 690 [M + H] +

Example 48

(3 - {(3-carbannimidoyl-phenylamino) - [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -2] - (oxoethylcarbamoyl] methyl} phenoxy) acetic acid.

C30H33N5O7 (575.6268)

ESI-TOF-MS: 576 [M + H] +

Example 49

Analogously to Example 1, using the appropriate corresponding starting materials, {3 - [[2- (4-acetyl-4-phenylpiperidin-1-yl) -2-oxoethylcarbamoyl] - (3-carbamimidoyl-phenylamino) methyl] phenoxy was obtained. } -octová.

C32H35N5O6 (585.6657)

ESI-TOF-MS: 586 [M + H] +

Example 50

[3 - ((3-Carbamimidoyl-phenylamino) - {2- [4- (2,4-difluorophenyl) piperazin-1-yl] -2-oxoethylcarbamoyl) tert-butyl ester was obtained analogously to Example 1 using appropriate corresponding starting materials. (methyl) phenoxy] acetic acid.

C ₃ 3H 3gF ₂ N ₆ O5 (636.7048)

ESI-TOF-MS: 637 [M + H] +

Example 51

Analogously to Example 1, 2- (5-carbamimidoyl-2-methoxyphenylamino) -N- {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethyl} -2-oxoethyl} was obtained using the appropriate starting materials. 2- [2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -phenyl] -acetamide.

CashtwNeOio (708,7751)

ESI-TOF-MS: 709 [M + H] < + > ^.

Example 52

Analogously to Example 1, using the appropriate corresponding starting materials, 4- [4 - ((3-carbamimidoyl-phenylamino) - {2- [4- (2-methoxyphenyl) piperazin-1-yl] -2-oxoethylcarbamoyl} methyl) was obtained -3-methoxyphenoxy} -butyrate.

CaaH ^ NeOy (632.7228)

ESI-TOF-MS: 633 [M + H] +

Chromogenic peptide substrates were used to demonstrate inhibitory activity on factor Xa activity. The inhibition of the amidolytic activity of Factor Xa by the compounds described above was demonstrated as follows. Measurements were performed on microtiter plates at room temperature. Compounds were dissolved in dimethylsulfoxide and 5 μΙ of this solution was added to a 1 nM solution of recombinant factor Xa (Enzyme Research Laboratories, South Bend, IN, USA) in buffer (pH: 8.0 and using 50 mM Tris-HCl, 100 mM NaCl). , 0.1% PEG 6000 and 0.05% Tween 80). Finally, 200 μΜ of N-methoxycarbonyl-D-norleucyl-glycyl-L-arginine-4-nitranilide acetate (Roche Diagnostics, Mannheim, Germany) was added in buffer and the hydrolysis was monitored for 20 min using a Spectra Fluor Plus spectrophotometer (Tecan, Crailsheim, Germany). ). IC 50 values were calculated using the graphite 4 program of Erithacus Software Ltd. (Staines, Middlesex, UK). Assuming that the kinetics showed competitive inhibition, the K value could be determined according to the Cheng-Prusoff equation: K = IC 50 / (1 + [S] / Km) [Cheng and Prusoff, Biochemical Pharmacology 22, 3099-3108 (1973)]. The same method, but using tosyl glycylprolyl-lysine-4-nitranilide acetate as a substrate in Hepes buffer (pH 7.8), was used to determine the inhibition of the proteolytic activity of recombinant human tryptase (Promega Madison, Wi, USA) ) with the named compounds.

The IC50 values of the above examples range from 1 nM to 1 μΜ.

Claims (15)

PATENT CLAIMS 1. Compounds of formula (I): in which X represents Cl, Br, or R ¹ -N = C (-NH ₂ ) -, wherein R ¹ is H, OH, -C (= O) OR ² , alkyl, aralkyl, aralkyloxy or heteroalkyl group such as alkyloxy, acyl or acyloxy, wherein R ² is equal to alkyl, heteroalkyl, carbocycle, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl; Ar is equal to arylene, heteroarylene, heteroarylalkylene or aralkylene, wherein X is attached directly to the aromatic ring system; R ³ equals H, alkyl, heteroalkyl or aralkyl; R ⁴ groups are independent alkyl groups which may be substituted by one or more -OH or -NH ₂ radicals, heteroalkyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups or aralkyl groups, which groups may be substituted by one or more unsubstituted groups selected from alkyl, heteroalkyl such as alkyloxy, acyl or acyloxy, carbocyclic groups, heterocycloalkyl, aryl, heteroaryl or aralkyl, or are hydroxy or glycosyloxy groups; n is an integer from 0 to 5; R ⁵ is equal to H, alkyl, heteroalkyl, carbocyclic, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl; R ⁶ and R ⁷ independently of one another are H, alkyl, heteroalkyl, carbocyclic group, heterocycloalkyl such as arylheterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, which groups may be substituted by one or more groups selected from alkyl, heteroalkyl such as alkyloxy , acyl or acyloxy, carbocyclic groups, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, aralkyl, -OH or -NH _2, or together are part of a heterocycloalkyl ring system, especially an arylheterocycloalkyl ring system such as an aryl-piperazinyl, or a heteroaryl ring a system which may be substituted by one or more groups selected from alkyl, heteroalkyl such as alkyloxy, acyl or acyloxy, carbocyclic groups, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, aralkyl, -OH or -NH ₂ ; and R ^{5 6 7 8 9} is H, alkyl, heteroalkyl, carbocyclic, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl or, together with R ^5, is part of a heterocycloalkyl ring system; or a pharmaceutically acceptable salt, solvate, hydrate or pharmacologically acceptable formulation thereof. Compounds according to claim 1, wherein X is R ¹ -N = C (-NH ₂ ) -. Compounds according to claim 1 or 2, wherein R ¹ is H, OH or C 1 -C ₄ -alkyloxy. Compounds according to any one of claims 1 to 3, wherein Ar is optionally substituted metaphenylene. Compounds according to any one of claims 1 to 4, wherein Ar at para-position to X is substituted with -OH, -NH ₂ , C 1 -C 4 -alkyloxy, C 1 -C ₄ -alkylamino, C 1 -C 4 -alkyloxy C ₂ -CE-dialkylamino group or a halogen atom. Compounds according to any one of claims 1 to 5, wherein R ³ is H. Compounds according to any one of claims 1 to 6, wherein the radicals R ⁴ are independently -OH, -OCH ₂ COOH, -COOH, C 1 -C ₄ -alkyloxy, glycosyloxy or a halogen atom. Compounds according to any one of claims 1 to 7, wherein n = 0, 1 or 2. 9. Compounds according to any of claims 1-8, wherein ^R is H, alkyl CICE, CICE or heteroalkyl side chain of a natural amino acid. • φ · φ · · · · · · · · · · · · Compounds according to any one of claims 1 to 9, wherein R ⁶ and R ⁷ together are part of an arylpiperazinyl ring. Compounds according to any one of claims 1 to 10, wherein R ⁸ is H or C 1 -C ₆ alkyl. Pharmaceutical compositions, characterized in that they contain, as active ingredient, a compound according to claims 1 to 11 and optionally carriers and / or adjuvants. Use of a compound or pharmaceutical composition according to any one of claims 1 to 12 for inhibiting factor Xa. Use of a compound or pharmaceutical composition according to any one of claims 1 to 12 for the treatment and / or prevention of thromboembolic diseases, arterial restenosis, blood poisoning, cancer, acute inflammation or other diseases which are mediated by factor Xa activity. Use of a compound or pharmaceutical composition according to any one of claims 1 to 12 for administration in vascular surgery.