WO2005007157A1 - Pyrazolines as par-1 antagonists for treatment of cardiovascular diseases - Google Patents

Abstract

The invention relates to pyrazolines of formula (I), where E = methylene, NH, O or S and R2 = a group of formula (II), methods for the production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases, in particular, cardiovascular diseases, such as thromboembolitic diseases.

Description

PYRAZOLINE AS A PAR-1 ANTAGONIST FOR THE TREATMENT OF HEART CIRCULAR DISEASES

The present invention relates to the field of blood coagulation. The present invention relates in particular to the use of pyrazolines as medicaments, new pyrazolines and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases, preferably thromboembolic diseases ,

Platelets (platelets) are an important factor both in physiological hemostasis (hemostasis) and in thromboembolic disorders. In the arterial system in particular, platelets are of central importance in the complex interaction between 10 blood components and the wall of the vessel. Undesired thrombocyte activation can lead to thromboembolic disorders and thrombotic complications with life-threatening conditions through the formation of platelet-rich thrombi.

One of the most potent platelet activators is the coagulation protease thrombin, which is formed on injured blood vessel walls and, in addition to fibrin formation, leads to the activation of thrombocytes, 15 endothelial cells and mesenchymal cells (Vu TKH, Hung DT, Wheaton VI, Coughlin SR, Cell 1991, 64, 1057- 1068). Thrombin inhibitors inhibit platelet aggregation or the formation of platelet-rich thrombi on platelets in vitro and in animal models. In humans, arterial thrombosis can be successfully treated with inhibitors of platelet function as well as inhibitors of platinum (Bhatt DL, Topol EJ, Nat. Rev. Drug Discov. 2003, 20 2, 15-28). Therefore, there is a high probability that antagonists of thrombin effects on platelets reduce thrombus formation and the occurrence of clinical consequences such as heart attack and stroke. Other cellular thrombin effects, e.g. on vascular endothelial and smooth muscle cells, leukocytes and fibroblasts, may be responsible for inflammatory and proliferative diseases.

25 The cellular effects of thrombin are mediated, at least in part, by a family of G protein-coupled receptors (Protease Activated Receptors, PARs), the prototype of which is the PAR-1 Rezeppr. PAR-1 is activated by binding thrombin and proteolytic cleavage of its extracellularly located N-terminus. Proteolysis exposes a new N-terrinin with the amino acid sequence SFLLR ... which, as an agonist ("tethered ligand"), leads to intramolecular receptor activation and transmission of intracellular signals. Peptides derived from the tethered ligand sequence can act as agonists of the receptor and are used on platelets for activation and aggregation. Antibodies and other selective PAR-1 antagonists inhibit thrombin-induced platelet aggregation in vitro at low to medium thrombin concentrations (Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR, J. Clin. Luvest. 1999, 103, 879-887). Another thrombin receptor with possible significance for the pathophysiology of thrombotic processes, PAR-4, was identified on human and animal platelets. In experimental thromboses in animals with a PAR expression pattern comparable to humans, PAR-1 antagonists reduce the formation of platelet-rich thrombi (Derian CK, Damiano BP, Addo MF, Darrow AL, D'Andrea MR, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861).

In recent years, a large number of substances have been tested for their anti-platelet effect. Only a few platelet inhibitors have proven themselves in practice. There is therefore a need for pharmaceuticals which specifically inhibit an increased platelet reaction without significantly increasing the risk of bleeding and thus reducing the risk of thromboembolic complications. In contrast to inhibiting the protease activity of thrombin with direct thrombin inhibitors, blocking the P R-1 should inhibit platelet activation without reducing the blood's ability to clot.

An object of the present invention is therefore to develop new PAR-1 antagonists for the treatment of cardiovascular diseases, such as e.g. to provide thromboembolic disorders in humans and animals.

EP-A 466 408, EP-A 438 690, EP-A 532 918 and WO 93/24463 describe structurally similar pyrazoline derivatives and their use as pesticides.

WO 02/00651 describes pyrazoline derivatives as factor Xa inhibitors for the treatment of thromboembolic disorders.

The present invention relates to compounds of the formula

in which E represents methylene, MI, an oxygen atom or a sulfur atom,

m represents 0, 1, 2 or 3,

n represents 1, 2 or 3,

R ^{1 represents} halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl, alkylaminocarbonyl or -NH (C = 0) OR ⁹ , where

R ^{9 represents} (QC -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₆ -Cι ₀ ) -aryl, (C ₃ -C ₇ ) -cycloalkylmethyl or (C6-C ₁₀ ) -arylmethyl,

R ² for a group of the formula

stands where

* X is the linkage site to the pyrazoline ring, for R ^3, or (C ₁ -C ₈₎ alkylene-R ^4, where alkylene having 1 to 4 fluorine atoms may be substituted, Y is R ³ or _(C, -C ₈ ) -Alkylene-R ⁴ , where alkylene can be substituted with 1 to 4 fluorine atoms,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin , Indanyl, 1,2,3,4-tetrahydronaphthyl, (C ₆ -Cιo) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₆ ) cycloalkyl or 5- to 10-membered heterocyclyl, where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl , Alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{4 is} hydrogen, 1, 3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3 -benzodioxin, indanyl, 1,2,3,4-tetra- ^ hydronaphthyl, (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₇ ) cycloalkyl, 5- to 10 -linked heterocyclyl, hydroxy, cyano, trifluoromethyl, alkylthio optionally substituted with fluorine, -OR ⁵ , -C (= O) R ⁶ or -NR ⁷ R ⁸ , where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted by 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, optionally substituted with alkoxycarbonyl alkoxy, alkylamino, aryl, benzyl , Hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ⁵ represents optionally fluorine-substituted alkyl, (C ₆ -Cι ₀₎ -aryl, benzyl, (C ₃ -C ₇₎ - cycloalkyl or alkylcarbonyl, where aryl, benzyl or cycloalkyl may be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylamino carbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{6 represents} hydroxyl, amino, alkyl, alkylamino, alkoxy, (C ₆ -Cι ₀ ) aryl, benzyloxy or 5- to 10-membered heterocyclyl, where aryl or benzyloxy can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino , Aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{7 represents} hydrogen, alkyl or benzyl, R ^{8 represents} hydrogen, alkyl, phenyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylcarbonyl optionally substituted by alkyl or arylsulfonyl optionally substituted by alkyl,

and their salts, their solvates and the solvates of their salts

for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases, such as thromboembolic disorders.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts; the compounds of formula (T) encompassed by the formulas mentioned below and their salts, solvates and solvates of the salts, and the compounds encompassed by formula (I) hereinafter referred to as exemplary embodiments and their salts, solvates and solvates of the salts, insofar as the Compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore encompasses the enantiomers or diastereomers and their respective mixtures. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the invention. Also included are salts for pharmaceutical Applications themselves are not suitable but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, triftuoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzene acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dime ylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.

In the context of the present invention, unless otherwise specified, the substituents have the following meaning:

Alkyl per se and "alk" and "alkyl" in alkoxy, all ylamino, alkoxycarbonvh alkylaminocarbonvh alkylcarbonyl. Alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl represent a linear or branched alkyl radical having 1 to 8, usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methyl, ethyl, propyl, isopropyl, "-Butyl, tert-butyl," -pentyl and w-hexyl.

Alkylene stands for a straight-chain or branched alkylene radical with generally 1 to 8, preferably 1 to 6 carbon atoms, which optionally contains one or more double or triple bonds. Examples include and are preferably methylene, ethylene, propylene, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl, pentane-2,4-diyl , 2-methyl-pentane-2,4-diyl. Alkoxy is exemplary and preferably methoxy, ethoxy, ra-propoxy, isopropoxy, tert-butoxy,. z-pentoxy and n-hexoxy.

Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, for example and preferably for memylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, "-pentylamino, .z-hexylamino, NN-dimethylamino, NN-diethylamino , N-ethyl-N-methylamino, N-methyl-N -? .- propylamino, N-isopropyl-N-rc-propylamino, N-tert-butyl-N-memylamino, N-ethyl-Nn-pentylamino and N - «- hexyl-N-methylamino. - C ₃ alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical each having 1 to 3 carbon atoms per alkyl substituent

Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and ra-hexoxycarbonyl.

Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, the alkyl substituents usually independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl. .-Propylamino-carbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, w-pentylaminocarbonyl, n-hexylamino-carbonyl, NN-dimemylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-memylamino-carbonyl, N-methyl-Nn-propylaminocarbonyl N-isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-myylaminocarbonyl, N-ethyl-N-λ.-pentylamino-carbonyl and N - «- hexyl-N-methylaminocarbonyl. -C-C ₃ -All ylan__nocarbonyl stands for example for a monoalkylamino carbonyl radical with 1 to 3 carbon atoms or for a dialkylaminocarbonyl radical with 1 to 3 carbon atoms per alkyl substituent.

Alkylcarbonyl is exemplified and preferably methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylca bonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.

Alkylcarbonyloxy is an example and preferably methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, w-pentylcarbonyloxy and n-hexylcarbonyloxy.

Alkylcarbonylamino is exemplary and preferably methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino. Alkylsulfonyl is exemplified and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

Cycloalkyl stands for a mono- or bicyclic cycloalkyl group with usually 3 to 8, preferably 5 or 6 carbon atoms, examples and preferably for cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and norbornyl.

Aryl per se and "aryl" in aryloxy and arylcarbonylamino stands for a mono- to tricyclic aromatic radical with generally 6 to 14, preferably 6 to 10 carbon atoms, by way of example and preferably for phenyl, naphthyl and phenanthrenyl.

Aryloxy is exemplary and preferably phenyloxy and naphthyloxy.

Arylcarbonylamino is exemplary and preferably phenylcarbonylamino and naphthylcarbonylamino.

Heteroaryl stands for an aromatic mono- or bicyclic radical with generally 5 to 10, preferably 5 or 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, for example and preferably for thienyl, furyl, Pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.

Heterocyclyl stands for an optionally benzocondensed, mono- or bicyclic, heterocyclic radical with usually 3 to 10, preferably 5 to 10, in particular 5 or 6 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N. , O, S, SO, SO ₂ . The heterocyclyl residues can be saturated or partially unsaturated. 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the O, N and S series are preferred, for example and preferably for oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, Tetrahydrofuranyl, tetrahydro-thienyl, pyranyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3- yl, perhydroazepinyl, piperazin-1-yl, piperazin-2-yl.

Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

A symbol # on a carbon atom means that the compound is present in enantiomerically pure form with regard to the configuration on this carbon atom, which in the context of the present invention is understood to mean an enantiomeric excess of more than 90% (> 90% ee). If radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted, the radicals can, unless otherwise specified, be substituted one or more times in the same or different ways. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.

The present invention furthermore relates to compounds of the formula (I)

in which

E represents methylene, NH, an oxygen atom or a sulfur atom,

m represents 0, 1, 2 or 3,

n represents 1, 2 or 3,

R ^{1 represents} halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl, alkylaminocarbonyl or - NH (C = 0) OR ⁹ , where R ^{9 represents} (C, -C ₆ ) Alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₇ ) cycloalkylmethyl or (C ₆ -Cιo) arylmethyl,

R ² for a group of the formula

stands where

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (CC ₈ ) alkylene-R ⁴ , where alkylene can be substituted with 1 to 4 fluorine atoms,

Y represents (CC ₈ ) alkylene-R ⁴ , where alkylene can be substituted by 1 to 4 fluorine atoms,

R ³ for 1,3-benzodioxol, 2,2-difluoro-l, 3-benzodioxol, 2,3-dihydro-l, 4-behzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin , Indanyl, 1,2,3,4-tetrahydronaphthyl, (C ₆ -Cιo) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₆ ) cycloalkyl or 5- to 10-membered heterocyclyl, where Aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, Alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{4 is} hydrogen, 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3 -benzodioxin, indanyl, 1,2,3,4-tetrahydronaphthyl, (C ₆ -Cιo) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₇ ) cycloalkyl, 5- to 10-membered Heterocyclyl, hydroxy, cyano, trifluoromethyl, optionally fluorine-substituted alkylthio, -OR ⁵ , -C (= O) R ⁶ or -NR ⁷ R ⁸ , where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents , independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxycarbonyl optionally substituted with alkoxycarbonyl, alkylamino, aryl, benzyl, hydroxycarbonyl , Alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{5 represents} alkyl which is optionally substituted by fluorine, (C ₆ -C ₀ ) aryl, benzyl, (C ₃ -C ₇ ) cycloalkyl or alkylcarbonyl, where aryl, benzyl or cycloalkyl can be substituted with 1 to 3 substituents, independently of one another selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy , Alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{6 represents} hydroxy, amino, alkyl, alkylamino, alkoxy, (C ₆ -Cι ₀ ) aryl, benzyloxy or 5- to 10-membered heterocyclyl, where aryl or benzyloxy can be substituted with 1 to 3 substituents, independently of one another from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{7 represents} hydrogen, alkyl or benzyl,

R ^{8 represents} hydrogen, alkyl, phenyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylcarbonyl optionally substituted by alkyl or arylsulfonyl optionally substituted by alkyl,

and their salts, their solvates and the solvates of their salts.

Compounds of the formula (I) are preferred

in which

E represents methylene, NH or an oxygen atom,

m represents 0, 1 or 2,

n represents 1, 2 or 3,

R ^{1 represents} halogen, amino, cyano, nitro, trifluoromethyl, alkyl or alkoxy,

R ² for a group of the formula -X -N- -YH

stands,

in which

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (CC ₈ ) alkylene-R ⁴ ,

Y represents (C, -C ₈ ) alkylene-R ⁴ ,

R ³ for 1,3-benzodioxole, 2,2-difluoro-1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, 2,2,4,4-tetrafluoro-4H-1,3-benzodioxin , Indanyl, 1,2,3, 4-tetrahydronaphthyl, phenyl, 5- or 6-membered heteroaryl, (C ₃ -C ₆ ) -cycloalkyl or 5- or 6-membered heterocyclyl, where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (CC ₄ ) alkyl, (CC ₄ ) -Alkoxy, (-C ^ -alkylamino, phenyl, hydroxycarbonyl, (Cι-C ₄ ) -alkoxycarbonyl, aminocarbonyl, (Ci- C) -alkylaminocarbonyl and (-CC ₄ ) -alkylcarbonyl,

R ^{4 is} hydrogen, 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3 -benzodioxin, indanyl, 1,2,3,4-tetrahydronaphthyl, phenyl, naphthyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) - cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl , -OR ⁵ , -C (= O) R ⁶ or -NR ⁷ R ⁸ , where phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, Amino, halogen ,. Cyano, nitro, oxo, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) alkyl, (QG-alkoxy, (CC ₄ alkylamino, phenyl, hydroxycarbonyl, (dC ₄ ) -alkoxycarbonyl, aminocarbonyl, ( CC ₄ ) -alkylaminocarbonyl and (CC ₄ ) -alkylcarbonyl, R ⁵ filr, optionally substituted with fluorine (-C-C ₄ ) -alkyl, phenyl, benzyl or (CC ₄ ) -alkylcarbonyl,

R ^{6 represents} (dC ₄ ) alkoxy,

R ^{7 represents} hydrogen or (CC ₄ ) alkyl,

R ^{8 represents} (C 1 -C ₄ ) alkyl or phenyl carbonyl optionally substituted with (C _r C ₄ ) alkyl,

and their salts, their solvates and the solvates of their salts.

Compounds of the formula (I) are particularly preferred

in which

E represents methylene, NH or an oxygen atom,

m represents 0, 1 or 2,

n represents 1, 2 or 3,

R ^{1 represents} halogen, amino, cyano, trifluoromethyl, (CC ₄ ) alkyl or (CC ₄ ) alkoxy,

R ² for a group of the formula

stands where

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (CC ₆ ) alkylene-R ⁴ , R ³ for 1,3-benzodioxol, 2,2-difluoro-l, 3-benzodioxol, 2,3-dihydro-l, 4-benzodioxm, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin , Phenyl, 5- or 6-membered heteroaryl or (C ₃ -C ₆ ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 or 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl , Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (C 1 -C ₄ ) -alkyl and (dC ₄ ) -alkoxy,

R ^{4 represents} hydrogen, phenyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl, -OR ⁵ or -NR ⁷ R ⁸ , where phenyl , Heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents, independently of one another selected from the group consisting of halogen, cyano, oxo, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (dC ₄ ) -alkyl and (Cι-C ₄ ) alkoxy,

R ^{5 represents} (dC ₄ ) -alkyl optionally substituted with fluorine,

R ^{7 represents} hydrogen or (CC ₄ ) alkyl,

R ^{8 represents} (CC ₄ ) alkyl,

and their salts, their solvates and the solvates of their salts.

Compounds of the formula (I) are very particularly preferred,

in which

E represents methylene,

m represents 1,

n stands for 1,

R ^{1 represents} halogen,

R ² for a group of the formula

stands where

* represents the point of attachment to the pyrazoline ring, X represents R ³ or (C _r C ₆ ) alkylene-R ⁴ ,

R ^{3 represents} phenyl, 5- or 6-membered heteroaryl or (C ₅ -C ₆ ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano , Trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (Cι-C) alkyl and (CC ₄ ) alkoxy,

R ^{4 represents} hydrogen, phenyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl or -OR ⁵ , where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (CC ₄ ) alkyl and (CC ₄ ) alkoxy,

R ^{5 represents} methyl or ethyl,

and their salts, their solvates and the solvates of their salts.

The compound N-butyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-ρyrazole-1-carboximidamide is particularly preferred

The compound 3- (4-chlorophenyl) -N-cyano-4- (2-oxopyolidin-l-yl) -N- (3,3,3-trifluoropropyl) -4,5-dihydro is also particularly preferred. lH-pyrazol-l-carboxi_nidamid

The present invention furthermore relates to compounds of the formula (I)

in which

E represents methylene, ΝH, an oxygen atom or a sulfur atom,

m represents 0, 1, 2 or 3,

n represents 1, 2 or 3,

R ^{1 represents} halogen, hydroxy, amino, cyano, nitro, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl or alkylaminocarbonyl,

R ² for a group of the formula

stands where

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (CC ₈ ) -alkylene-R ⁴ , Y represents R ³ or (dC ₈ ) -alkylene-R ⁴ ,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-1,3-benzodioxin , (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₆ ) cycloalkyl or 5- to 10-membered heterocyclyl, where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocylyl, alkylaminocylyl , Alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{4 is} hydrogen, 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4, 4-tetrafluoro-4H-l, 3 -benzodioxin, (C ₆ -Cι ₀ ) aryl, (C ₆ -C ₁₀ ) - aryloxy, benzyloxy, 5- to 10-membered heteroaryl, (C ₃ -C ₇ ) cycloalkyl, 5- to 10-membered heterocyclyl , Hydroxy, amino, alkoxy, alkylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylamino, optionally substituted with arylcarbonylamino or alkylcarbonyloxy, where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyl, alkylcarbonyl and alkyl sulfate onyl,

and their salts, their solvates and the solvates of their salts for the treatment and or prophylaxis of diseases, in particular cardiovascular diseases, such as thromboembolic diseases.

The present invention furthermore relates to compounds of the formula (I)

in which

E represents methylene, NH, an oxygen atom or a sulfur atom,

m represents 0, 1, 2 or 3,

n represents 1, 2 or 3,

R ^{1 represents} halogen, hydroxy, amino, cyano, nitro, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl or alkylaminocarbonyl,

R ² for a group of the formula

stands where

* represents the point of attachment to the pyrazoline ring, X represents R ³ or (C _r C ₈ ) alkylene-R ⁴ ,

Y represents (CC ₈ ) alkylene-R ⁴ ,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin , (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₆ ) cycloalkyl or 5- to 10-membered heterocyclyl, where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, Dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl, R ⁴ for hydrogen, 1,3-benzodifluorol -l, 3-benzodioxol, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin, (C ₆ -Cι ₀ ) aryl, (C ₆ -C ₁₀ ) - aryloxy, benzyloxy, 5- to 10-membered heteroaryl, (C ₃ -C ₇ ) cycloalkyl, 5- to 10-membered heterocyclyl, hydroxy, amino, alkoxy, alkylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Alkylcarbonyl, alkylcarbonylamino, optionally substituted with alkyl arylcarbonylamino or alkylcarbonyloxy, where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxyl, amino, halogen, cyano, nitro , Monohalogen hyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

and their salts, their solvates and the solvates of their salts.

Compounds of the formula (ϊ) are preferred,

in which

E represents methylene, NH or an oxygen atom,

m represents 0, 1 or 2,

n represents 1, 2 or 3,

R ^{1 represents} halogen, cyano, nitro, alkyl or alkoxy,

R ² for a group of the formula O 1 -X -N- -YH

stands,

in which

* • stands for the connection point to the pyrazoline ring,

X represents R ³ or (CC ₈ ) alkylene-R ⁴ ,

Y stands for (Cι-Q) alkylene-R ⁴ ,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin , Phenyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl or 5- or 6-membered heterocyclyl, where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (CC) alkyl, (Cr C ₄ ) alkoxy, (Cι-C) alkylamino, phenyl, hydroxycarbonyl , (-C-C) -alkoxy-carbonyl, aminocarbonyl, (-C-C ₄ ) -alkylaminocarbonyl and (Cι-C ₄ ) -alkyl carbonyl,

R ⁴ for hydrogen, 1,3-benzodioxole, 2,2-D_fluor-l, 3-benzodioxol, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3 -benzodioxin, phenyl, naphthyl, phenyloxy, benzyloxy, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl, 5- or 6-membered heterocyclyl, (Cι-C ₄ ) alkoxy, (CC ) -Alkylamino, (-C-C ₄ ) -alkoxy-carbonyl, optionally substituted with (-CC) -alkyl substituted phenylcarbonylamino or (-C-C) -alkylcarbonyloxy, where phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, trichloromethyl, Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (dC ₄ ) - alkyl, (CC ₄ ) -alkoxy, (C _r C ₄ ) -alkylamino, phenyl, hydroxycarbonyl, (dC ₄ ) - alkoxycarbonyl, aminocarbonyl, (dC) -All < ylaminocarbonyl and (C ₁ -C ₄ ) alkylcarbonyl,

and their salts, their solvates and the solvates of their salts.

Compounds of the formula (I) are particularly preferred

in which

E represents methylene, NH or an oxygen atom,

m represents 0 or 1,

n represents 1, 2 or 3,

R ^{1 represents} halogen, cyano, (dC ₄ ) -alkyl or (C_-C ₄ ) -alkoxy,

R ² for a group of the formula

stands where

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (C _r C ₆ ) alkylene R ⁴ ,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-1,3-benzodioxin , Phenyl, 5- or 6-membered heteroaryl or (C ₅ -C ₆ ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 or 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl , Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (Cι-C) alkyl and (C_-C ₄ ) alkoxy, R ^{4 represents} hydrogen, phenyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl, 5- or 6-membered heterocyclyl, (CC ₄ ) alkoxy or (CC ₄ ) -allylamine, where phenyl , Heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (C 1 -C ₄ ) alkyl and (C 1 -C ₄ ) ) alkoxy,

and their salts, their solvates and the solvates of their salts.

Compounds of the formula (I) are very particularly preferred,

in which

E represents methylene,

m represents 1,

n stands for 1,

R ^{1 represents} halogen,

R ² for a group of the formula

stands where

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (-CC ₆ ) alkylene-R ⁴ , R ^{3 represents} phenyl, 5- or 6-membered heteroaryl or (C ₅ -C ₆ ) cycloalkyl, phenyl, heteroaryl or cycloalkyl being substituted can with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (-C-C ₄ ) alkyl and (CrC ₄ ) alkoxy, R ^{4 represents} hydrogen, phenyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl or 5- or 6-membered heterocyclyl, where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents , independently selected from the group consisting of halogen, cyano, trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (CC ₄ ) alkyl and (CC) alkoxy,

and their salts, their solvates and the solvates of their salts.

The present invention further provides a process for the preparation of the new compounds of the formula (I), compounds of the formula

in which

R ¹ , E, m and n have the meaning given above,

either

[A] with compounds of the formula

in which

X has the meaning given above and

Z ^{1 represents} halogen, preferably chlorine or bromine, or hydroxy,

to compounds of the formula

in which

R ¹ , E, X, m and n have the meaning given above,

or

[B] with compounds of the formula

Y - NGO (IV), in which

Y has the meaning given above,

to compounds of the formula

in which

R ¹ , E, Y, m and n have the meaning given above,

or

[C] with compounds of the formula

Y - NCS (V), in which

Y has the meaning given above,

to compounds of the formula

in which

R ¹ , E, Y, m and n have the meaning given above,

or

[D] with compounds of the formula

in which

X has the meaning given above,

to compounds of the formula

in which R, E, X, m and n have the meaning given above,

or

[E] in two stages, first with diphenylcyanocarboimidate and then with compounds of the formula X-NH ₂ (VJJ), in which

X has the meaning given above,

to formulas

in which

R ¹ , E, X, m and n have the meaning given above,

be implemented.

The general formula (I) comprises the compounds of the formulas (Ia), (Ib), (Ic), (Id) and (Ie).

The reaction according to process [A] (Z ¹ = halogen), process [B], process [C] and process [D] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to 40 ° C at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, tetrahydrofuran or is preferred methylene chloride. Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanol or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropyl amide, or others Bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, diisopropylethylamine or triethylamine is preferred.

The reaction according to process [A] (Z ¹ = hydroxy) is generally carried out in inert solvents, in the presence of dehydrating reagents, if appropriate in the presence of a base, preferably in a temperature range from -70 ° C. to 40 ° C. at atmospheric pressure.

Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, -dipropyl, NN-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N - propyloxymethyl polystyrene (PS carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-

Butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 0- (benzotriazol-l -yl) -NNN ', N'-tetra-methyluromumhexa- fluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) -l, 1,3,3 -tetramethyluronium tetrafluoroborate

(TPTU) or 0- (7-azabenzotriazole-l -y ^ -NNN'N'-tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-l-yloxytos (dimethylamino) - phosphoniumhexafluorophosphate (BOP Mixtures of these, with bases.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or DBU, DBΝ, pyridine, or mixtures of the bases, a mixture of 4-dimethylaminopyridine and N-methylmorpholine is preferred.

The condensation is preferably carried out with N- (3-dimethylaminoisopropyl) -N-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), 4-dimethylaminopyridine and N-methylmorpholine.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol ether dimethyl ether or diethylene dimethyl ether such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, in the case of water-miscible solvents, mixtures of these with water are preferred, dimethylformamide is preferred.

The reaction according to process [E] is preferably carried out in two stages:

The reaction in the first stage is generally carried out in inert solvents, preferably in a temperature range from 50 ° C. to the reflux of the solvent at normal pressure.

Inert solvents are, for example, alcohols such as methanol, ethanol, ra-propanol or isopropanol, preference is given to “O-propanol.

The reaction in the second stage is generally carried out in inert solvents, preferably in a temperature range from 50 ° C. to the reflux of the solvent at normal pressure.

Inert solvents are, for example, alcohols such as methanol, ethanol, propanol or isopropanol, ethanol being preferred.

The compounds of the formula (E) are known or can be prepared by using compounds of the formula

in which

R ¹ , E, m and n have the meaning given above,

in a two-stage process, first with formaldehyde and then with hydrazine hydrate.

The reaction in the first stage is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure. Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, ethanol is preferred.

Bases are, for example, organic bases such as amine bases, e.g. Piperidine, triethylamine, diisopropylethylamine or DBU, piperidine is preferred.

The reaction in the second stage is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at normal pressure.

Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, ethanol is preferred.

The compounds of formula (VIII) are known or can be prepared by using compounds of formula

in which

R ¹ and m have the meaning given above,

with compounds of the formula

in which

E and n have the meaning given above,

be implemented. The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, if appropriate with the addition of potassium iodide, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, or other solvents such as ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, Acetonitrile or pyridine, dimethylformamide or tetrahydrofuran is preferred.

Bases are, for example, alkali metal hydroxides such as sodium, potassium or lithium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methanolate, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis- (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, pyridine or DBU, sodium hydride is preferred.

In an alternative process, compounds of the formula can also be used instead of compounds of the formula (X) under the same reaction conditions

in which

E and n have the meaning given above,

be implemented.

The compounds of the formulas (DJ), (TV), (V), (VT), (VII), <TX) and (X) are known or can be synthesized from the corresponding starting compounds by known processes.

The preparation of the compounds of formula (I) can be illustrated by the following synthesis scheme. Scheme 1:

The compounds according to the invention show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action. These are PAR-1 antagonists.

They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

The present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably cardiac Circulatory diseases, for example thromboembolic diseases and / or thrombotic complications.

For the purposes of the present invention, this includes in particular heart attack, stable angina pectoris, unstable angina pectoris, stroke, such as e.g. thrombotic stroke and thromboembolic stroke, transient ischemic attacks, reocclusion and restenosis after coronary interventions (reocclusion and restenosis after percutaneous coronary interventions, reocclusion and restenosis after coronary artery bypass surgery), disseminated intravascular coagulation and deep venous thrombosis, deep venom thrombosis,

Furthermore, the compounds according to the invention can be used to support thrombolytic therapy, to influence wound healing, in the prevention and treatment of atherosclerotic vascular diseases, such as e.g. Restenosis, coronary heart disease, cerebral ischemia and peripheral arterial disease, heart failure, hypertension, inflammatory diseases such as e.g. Asthma, inflammatory lung diseases, glomerulonephritis, inflammatory bowel diseases and rheumatic diseases of the musculoskeletal system, degenerative diseases such as e.g. neurodegenerative diseases and osteoporosis and neoplastic diseases such as Cancer.

The present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

The present invention furthermore relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment and or prophylaxis of eradications, in particular the aforementioned diseases.

The present invention furthermore relates to a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound according to the invention.

The present invention further relates to medicaments containing a compound according to the invention and one or more further active substances.

The active ingredient, the compound according to the invention, can act systemically and / or locally. For this purpose, it can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically or as an implant or stent. The active ingredient can be administered in suitable administration forms for these administration routes.

For oral administration, state-of-the-art, fast and / or modified administration forms which give off the compounds according to the invention and contain the compounds according to the invention in crystalline and / or amorphized and or dissolved form, such as e.g. Tablets (non-coated or coated tablets, for example with gastric juice-resistant, delayed dissolving or insoluble coatings which control the release of the compounds according to the invention), rapidly disintegrating tablets or films / wafers, capsules, dragees, granules, pellets, powder, emulsified tablets in the oral cavity ions, suspensions, aerosols or solutions.

Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

Oral application is preferred.

For the other application routes, e.g. Inhaled drug forms (including powder inhalers, nebulizers), nasal drops, Z solutions, sprays; tablets or capsules to be applied lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder, stents or implants.

The compounds according to the invention can be converted into the application forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include Carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments) such as iron oxides) or taste and / or smell.

The present invention furthermore relates to medicaments which contain at least one compound according to the invention, preferably together with one or more inert non- contain toxic, pharmaceutically suitable excipient, and their use for the aforementioned purposes.

In general, it has proven to be advantageous to administer amounts of about 5 to 250 mg per 24 hours in the case of parenteral administration in order to achieve effective results. When administered orally, the amount is about 5 to 100 mg per 24 hours.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume. "W / v" means "weight / volume". For example, "10% w / v" means: 100 ml of solution or suspension contain 10 g of substance.

A. Examples

Abbreviations:

Boc tert-butoxycarbonyl

CDC1 ₃ Deuterochloroform

C0 ₂ carbon dioxide d day

DIEA N, N-diisopropylethylamine

DMAP 4-NN-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory

EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide x HCl eq. equivalent to

ESI electrospray ionization (for MS) sat. saturated h hour

HOBt 1-hydroxy-1H-benzotriazole x H ₂ O

HPLC high pressure, high performance liquid chromatography conc. Konzen Animal T

LC-MS liquid chromatography-coupled mass spectroscopy min. minutes

MS mass spectroscopy

MW molecular weight [g / mol]

NMM N-methylmorpholine

NMR nuclear magnetic resonance spectroscopy

R _f retention index (at DC)

RP-HPLC reverse phase HPLC

RT room temperature

Rt retention time (with HPLC)

TEA triethylamine

THF tetrahydrofuran HPLC and LC-MS methods:

Method 1 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60mm x 2mm, 3.5μm; Eluent A: 5 ml HCIO ₄ / I water, eluent B: acetonitrile; Gradient: 0min 2% B, 0.5min 2% B, 4.5min 90% B, 6.5min 90% B; Flow: 0.75ml / min, temp .: 30 ° C, UV detection: 210 n.

Method 2 (LC-MS): Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom-S_L120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm; Eluent A: 11 water + 1ml 50% formic acid, eluent B: 11 acetonitrile + 1ml 50% formic acid; Gradient: 0.0min 100% A -> 0.2min 100% A -> 2.9min 30% A ^■ 3.1min 10% A - 4.5min 10% A; Oven: 55 ° C, flow: 0.8ml / min, UV detection: 208-400 nm.

Method 3 (LC-MS): Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm; Eluent A: water + 500μl 50% formic acid / 1, eluent B: acetonitrile + 500μl 50% formic acid / 1; Gradient: 0.0min 0% B -> 2.9min 70% B - »3.1min 90% B - 4.5min 90% B; Oven: 50 ° C, flow: 0.8ml / min, UV detection: 210 nm.

Method 4 (LC-MS): Instrument MS: Micromass TOF (LCT); HPLC instrument: 2-column circuit, Waters2690; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 95% A - »1.8 min 25% A -> 1.9 min 10% A - ^ 2.0 min 5% A -» 3.2 min 5% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.

Method 5 (LC-MS): Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-S1L120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm; Eluent A: 11 water + 1ml 50% formic acid, eluent B: 11 acetonitrile + 1ml 50% formic acid; Gradient: 0.0min 100% A - 0.2min 100% A - »2.9min 30% A ^■ » 3.1min 10% A - »4.5min 10% A; Oven: 55 ° C, flow: 0.8ml / min, UV detection: 210 nm.

Method 6 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent A: 5ml HC10V1 water, eluent B: acetonitrile; Gradient: 0min 2% B, 0.5min 2% B, 4.5min 90% B, 15min 90% B; Flow: 0.75ml / min, temp .: 30 ° C, UV detection: 210 nm.

Method 7 (GC-MS): Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30m x 250μm x 0.25μm; constant flow with helium: 0.88ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (hold 0.30 min), 50 ° C / min - »120 ° C, 16 ° C / min ^■ » 250 ° C, 30 ° C / min - »300 ° C (hold 1.7 min). Method 8 (HPLC, enantiomer separation): Chiral silica gel selector KBD 6136 (10μm, 350x30mm) based on the selector poly (N-methacryloyl-L-leucine-l-menthylamide); Eluent: tert-butyl methyl ether / ethyl acetate 90/10; Temperature: 24 ° C; Flow: 50 ml / min; TJV detection: 254 nm.

Method 9 (HPLC): Chiral silica gel selector KBD 8361A (250x4.6mm) based on the selector poly (N-methacryloyl-L-leucine-l-menthylamide); Eluent: tert-butyl methyl ether / ethyl acetate 40/10; Temperature: 24 ° C; Flow: 1 ml / min; UV detection: 254 nm.

Method 10 (HPLC, enantiomer separation): Chiral silica gel selector KBD 8361A (250x20mm) based on the selector poly (N-methacryloyl-L-leucine-l-menthylamide); Iso-hexane / ethyl acetate 20/10; Temperature: 24 ° C; Flow: 25 ml / rnin; UV detection: 254 nm.

Method 11 (HPLC): Analytical HPLC: Chiral silica gel selector KBD 8361A (250x4.6mm) based on the selector poly (N-methacryloyl-L-leucine-l-menthylamide); Iso-hex / ethyl acetate 3/7; Temperature: 24 ° C; Flow: 1 ml / min; UV detection: 254 nm.

Method 12 (HPLC, enantiomer separation): column: Chiralcel OD (250x20mm); Methanol / isopropanol 1/1; Temperature: 24 ° C; Flow: 20 ml / min; UV detection: 254 nm.

Method 13 (LC-MS): Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A - ^ 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml min; Oven: 50 ° C; UV detection: 210 nm.

Method 14 (LC-MS): Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A - ^ 2.5 min 30% A - 3.0 min 5% A -_ 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 15 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A ^■ »3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm. Method 16 (LC-MS): Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A - 2.5 min 30% A - 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 17 (HPLC, diastereomer / enantiomer separation): Chiral selector Chiralpak AD-H (250 mm x 20 mm); wo-hexane ethanol 55:45 (vol / vol); Temperature: 25 ° C; Flow: 15 ml / min; UV detection: 220 nm.

Method 18 (HPLC, enantiomer separation): Chiral silica gel sector KBD 5326 (250 mm x 20 mm) based on the sector poly (N-methacryloyl-L-leucine-l-menthylamide); ethyl acetate; Temperature: 24 ° C; Flow: 25 ml / min; UV detection: 254 nm.

Method 19 (HPLC, enantiomer separation): Chiral silica gel selector KBD 5326 (250 mm x 20 mm) based on the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 25 ml / min; UV detection: 260 nm.

Method 20 (HPLC, enantiomer separation): Chiral silica gel selector KBD 5326 (250 mm x 20 mm) based on the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 25 nd / min; UV detection: 280 nm.

Method 21 (HPLC, enantiomer separation): Chiral selector Daicel Chiralcel OD-H (250 mm x 20 mm); wo-hexane / ethanol 40:60 (vol / vol); Temperature: 40 ° C; Flow: 15 ml / min; UV detection: 220 nm.

Method 22 (HPLC, enantiomer separation): Chiral selector Daicel Chiralcel OD-H (250 mm x 20 mm); wo-hexane ethanol 50:50 (vol / vol); Temperature: 25 ° C; Flow: 15 ml / min; UV detection: 220 nm. Starting Compounds:

Example I

5-methoxy-3,4-dihydro-2H-pyrrole

20 g (235 mmol) pyrrolidin-2-one are added to 22.2 ml (235 mmol) dimethyl sulfate and the mixture obtained is stirred at 60 ° C. for 16 h. After cooling, it is saturated to 200 ml. added aqueous potassium carbonate solution and stirred for 30 min. It is extracted three times with diethyl ether and the combined organic phases are dried over sodium sulfate. After removing the solvent, the mixture is purified by distillation (70 mbar). 10.2 g (44% of theory) of the desired product are obtained.

GC-MS (Method 7): R _t = 2.57 min

MS (ESIpos): m / z = 99 (M + H) ⁺

'H NMR (200 MHz, CDC1 ₃ ): δ = 1.95-2.12 (m, 2H), 2.46 (dd, 2H), 3.66 (tt, 2H), 3.81 (s, 3H) ppm.

Example H

l- [2- (4-Bromphenyι) -2-oxo-ethyl] -pyrrolidin-2-one

A solution of 26.4 g (94.9 mmol) of 2-bromo-1- (4-bromophenyl) -2-ethanone in 90 ml of DMF is added

11.3 g (114 mmol) of 5-methoxy-3,4-dihydro-2H-pyrrole are added and then the mixture is stirred for 24 h

50 ° C stirred. After cooling, the solution is stirred into water and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and after Concentration is purified by flash chromatography on silica gel (mobile solvent: ethyl acetate). 17.2 g (64% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 3.93 min

MS (ESIpos): m / z = 282 (M + H) ⁺

* H-NMR (300 MHz, CDC1 ₃ ): δ = 2.12 (dt, 2H), 2.47 (dd, 2H), 3.48 (dd, 2H), 4.66 (s, 2H), 7.62 (d, 2H), 7.83 (d, 2H) ppm.

Example HI

l- [2- (4-Flubrphenyl) -2-oxo-ethyl] -pyrrolidin-2-one

2.19 g (22.1 mmol) of 5-methoxy-3,4-dihydro-2H-pyrrole are added to a solution of 4.00 g (18.4 mmol) of 2-bromo-1- (4-fluoro-phenyl) -2-ethanone in 15 ml of DMF and then the mixture is stirred at 50 ° C. for 24 h. After cooling, the solution is stirred into water and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and, after concentration, the mixture is purified by flash chromatography on silica gel (mobile phase cyclohexane / ethyl acetate 4: 1 -> ethyl acetate). 3.93 g (90% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 3.56 min

MS [DCI (NH ₃ )]: m / z = 222 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.93-2.07 (m, 2H), 2.30 (dd, 2H), 3.39 (dd, 2H), 4.74 (s, 2H), 7.34-7.44 (m, 2H ), 8.03-8.11 (d, 2H) ppm.

The compounds of Examples IV to IX are prepared analogously to Example II.

Production process for example IX

l- [2- (4-chlorophenyl) -2-oxoethyl] pyrrolidin-2-one

29.44 g (126.09 mmol) of 4-chlorophenacyl bromide are warmed to 50 ° C. overnight with 15 g (151.31 mmol) of 5-methoxy-3,4-dihydro-2H-pyrrole in 100 ml of dimethylformamide. The solution is then poured into 800 ml of water and extracted three times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulfate. After removal of the solvent in vacuo, 30 g (98% of theory) of the product are obtained.

LC-MS (method 14): R _t = 1.65 min,

MS (ESIpos): m / z = 238 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 2.00 (m, 2H), 2.29 (t, 2H), 3.38 (t, 2H), 4.75 (s, 2H), 7.64 (m, 2H), 7.99 (d, 2H).

Example X

3- [2- (4-bromophenyl) -2-oxoethyl] -l, 3-oxazolidin-2-on

A suspension of 79 mg (2.0 mmol) sodium hydride in 3.6 ml THF is mixed with 157 mg (1.80 mmol) 1,3-oxazolidin-2-one and the mixture is stirred for 1 h at RT. 60 mg (0.36 mmol) of potassium iodide and a solution of 500 mg (1.80 mmol) of 2-bromo-1- (4-bromophenyl) -2-ethanone in 3.6 ml of THF are added and the mixture is then stirred at 70 ° C. for 20 h. After cooling, 15 ml of water are carefully added and the mixture is extracted three times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration, the mixture is purified by flash chromatography on silica gel (mobile phase cyclohexane / ethyl acetate 4: 1). 49 mg (8% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 3.94 min

MS [DCI (NH ₃ )]: m / z = 301 (M + NH ₄ ) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 3.55 (t, 2H), 3.93 (t, 2H), 4.66 (s, 2H), 7.63-7.68 (m, 2H), 7.81- 7.85 (m, 2H) ) ppm.

Example XI

1-Acetyl-3 - [2- (4-bromophenyl) -2-oxoethyljimidazolidin-2-one

230 mg (1.80 mmol) of 1-acetylimidazolidin-2-one are added to a suspension of 79 mg (2.0 mmol) of sodium hydride in 4 ml of THF, and the mixture is stirred at RT for 1 h. It is diluted with 4 ml of THF and the suspension becomes a mixture of 60 mg (0.36 mmol) of potassium iodide and 500 mg (1.80 mmol) 2-bromo-1- (4-bromophenyl) -2-ethanone added to 4 ml THF. The mixture is then stirred at 70 ° C for 20 h. After cooling, 15 ml of water are carefully added and the mixture is extracted three times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration, the mixture is purified by flash chromatography on silica gel (mobile phase dichloromethane ethanol 100: 1). 139 mg (24% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 4.05 min

MS (ESIpos): m / z = 325 (M + H) ⁺

^J H-NMR (300 MHz, CDC1 ₃ ): δ = 1.26 (s, 3H), 3.73 (dd, 2H), 4.44 (dd, 2H), 4.67 (s, 2H), 7.62-7.67 (m, 2H) , 7.79-7.86 (m, 2H) ppm.

Example XH

l- [3- (4-bromophenyl) -4,5-dihydro-lH-ρyrazol-4-yl] -pyrrolidin-2-one

To a solution of 4.67 g (16.6 mmol) of l- [2- (4-bromophenyl) -2-oxo-ethyl] pyrrolidin-2-one (Example T) and 2.01 g (24.8 mmol) of formaldehyde in 25 ml of ethanol 2.46 ml (24.8 mmol) of piperidine were added dropwise. The mixture is stirred at RT for 20 h. The resulting precipitate is filtered off, washed with 6 ml of ethanol and dried in vacuo. The crude product is suspended in 100 ml of ethanol and mixed with 2.86 g (57.1 mmol) of hydrazine hydrate. The suspension is heated under reflux for 1 h. After cooling, the solvent is removed and the residue is stirred with a mixture of 24 ml of diethyl ether and 8 ml of water. The solid is filtered off, washed twice with 3 ml of diethyl ether and then dried in vacuo. 3.70 g (73% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 3.69 min

MS (ESIpos): m / z = 308 (M + H) ^{+ J} H-NMR (300 MHz, CDC1 ₃ ): δ = 1.78-2.05 (m, 2H), 2.29-2.40 (m, 2H), 2.98 (ddd, 1H), 3.38 (ddd, 1H), 3.49 (dd, 1H), 3.66 (dd, 1H), 5.87 (dd, 1H), 7.46-7.52 (m, 2H), 7.55-7.62 (m, 2H) ppm.

Example Xffl

l- [3- (4-Fluoφhenyl) -4,5-dihydro-lH-pyrazol-4-yl] -pyrrolidin-2-one

To a solution of 3.90 g (17.6 mmol) of l- [2- (4-fluorophenyl) -2-oxo-ethyl] pyrrolidin-2-one (example DT) and 2.15 g (26.4 mmol) of formaldehyde in 30 ml of ethanol 2.62 ml (26.4 mmol) of piperidine were added dropwise. The mixture is stirred at 70 ° C. for 18 h. After the solvent has been removed, the crude product is suspended in 30 ml of ethanol and 4.49 g (90 mmol) of hydrazine hydrate are added. The suspension is heated under reflux for 1 h. After cooling, the solid is filtered off and washed with methanol. 2.19 g (34% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 3.28 min

MS (ESIpos): m / z = 248 (M + H) ⁺

'H NMR (300 MHz, CDC1 ₃ ): δ = 1.76-2.05 (m, 2H), 2.23-2.48 (m, 2H), 3.01 (ddd, 1H), 3.38 (ddd, 1H), 3.48 (dd, 1H), 3.65 (dd, 1H), 5.83 (dd, 1H), 7.01-7.19 (m, 2H), 7.65-7.74 (m, 2H) ppm.

The compounds of Examples XIV to XX are prepared analogously to Example XU.

Manufacturing process for example XVEH

1st stage

l- [l- (4-chlorobenzoyl) vinyl] pyrrolidin-2-one

13 g (54.69 mmol) of l- [2- (4-chloro-phenyl) -2-oxo-ethyl] pyrrolidin-2-one are initially charged with 6.65 g (82.04 mmol) of 37% formaldehyde in 150 ml of ethanol and mixed with 6.98 g ( 82.04 mmol) piperidine heated to 70 ° C. overnight. After cooling to room temperature, the solvent is removed in vacuo and the product is reacted further without further purification.

LC-MS (method 13): R _t = 1.97 min,

MS (ESIpos): m / z = 249 (M + H) ⁺

2nd stage

l- [3- (4-ChlorphenyI) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one

17.58 g (70.40 mmol) of l- [l- (4-chlorobenzoyl) vinyl] pyrrolidfn-2-one are dissolved in 100 ml of ethanol and heated to 100 ° C. for one hour under argon with 12.33 g (246.4 mmol) of hydrazine hydrate. After cooling to room temperature, the precipitated product is filtered off and washed twice with a little ethanol. 7.05 g (44% of theory) of product are obtained.

LC-MS (method 13): R _t = 1.72 min,

MS (ESIpos): m / z = 264 (M + H) ⁺

'H NMR (300 MHz, DMSO-d ₆ ): δ = 1.74 (m, 1H), 1.85 (m, 1H), 2.18 (m, 2H), 2.76 (m, 1H), 3.27 (m, 1H) , 3.42 (m, 2H), 5.66 (dd, 1H), 7.43 (, 2H), 7.55 (d, 2H), 7.61 (m, 1H). Example XXI

l- [3- (4-bromophenyl) -4,5-dihydro-lH-pyrazol-4-yl] -azepane-2-one

A solution of 1.90 g (6.31 mmol) of l- [2- (4-bromophenyl) -2-oxo-ethyl] azepan-2-one (example VHI) and 0.75 g (9.19 mmol) of formaldehyde in 15 ml of ethanol is added 0.67 ml (6.74 mmol) of piperidine was added dropwise. The mixture is stirred at RT for 23 h, then at 50 ° C. for 44 h. After adding 0.20 g (2.45 mmol) of formaldehyde, the mixture is stirred at 70 ° C. for 24 h. After concentration in vacuo, 2.63 g of crude product are obtained. 0.69 g (2.15 mmol) of the crude product are suspended in 15 ml of ethanol and 0.38 g (7.52 mmol) of hydrazine hydrate are added. The suspension is heated under reflux for 24 h. After cooling, the solvent is removed and the residue is stirred with 7.5 ml of diethyl ether. The solid is filtered off, washed twice with 3 ml of diethyl ether and then dried in vacuo. 0.55 g (71% of theory) of the desired product is obtained.

HPLC (method 1): R _t = 3.89 min

MS (ESIpos): m / z = 338 (M + H) ⁺

TL-NMR (300 MHz, CDC1 ₃ ): δ = 1.39-1.76 (m, 6H), 2.54 (dd, 2H), 3.19 2H), 3.45 (dd, IH), 3.72 (dd, IH), 5.85 (br .s, IH), 6.35 (dd, IH), 7.45-7.52 (m, 2H), 7.56-7.63 (m, 2H) ppm.

Example XXH

3 - (4-Bromophenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -4,5-dihydπ. -pyrazole-1-phenylimidate

A suspension of 387 mg (1.62 mmol) diphenylcyanocarboimidate in 7.5 ml 2-propanol is mixed with 500 mg (1.62 mmol) l- [3- (4-bromophenyl) -4,5-dihydro-lH-pyrazol-4-yl] - pyrrolidin-2-one (Example XU) added. The mixture is heated under reflux for 3 d. After cooling, the precipitate obtained is suction filtered and washed with a little diethyl ether. 409 mg (56% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 4.43 min

MS (ESIpos): m / z = 452 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.83-2.20 (m, 2H), 2.25-2.57 (m, 2H), 3.01 (ddd, IH), 3.36 (ddd, IH), 4.19 (dd, IH ), 4.38 (dd, IH), 6.21 (dd, IH), 7.10-7.20 (m, 2H), 7.29-7.37 (m, IH), 7.38-7.50 (m, 2H) 7.52-7.61 (m, 2H) , 7.65-7.77 (m, 2H) ppm.

Example XXHI

3- (4-Fluoφhenyl) -N-cyano-4- (2-oxo-pyrrolidin-l-yl) -4,5-dihydro-pyrazol-l-phenylimidat

A suspension of 482 mg (2.02 mmol) of diphenylcyanocarboimidate in 9 ml of 2-propanol is mixed with 500 mg (2.02 mmol) of l- [3- (4-fluorophene) -4,5-dihydro-lH-pyrazol-4-yl] - ρyrrolidin-2-one (Example XIH) added. The mixture is heated under reflux for 3 d. After cooling, the precipitate obtained is suction filtered and washed with diethyl ether. 570 mg (72% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 4.30 min

MS (ESIpos): mz = 392 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.88-2.15 (m, 2H), 2.30-2.53 (m, 2H), 3.02 (ddd, IH), 3.36 (ddd, IH), 4.20 (dd, IH ), 4.38 (dd, IH), 6.21 (dd, IH), 7.08-7.20 (m, 4H), 7.29-7.35 (m, IH), 7.39-7.48 (, 2H), 7.82-7.90 (m, 2H) ppm. Example XIV

Cyclobutylacetonitril

181 mg (3.69 mmol) sodium cyanide and 50 mg (0.34 mmol) sodium iodide are added to a solution of 500 mg (3.36 mmol) bromomethylcyclobutane in 4 ml dimethyl sulfoxide. The mixture is stirred at room temperature for 3 days, then saturated sodium chloride solution is added and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. As an intermediate, 100 mg (31% of theory) of cyclobutylacetonitrile are obtained in the form of an oil.

GC-MS (Method 7): R _t = 3.14 min.

MS (ESI pos) m / z = 95 (M) ⁺

'H NMR (300 MHz, DMSO-d_): δ = 1.65-1.9 (m, 4H), 2.0-2.15 (m, 2H), 2.53-2.64 (m, 3H).

Example XXV

2-Cyclobutylethylamin

3.15 ml (3.15 mmol) of an 1M solution of borane-tetrahydrofuran complex in THF are added to a solution of 100 mg (1.05 mmol) of cyclobutylacetonitrile in 2 ml of absolute THF under argon, and the mixture is stirred at room temperature for 1 h. Then methanol is carefully added and, after 1 h, the solution is concentrated in vacuo. The product obtained is 120 mg (quant.) 2-cyclobutylethylamine in the form of an oil which is used in the next step without further purification.

GC-MS (Method 7): R _t = 2.73 min.

MS (ESI pos): m / z = 100 (M + H) ⁺ Example XXVI

TGRT-butyl [2- (3-methoxy-2,5-dioxo-pyrrolidin-l-yl) ethyl] carbamate

0.123 g (0.769 mmol) of N-Boc-ethylenediamine are mixed with 0.1 g (0.769 mmol) of 3-methoxy-dihydrofuran-2,5-dione and slowly heated to 160 ° C. The temperature is held for two hours. After cooling to room temperature, the product is converted to 1 - (2-aminoethyl) -3-methoxypyrrolidine-2,5-dione-trifluoroacetate without further purification.

Example XXVH

l- (2-aminoethyl) -3-methoxypyrrolidine-2,5-dione trifluoroacetate

0.21 g (0.77 mmol) of tert-butyl- [2- (3-methoxy-2,5-dioxopyrrolidin-l-yl) ethyl] carbamate in 1 ml of tetrahydrofuran are mixed with 1 ml of trifluoroacetic acid and stirred for 30 min. The solvent is removed in vacuo and the product is converted to Example 414 without further purification.

Example XXVHI

PhenyI-3- (4-chlorophenyl) -iv-cyano-4- (2-oxopyrrolidin-l-yl) - 4,5-dihydro-lH-pyrazole-l-carboximidoate

10 g (37.91 mmol) of l- [3- (4-chloro-phenyl) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one are mixed with 9 g (37.91 mmol) of diphenylcyanocarboimidate under argon in 180 ml 2-Propanol heated to reflux overnight. After cooling to room temperature, the precipitate is filtered off and washed several times with diethyl ether. 10.85 g (70% of theory) of the product are obtained.

LC-MS (method 15): R _t = 2.29 min,

MS (ESI pos): m / z = 408 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.85 (m, 2H), 2.24 (m, 2H), 2.80 (m, IH), 3.49 (m, IH), 4.44 (m, 2H), 6.10 (dd, IH), 7.31 (m, 3H), 7.47 (d, 2H), 7.62 (m, 2H), 7.71 (m, 2H).

Ausftihrnngsbeispiele:

example 1

l- [3- (4-bromophenyl) -l- (3-phenylproρionyl) -4,5-dihydro-iH - pyrazol-4-yl] -pyrrolidin-2-one

A mixture of 77.1 mg (0.25 mmol) l- [3- (4-bromophenyl) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one (example XU) and 0.04 ml (0.30 mmol ) TEA in 2 ml dichloromethane are added to 50.6 mg (0.30 mmol) 3-phenylpropionyl chloride at RT. The solution is stirred at RT for 18 h. After concentration, the mixture is stirred while warm with 1 ml of dimethyl sulfoxide and 0.4 ml of methanol. It is suctioned off through a silica gel cartridge and the remaining residue is washed with diethyl ether. 79.2 mg (72% of theory) of product are obtained.

HPLC (method 1): R _t = 4.90 min

MS [DCI (NH ₃ ] _: m / z = 440 (M + H) ⁺

^! H-NMR (200 MHz, CDC1 ₃ ): δ = 1.73-2.08 (m, 2H), 2.20-2.47 (m, 2H), 2.65-2.78 (m, IH), 2.99-3.22 (m, 5H), 3.90 -4.09 (m, 2H), 6.01 (dd, IH), 7.14-7.31 (m, 5H), 7.49-7.65 (m, 4H) ppm.

The compounds of Examples 2 to 25 are prepared analogously to Example 1. The raw products from the reactions are purified by stirring and / or by preparative HPLC.

Example 26

l- [3- (4-bromophenyl) -l- (3-cyclopen1ylρropionyl) -4,5-dihydro-lH-pyrazol-4-yl] -pyrrolidin-2-one

19.6 mg (0.15 mmol) HOBt, 55.6 mg (0.29 mmol) EDC and 1 mg (0.01 mmol) DMAP are added as a suspension in 0.5 ml DMF to 24.7 mg (0.17 mmol) 3-cyclopentylcarboxylic acid. After 5 min, a suspension of 0.06 ml (0.58 mmol) of N-methylmoφholin and 44.7 mg (0.15 mmol) of l- [3- (4-bromophenyl) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidine -2-one (Example XII) added and the mixture is left at RT for 18 h. Preparative HPLC (Grom-Sil RP18; eluent acetomtril water / 0.3%> formic acid gradient 10:90 -> 90:10) provides 17.3 mg (28% of theory) of product.

HPLC (method 1): R _t = 5.19 min

MS [DCI (ΝH ₃ )]: m / z = 432 (M + H) ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.05-1.28 (m, 2H), 1.41-2.07 (m, 11H), 2.38 (ddd, 2H), 2.72-2.94 (m, 3H), 3.22 (ddd , IH), 3.93-4.09 (m, 2H), 6.04 (dd, IH), 7.49-7.68 (m, 4H) ppm.

The compounds of Examples 27 to 60 are prepared analogously to Example 2.

Example 61

- {3- (4-bromophenyl) -l- [4- (2-thienyl) butanoyl] -4,5-dihydro-lH-pyrazol-4-yl} -pyrrolidin-2-one

13.5 mg (0.10 mmol) HOBt, 28.8 mg (0.15 mmol) EDC, 40.4 mg (0.40 mmol) 4-methylmoφholin and 17.0 mg (0.10 mmol) 4-thioρhenbutanoic acid are added as a suspension in DMF to 30.8 mg (0.10 mmol) l- [ 3- (4-Bromophenyl) -4,5-dihydro-1H-pyrazol-4-yl] pyrrolidin-2-one (Example X_X). The mixture is left at RT for 18 h. Preparative HPLC (Grom-Sil RP18; mobile phase acetonitrile-water / 0.1% formic acid gradient 30:70 -> 90:10) provides 18.9 mg (41% of theory) of product.

LC-MS (Method 4): R _t = 2.19 min

LC-MS (ESIpos): m / z = 460 (M + H) ⁺

The compounds of Examples 62 to 76 are prepared in analogy to Example 61.

Example 77

3- (4-Bromo-phenyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-pyrazole-l-carboxylic acid (3-chloro-4-difluoromethoxy-phenyl) -amide

To a solution of 4300 mg (13.95 mmol) of l- [3- (4-bromophenyl) -4,5-dihydro-1H-pyrazol-4-yl] pyrrolidin-2-one (Example XU) in 140 ml of dichloromethane 3060 mg (13.95 mmol) of 2-chloro-l-difluoromethoxyphenyl-4-isocyanate. The mixture is stirred at RT for 1 h. After concentration, the mixture is stirred with diethyl ether, filtered and the residue which remains is washed with diethyl ether. The solid obtained in this way is purified by silica gel chromatography (mobile phase dichloromethane / methanol gradient 95: 5). It is then triturated with diethyl ether, the residue is filtered off and washed with diethyl ether. 6500 mg (88% of theory) of product are obtained. HPLC (method 1): R _t = 4.94 min

MS (ESIpos): mz = 527 (M + H) ⁺

'H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.68-1.98 (m, 2H), 2.12-2.34 (m, 2H), 2.48-2.54 (, IH), 2.72-2.80 (m, IH) , 3.95-4.10 (m, 2H), 5.98 (dd, IH), 7.19 (dd, IH), 7.33 (d, IH), 7.68-7.82 (m, 5H), 7.99 (s, IH), 9.42 (s , IH) ppm.

Example 78

3 - (4-Bromo-phenyl) -4- (2-oxopyrrolidin-1-yl) -4,5 -dihydro-pyrazole-1-carboxylic acid- (3-chloro-4-difluoromethoxy-phenyl) -amide

Enantiomer separation of Example 77 by Method 8 gives the title compound as Enantiomer A (97.9% ee).

HPLC (method 9): R _t = 5.35 min.

Example 79

3 - (4-Bromophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-pyrazole-1-carboxylic acid (3-chloro-4-difluoromethoxy-phenyl) -amide

Enantiomer separation from Example 77 by Method 8 gives the title compound as enantiomer B (97.9% ee). HPLC (method 9): R _t = 7.56 min.

Example 80

N- [3-Chloro-4- (difluoromethoxy) phenyl] -3- (4-chloro-phenyl) -4- (2-oxo-l, 3-oxazolidin-3-yl) -4,5-dihydro-1H-pyrazole - 1-carboxamide

A solution of 45 mg (0.17 mmol) of 3- [3- (4-chloro-phenyl) -4,5-dihydro-lH-pyrazol-4-yl] -l, 3-oxazolidin-2-one in 2 ml of dichloromethane is added 45 mg (0.20 mmol) of 2-chloro-l-difluoro-methoxy-phenyl-4-isocyanate. The mixture is stirred at RT for 18 h. After concentration, the mixture is stirred with DMSO and methanol, filtered and the remaining residue is washed twice with diethyl ether. 48 mg (58% of theory) of product are obtained.

HPLC (method 1): R _t = 4.97 min

MS (ESIpos): m / z = 485 (M + H) ⁴ .

Η NMR (300 MHz, CDC1 ₃ ): δ = 3.13 (ddd, IH), 3.52 (ddd, IH), 4.08-4.38 (m, 4H), 5.88 (dd, IH), 6.48 (dd, IH), 7.17-7.49 (m, 4H), 7.72-7.83 (m, 3H), 8.01 (s, IH) ppm.

Example 81

N- [3-Chloro-4- (difluoromethoxy) phenyl] -3- (4-chloro-phenyl) -4- (2-oxo-l, 3-oxazolidin-3-yl) -4,5-dihydro-1H-pyrazole -1-carboxamide

Enantiomer separation from Example 80 by Method 10 gives the title compound as Enantiomer A (> 99% ee).

HPLC (method 11): R _t = 2.74 min.

Example 82

N- [3-Chloro-4- (difluoromethoxy) phenyl] -3- (4-chloro-phenyl) -4- (2-oxo-l, 3-oxazolidin-3-yl) -4,5-dihydro-1H-pyrazole -1-carboxamide

Enantiomer separation of Example 80 by Method 10 gives the title compound as Enantiomer B (96.8% ee).

HPLC (method 11): R _t = 4.09 min.

Example 83

3- (4-Bromophenyl) -4- (2-oxo-azepan-l-yl) -4,5-dihydro-lH-pyrazole-l-carboxylic acid- (3-chloro-4-difluoromethoxyphenyl) amide

A solution of 79.4 mg (0.24 mmol) of l- [3- (4-bromophenyl) -4,5-dihydro-1H-ρyrazol-4-yl] azepan- 2-one (Example XXI) in 2.0 ml of dichloromethane are added 62.2 mg (0.28 mmol) of 2-chloro-l-difluoromethoxyphenyl-4-isocyanate were added. The mixture is stirred at RT for 18 h. After constriction, with 1 ml of DMSO and 0.4 ml of methanol are stirred warm, suction filtered through a silica gel cartridge and the remaining residue is washed with diethyl ether. 119.5 mg (91% of theory) of product are obtained.

HPLC (method 1): R _t = 5.21 min

MS [DCI (NH ₃ )]: m / z = 572 (M + NH ₄ ) ⁴

'H NMR (200 MHz, CDC1 ₃ ): δ = 0.98-1.21 (, IH), 1.34-1.81 (m, 5H), 2.55 (dd, 2H), 3.11 (dddd, 2H), 4.07 (dddd, 2H ), 6.49 (dd, IH), 6.63 (dd, IH), 7.21 (dd, IH), 7.44 (dd, IH), 7.62 (ni _e , 4H), 7.77 (dd, IH), 8.01 (s, lH ) ppm.

The compounds of Examples 84 to 97 are prepared in analogy to Example 83.

Example 98

3- (4-Bromophenyl) -N-cyano-N- (4-difluoromethoxyphenyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydropyrazole-1-carboxamidine

A suspension of 150 mg (0.33 mmol) of 3- (4-bromophenyl) -N-cyano-4- (2-oxo-pyrrolidin-l-yl) - 4,5-dihydro-pyrazole-l-phenylimidate (Example XXH) and 105 mg (0.66 mmol) of 4-difluoromethoxyphenylamine in 2 ml of ethanol are heated under reflux for 3 d. After cooling, the precipitate obtained is suction filtered and washed with a little diethyl ether. It is pre-cleaned on a preparative HPLC (Grom-Sil RP18 column; eluent: water / 0.3% formic acid-acetonitrile gradient: 90:10 -> 10:90). The product fractions are combined and finely cleaned by means of another preparative HPLC (Grom-Sil RP18 column; mobile phase: water-acetonitrile gradient: 90:10 -> 10:90). 19 mg (11% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 4.61 min

MS [DCI (NH ₃ )]: m / z = 517 (M + H) ⁺ Η NMR (200 MHz, CDC1 ₃ ): δ = 1.83-2.20 (m, 2H), 2.24-2.57 (m, 2H), 2.94 (ddd, IH), 3.40 (ddd, IH), 4.33 (dd, IH ), 4.53 (dd, IH), 6.25 (dd, IH), 6.53 (t, IH), 7.16 (d, 2H), 7.44 (d, 2H) 7.53-7.72 (m, 4H), 8.06 (s, IH ) ppm.

Example 99

N-cyano-3- (4-fluoφhenyl) -4- (2-oxopyrrolidin-l-yl) -N- (2-phenylethyl) -4,5-dihydro-p3τ: azole-l-carboxamidine

A suspension of 60 mg (0.15 mmol) of 3- (4-fluorophenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-pyrazol-1-phenylimidate (Example XX_H) and 37 mg (0.31 mmol) (2-phenylethyl) amine in 2 ml of ethanol is heated under reflux for 3 d. After cooling, the solvent is removed and the precipitate obtained is stirred with 2 ml of diethyl ether. 61 mg (95% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 4.46 min

MS (ESIpos): m / z = 419 (M + H) ⁴

^J H-NMR (300 MHz, CDC1 ₃ ): δ = 1.79-2.11 (m, 2H), 2.22-2.49 (m, 2H), 2.85 (ddd, IH), 2.93-3.02 (m, 2H), 3.32 ( ddd, IH), 3.85 (q, 2H), 4.15 (dd, IH), 4.40 (dd, IH), 6.13 (dd, IH), 6.39 (t, IH), 7.06-7.15 (m, 2H), 7.25 -7.39 (m, 5H) 7.63-7.70 (m, 2H) ppm.

Example 100

NC ^ ano-3- (4-fluoro-phenyl) -4- (2-oxopyrrolidin-l-yl) -N- (2-phenylethyl) -4,5-dihydro-pyrazole-l-carboxamidine

Enantiomer separation of Example 99 by Method 12 gives the title compound as Enantiomer A (99.3% ee).

HPLC (method 12): R _t = 7.39 min.

Example 101

N-Cyano-3- (4-fluoφhenyl) -4- (2-oxopyrrolidin-l-yl) -N- (2-phenylethyl) -4,5-dihydro-pyrazole-l-carboxamidine

Enantiomer separation of Example 99 by Method 12 gives the title compound as enantiomer B (99.5% ee).

HPLC (method 12): R _t = 10.46 min.

Example 102

N - (^ ano-3- (4-fluorophenyl) -4- (2-oxo-pyrrolidin-l-yl) -N- (2-pyridin-2-ylethyl) -4,5- <hhydro-pyrazole-1 -carboxamidin

A suspension of 40 mg (0.10 mmol) of 3- (4-fluorophenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-pyrazol-1-phenylimidate (Example XXIII) and 25 mg (0.20 mmol) (2-pyridin-2-ylethyl) amine in 1.5 ml ethanol is heated under reflux for 1 day. After cooling, the solvent is removed and the precipitate obtained is taken up in 1 ml of diethyl ether and 0.5 ml of ethanol. After silica gel chromatography (mobile phase dichloromethane / ethanol 40: 1), 13 mg (31% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 3.62 min

MS (ESIpos): m / z = 420 (M + H) ⁺

Η NMR (300 MHz, CDC1 ₃ ): 6 = 1.79-2.11 (m, 2H), 2.22-2.49 (m, 2H), 2.85 (ddd, IH), 2.93-3.00 (m, 2H), 3.31 (ddd , IH), 3.85 (q, 2H), 4.15 (dd, IH), 4.40 (dd, IH), 6.13 (dd, IH), 6.39 (t, IH), 7.06-7.15 (m, 2H), 7.25- 7.39 (, 4H) 7.63-7.70 (m, 2H) ppm.

The compounds of Examples 103 to 118 are prepared analogously to Example 98.

Example 119

3- (4-bromophenyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydropyrazole-l- (4-trifluoromethylphenyl) carboxylic acid ester

A solution of 77 mg (0.25 mmol) of l- [3- (4-bromophenyl) -4,5-dihydro-1H-pyrazol-4-yl] pyrrolidine-2-one (Example XB) in dichloromethane is added RT mixed with 0.04 ml (0.30 mmol) TEA and 67.4 mg (0.30 mmol) chloroformic acid 4-triflourmethylphenylester. After 2 h, the solvent is removed in vacuo and the crude product is purified by preparative HPLC (Grom-Sil RP18 column; mobile phase: water / 0.3% formic acid-acetonitrile gradient: 70:30 -> 10:90). 65.6 mg (53% of theory) of the desired product are obtained.

HPLC (method 1): R _t = 4.94 min

MS [DCI (NH ₃ )]: m / z = 513 (M + NH ₄ ) ⁴ H-NMR (300 MHz, CDC1 ₃ ): δ = 1.83-2.12 (m, 2H), 2.27-2.51 (m, 2H ), 2.98 (ddd, IH), 3.35 (ddd, IH), 3.98-4.10 (m, IH), 4.15-4.29 (m, IH), 6.15 (dd, IH), 7.37 (d, 2H), 7.51- 7.59 (m, 2H), 7.64-7.74 (m, 4H) ppm.

Example 120 is produced in analogy to Example 119.

Example 121

3- (4-bromophenyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-pyrazole-l- (2-chlorobenzyl) carboxamide

A mixture of 50 mg (0.16 mmol) l- [3- (4-bromophenyl) -4,5-dihydro-1H-pyrazol-4-yl] pyrrolidin-2-one (Example XU) and 32.3 mg (0.19 mmol ) 2-Chlorobenzyl isocyanate in 2 ml dichloromethane are stirred at RT for 18 h. After concentration, preparative HPLC (Grom-Sil RP18; eluent acetonitrile-water / 0.3% formic acid gradient 10:90 -> 90:10) provides 29.1 mg (37% of theory) of the product.

HPLC (method 1): R _t = 4.85 min

MS (ESIpos): m z = 475 (M + Hf

Η NMR (400 MHz, CDC1 ₃ ): δ = 1.80-2.05 (m, 2H), 2.36 (m,., 2H), 2.89 (dt, IH), 3.29 (dt, IH), 3.98 (dd, IH ), 4.04 (dd, IH), 4.62 (d, 2H), 6.04 (dd, IH), 6.52 (t, IH), 7.22-7.29 (m, 2H), 7.36-7.48 (m, 2H), 7.52 ( d, 2H), 7.59 (d, 2H) ppm.

Example 122

3- (4-Fluoφhenyl) -4- (2-oxopyrrolidin-l-yl) -N- (2-phenylethyl) -4,5-dihydro-lH-pyrazole-l-carboxamide

A solution of 60 mg (0.24 mmol) of l- [3- (4-fluorophene) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one (example XHI) in 2 ml of dichloromethane is added 43 mg (0.29 mmol) (2-isocyanatoethyl) benzene are added and the mixture is stirred at RT for 18 h. After concentration, preparative HPLC (Grom-Sil RP18; mobile phase acetonitrile-water / 0.3% formic acid gradient 10:90 -> 90:10) yields 42 mg (44% of theory) of the product.

HPLC (method 1): R _t = 4.48 min

MS (ESIpos): m / z = 395 (M + Hf

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.78-2.08 (m, 2H), 2.34 (m _. , 2H), 2.83-2.95 (m, 3H), 3.28 (ddd, IH), 3.60 (m. , 2H), 3.91-4.06 (m, 2H), 6.02 (dd, IH), 6.09 (t, IH), 7.04-7.12 (m, 2H), 7.21-7.28 (m, 3H), 7.30-7.35 (m , 2H), 7.63-7.72 (m, 2H) ppm.

Example 123

3- (4-Fluoφhenyl) -4- (2-oxopyrrolidfn-l-yl) -N- (2-phenylethyl) -4,5-dihydro-lH-ρyrazole-l-carboxamide

Enantiomer separation from Example 122 by Method 12 gives the title compound as Enantiomer A (99.6% ee).

HPLC (method 12): R _t = 6.51 min. Example 124

3- (4-Fluoφhenyl) -4- (2-oχopyrrolidin-l-yl) -N- (2-phenylethyl) -4,5-dihydro-lH-pyrazole-l-carboxamide

Enantiomer separation of Example 122 by Method 12 gives the title compound as enantiomer B (99.5% ee).

HPLC (method 12): R _t = 12.30 min.

Example 125

3 - (4-Fluoφhenyl) -N-hexyl-4- (2-oxopyrrolidin- 1 -yl) -4,5-dihydro-1H-pyrazole-1-carboxylic acid amide

A solution of 50 mg (0.20 mmol) of l- [3- (4-fluorophene) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one (Example XIH) in 2 ml of dichloromethane is added 31 mg (0.24 mmol) of hexyl isocyanate are added and the mixture is stirred at RT for 18 h. After concentration, preparative HPLC (Grom-Sil RP18; mobile phase acetonitrile-water / 0.3% formic acid gradient 10:90 -> 90:10) provides 31 mg (39% of theory) of the product.

HPLC (method 3): R _t = 2.55 min

MS (ESIpos): m / z = 375 (M + Hf 'H NMR (200 MHz, CDC1 ₃ ): δ = 0.91 (t, 3H), 1.20-1.46 (m, 6H), 1.51-1.68 (m, 2H), 1.73-2.08 (m, 2H), 2.37 ( m _e , 2H), 2.90 (ddd, IH), 3.22-3.39 (m, 3H), 3.91-4.06 (m, 2H), 5.93-6.09 (, 2H), 7.02-7.15 (m, 2H), 7.66- 7.78 (m, 2H) ppm.

The compounds of Examples 126 to 137 are prepared analogously to Example 122.

Example 138

N-Cyano-3- (4-fluoφhenyl) -4- (2-oxo-pyrrolidin-l-yl) -N- (2-pyridin-2-ylethyl) -4,5-dihydro-pyrazole-1-carboxamidine

Enantiomer separation of Example 102 by Method 19 gives the title compound as Enantiomer 2 (99.3% ee).

HPLC (method 19): R _t = 21.97 min. (second fraction)

Example 139

N-Cyano-3- (4-fluoφhenyl) -4- (2-oxopyolidin-l-yl) -N- (2-pyridin-3-ylethyl) -4,5-dihydro-pyrazole-1-carboxamidine

Enantiomer separation of Example 117 by Method 20 gives the title compound as Enantiomer 2 (100% ee).

HPLC (method 20): R _t = 21.23 min. (second fraction)

Example 140

3- (4-Chlθφhenyl) -N- [2- (2-chlorophenyl) ethyl] -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chlθφhenyl) -N-cyano-4- (2-oxopyrrolidin-l-yI) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.076 g (0.49 mmol) 2- (2-chloro-phenyl) -ethylamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the reaction mixture is mixed with the same volume of water, the product being Solid crystallized. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.082 g (71% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.6 min.

MS (ESI pos): m / z = 469 (M + H) ⁴

Η-NMR (300 MHz, DMSO-d _. ): Δ = 1.81 (m, IH), 1.89 (m, IH), 2.21 (m, 2H), 2.75 (m, IH), 3.02 (t, 2H), 3.25 (m, IH), 3.64 (m, 2H), 4.24 (m, 2H), 6.03 (dd, IH), 7.29 (m, 2H), 7.41 (m, 2H), 7.59 (d, 2H), 7.80 (d, 2H), 8.09 (t, IH).

Example 141

3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -N- [2- (2-thienyl) ethyl] -4,5-dihydro-1H-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.062 g (0.49 mmol) 2- (2-thienyl) ethanamine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.081 g (75% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.43 min.

MS (ESI pos): m z = 441 (M + Hf

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.78 (m, IH), 1.92 (m, IH), 2.19 (m, 2H), 2.76 (m, IH), 3.10 (t, 2H), 3.28 (m, IH), 3.61 (m, 2H), 4.20 (m, 2H), 6.04 (dd, IH), 6.95 (, 2H), 7.35 (dd, IH), 7.59 (d, 2H), 7.76 ( d, 2H), 8.10 (t, IH). Example 142

3- (4-Chlθφhenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -N- [2- (2-thienyl) ethyl] -4,5-dihydro-lH-pyrazole-1-carboximidamide

Enantiomer separation of Example 141 by Method 18 gives the title compound as Enantiomer 2 (99.2% ee).

HPLC (method 18): R _t = 10.83 min. (second fraction)

Example 143

3- (4-chloro-phenyl) -N-cyano-N- (cyclohexylmethyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.055 g (0.49 mmol) l-cyclohexylmethanamine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.057 g (60% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.68 min.

MS (ESI pos): m / z = 427 (M + H) ⁴ Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.93 (m, 2H), 1.17 (m, 3H), 1.68 (m, 7H), 1.91 (m, IH), 2.22 (m, 2H), 2.76 (m, IH), 3.27 (m, 3H), 4.20 (m, 2H), 6.01 (dd, IH), 7.57 (d, 2H), 7.77 (d, 2H), 7.95 (t, IH).

Example 144

3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -N- [3- (lH-pyrazol-l-yl) propyl] -4,5-dihydro- 1 H- pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.062 g (0.49 mmol) 3- (1H-pyrazol-1-yl) propane-1-amine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying in a high vacuum, 0.071 g (66% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.01 min.

MS (ESI pos): m / z = 439 (M + Hf

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.95 (m, IH), 1.88 (m, IH), 2.06 (m, 2H), 2.21 (m, 2H), 2.77 (m, IH), 3.3 (m, 3H), 4.22 (m, 4H), 6.03 (m, IH), 6.23 (t, IH), 7.44 (d, IH), 7.58 (d, 2H), 7.75 (d, IH), 7.80 (d, 2H), 7.99 (t, IH).

Example 145

N, 3-bis (4-chlorophenyl) -N'-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-l-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.062 g (0.49 mmol) 4-chloroaniline are dissolved in 3 ml ethanol and heated to reflux for six days. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.039 g (36% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.27 min.

MS (ESI pos): m / z = 441 (M + H) ⁴

^X H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.80 (, IH), 1.90 (m, IH), 2.22 (m, 2H), 2.81 (m, IH), 3.39 (m, IH), 4.29 (m, 2H), 6.08 (dd, IH), 7.42 (dd, 4 H), 7.59 (d, 2H), 7.79 (d, 2H), 9.82 (s, IH).

Example 146

3 - (4-chloro-phenyl) -N-cyano-N-cyclohexyl-4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidfn-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.048 g (0.49 mmol) of cyclohexylamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product being removed as a solid. crystallized. The product is suctioned off and washed several times with diethyl ether. After drying in a high vacuum, 0.080 g (79% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.49 min.

MS (ESI pos): m z = 413 (M + Hf

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.12 (m, IH), 1.29 (m, 2H), 1.41 (m, 2H), 1.15 (d, IH), 1.74 (m, 3H), 1.87 (m, 3H), 2.23 (m, 2H), 2.76 (m, IH), 3.31 (m, IH), 3.88 (m, IH), 4.20 (m, 2H), 6.02 (dd, IH), 7.53 (d, IH), 7.56 (d, 2H), 7.79 (d, 2H).

Example 147

N- {3 - [(4-tert-Butylcyclohexyl) oxy] propyl} -3- (4-chlθφhenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) - 4,5-dihydro-lH- pyrazol-l-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.261 g (1.22 mmol) 3 - [(4-tert-butylcyclohexyl) oxy] propane-l-amine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the solvent is removed in vacuo and the product is purified by preparative HPLC. 0.12 g (93% of theory) of the product are obtained.

LC-MS (method 13): R _t = 3.16 min.

MS (ESIpos): mz = 527 (M + H) ⁴

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.80 (s, 9H), 1.00 (m, 4H), 1.75 (m, 6H), 1.88 (m, 2H), 1.98 (m, 2H), 2.22 (m, 2H), 2.76 (m, IH), 3.10 (m, IH), 3.47 (m, 4H), 4.20 (m, 2H), 6.02 (dd, IH), 7.56 (d, 2H), 7.87 (d, 2H), 7.87 (t, lH). Example 148

Isopropyl-N - [(E) - [3- (4-chlorophenyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazol-l-yl] (cyanoimino) methyl] - betaalaninat

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.064 g (0.49 mmol) of isopropyl beta-alaninate are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the solvent is removed in vacuo and the product is purified by preparative HPLC. 0.1 g (92% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.08 min.

MS (ESI pos): m / z = 445 (M + Hf

Η NMR (300 MHz, DMSO-ds): δ = 1.19 (d, 6H), 1.77 (m, IH), 1.91 (m, IH), 2.23 (m, 2H), 2.59 (t, 2H), 2.76 (m, IH), 3.26 (m, IH), 3.61 (, 2H), 4.23 (m, 2H), 4.91 (m, IH), 6.04 (dd, IH), 7.58 (d, 2H), 7.75 (d , 2H), 7.92 (t, lH).

Example 149

3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -N-pentyl-4,5-dihydro-1 H-pyrazole-1 - carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chlθφhenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.042 g (0.49 mmol) 7Z-pentylamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the solvent is removed in vacuo and the product is purified by preparative HPLC. 0.086 g (87% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.4 min.

MS (ESI pos): m / z = 401 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.88 (t, 3H), 1.30 (, 4H), 1.57 (m, 2H), 1.77 (m, IH), 1.89 (m, IH), 2.22 (m, 2H), 2.76 (m, IH), 3.25 (m, IH), 3.38 (m, 2H), 4.19 (m, 2H), 6.01 (dd, IH), 7.57 (d, 2H), 7.77 ( d, 2H), 7.95 (t, IH).

Example 150

3- (4-Chlθφhenyl) -N-cyano-N-cycloheptyl-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-l-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chlθφhenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.055 g (0.49 mmol) of heptylamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying in a high vacuum, 0.09 g (85% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.55 min.

MS (ESI pos): m / z = 427 (M + H) ⁺ Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.51-1.66 (m, 11H), 1.89 (m, 3H), 2.26 (m, 2H), 2.77 (m, IH), 3.25 (m, IH ), 4.07 (m, IH), 4.20 (m, 2H), 6.01 (dd, IH), 7.49 (d, IH), 7.56 (d, 2H), 7.79 (d, 2H).

Example 151

3- (4-chloro-phenyl) -N-cyano-N- [2- (ethylthio) ethyl] -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chlθφhenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.069 g (0.49 mmol) of 2- (ethylmercapto) ethylam hydrochloride are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.077 g (74% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.18 min.

MS (ESI pos): mz = 419 (M + H) ⁴

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.20 (t, 3H), 1.75 (, IH), 1.91 (m, IH), 2.22 (m, 2H), 2.56 (q, 2H), 2.71 (m, 3H), 3.29 (m, IH), 3.54 (, 2H), 4.23 (m, 2H), 6.04 (dd, IH), 7.58 (d, 2H), 7.77 (d, 2H), 8.08 (t , IH).

Example 152

3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -N- [2- (3-thienyl) ethyl] -4,5-dihydro-1H-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.062 g (0.49 mmol) 2- (3-thienyl) ethanamine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying in a high vacuum, 0.069 g (64% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.44 min.

MS (ESI pos): mz = 441 (M + H) ⁴

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.77 (, IH), 1.89 (m, IH), 2.23 (m, 2H), 2.76 (m, IH), 3.11 (m, 2H), 3.27 (m, IH), 3.63 (m, 2H), 4.22 (m, 2H), 6.04 (dd, IH), 6.95 (m, 2H), 7.34 (dd, IH), 7.58 (d, 2H), 7.76 ( d, 2H), 8.06 (t, IH).

Example 153

3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -N- [2- (3-thienyl) ethyl] -4,5-dihydro-1H-pyrazole-1-carboximidamide

Enantiomer separation of Example 152 by Method 18 gives the title compound as Enantiomer 2 (> 98.9% ee).

HPLC (method 18): R _t = 10.87 min. (second fraction) Example 154

3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -N- (3-phenylpropyl) -4,5-dihydro-1H-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.066 g (0.49 mmol) 3-phenylpropan-l-amine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.094 g (85% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.59 min.

MS (ESI pos): m / z = 449 (M + H) ⁴

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.90 (m, 2H), 2.02 (t, 2H), 2.36 (m, 2H), 2.74 (t, 2H), 2.87 (m, IH), 3.34 ( m, IH), 3.59 (m, 2H), 4.16 (dd, IH), 4.40 (dd, IH), 6.15 (dd, IH), 6.30 (t, IH), 7.22 (m, 5H), 7.41 (d , 2H), 7.64 (d, 2H).

Example 155

3 - (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -N- (2-phenylethyl) -4,5-dihydro-1 H-pyrazole-1-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.059 g (0.49 mmol) of 2-phenylethanamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying in a high vacuum, 0.080 g (75% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.33 min.

MS (ESI pos): m / z = 435 (M + H) ⁴

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.76 (m, IH), 1.89 (, IH), 2.22 (m, 2H), 2.75 (m, IH), 2.89 (t, 2H), 3.26 (m, IH), 3.61 (m, 2H), 4.18 (m, 2H), 6.02 (dd, IH), 7.28 (m, 5H), 7.58 (m, 2H), 7.76 (d, 2H), 8.03 ( t, IH).

Example 156

3 - (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l -yl) -N- {[3 - (trifluoromethyl) cyclohexyl] methyl} - 4,5-dihydro-lH-pyrazole-l- carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.053 g (0.29 mmol) l- [3- (trifluoromethyl) cyclohexyl] methanamine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the solvent is removed in vacuo and the product is purified by preparative HPLC. 0.103 g (85% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.7 min.

MS (ESI pos): m / z = 495 (M + H) Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.90 (m, 2H), 1.23 (m, 2H), 1.49 (m, IH), 1.77 (m, 6H), 2.25 (m, 3H), 2.76 (m, IH), 3.27 (m, 3H), 4.20 (m, 2H), 6.02 (dd, IH), 7.59 (d, 2H), 7.77 (d, 2H), 8.08 (t. IH).

Example 157

3- (4-chloro-phenyl) -N-cyano-N- (3-methylbutyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydr -lH-pyrazole-l-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.042 g (0.49 mmol) 3-methylbutane-l-amine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the solvent is removed in vacuo and the product is purified by preparative HPLC. 0.087 g (88% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.38 min.

MS (ESI pos): m / z = 401 (M + H) ⁴

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.92 (d, 6H), 1.48 (m, 2H), 1.61 (m, IH), 1.77 (m, IH), 1.89 (m, IH), 2.22 (m, 2H), 2.76 (m, IH), 3.25 (, IH), 3.37 (m, 2H), 4.19 (m, 2H), 6.01 (dd, IH), 7.56 (d, 2H), 7.77 ( d, 2H), 7.92 (t, lH).

Example 158

l- {3- (4-Chlθφhenyl) -l- [4- (3-thienyl) butanoyl] -4,5-dihydro-lH-pyrazol-4-yl} pyrrolidin-2-one

0.1 g (0.379 mmol) of l- [3- (4-chloro-phenyl) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one are mixed with 0.064 g (0.379 mmol) of 4- (3-thienyl ) butanoic acid, 5 mg (0.038 mmol) dimethylaminopyridine, 0.145 g (0.758 mmol) N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride, 0.05 g (0.379 mmol) 1-hydroxy-1H-benzotriazole hydrate and 0.16 ml ( 1.138 mmol) of triethylamine in 2 ml of anhydrous tetrahydrofuran was stirred overnight. After the salts have been filtered, the solvent is removed in vacuo and the remaining residue is purified by preparative HPLC. 0.1 g (65% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.50 min.

MS (ESI pos): m / z = 416 (M + Hf

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.91 (m, 3H), 2.18 (m, 2H), 2.66 (m, 7H), 3.96 (m, 2H), 5.94 (t, IH), 6.99 (dd, IH), 7.17 (dd, IH), 7.46 (dd, IH), 7.56 (d, 2H), 7.63 (d, 2H).

Example 159

l- [3- (4-CMoφhenyl) -l- (4-cyclohexylbutanoyl) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one

0.1 g (0.379 mmol) of l- [3- (4-chloro-phenyl) -4,5-dihydro-lH-pyrazol-4-yl] pyrrolidin-2-one are mixed with 0.064 g (0.379 mmol) of 4-cyclohexylbutyric acid, 5 mg (0.038 mmol) dimethylaminopyridine, 0.145 g (0.758 mmol) N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride, 0.05 g (0.379 mmol) 1-hydroxy-lH-benzotriazole hydrate and 0.16 ml (1.138 mmol) triethylamine in 2 ml of anhydrous tetrahydrofuran stirred overnight. After filtration of the salts, the solution medium removed in vacuo and the remaining residue purified by preparative HPLC. 0.077 g (49% of theory) of the product are obtained.

LC-MS (method 14): R _t = 3.1 min.

MS (ESI pos): m / z = 416 (M + Hf

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.86 (m, 2H), 1.22 (m, 6H), 1.63 (m, 8H), 1.89 (m, IH), 2.23 (m, 2H), 2.71 (m, 3H), 3.26 (m, IH), 3.96 (, 2H), 5.94 (dd, IH), 7.51 (d, 2H), 7.66 (d, 2H).

Example 160

3- (4-Trifluoromethyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -N- [2- (3-chloro-phenyl) -ethyl] -4,5-dihydro-1 H-pyrazole-1 -carboximidamid

50 mg (0.113 mmol) phenyl-3- (4-trifluoromethylphenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-1 H-pyrazole-1-carboximidoate and 35 mg ( 0.227 mmol) 2- (3-chlorophenyl) -ethanamine are dissolved in 2 ml DMF and heated to 100 ° C overnight. The product is purified using RP-HPLC. 44 mg (77% of theory) of the product are obtained.

LC-MS (Method 4): R _t = 2.29 min.

MS (ESI pos): m / z = 503 (M + Hf

Example 161

l- [3- (4-Chloφhenyl) -l- (lH-inιidazol-l-ylcarbonyl) -4,5-dihydro-lH-pyrazol-4-yl] piperidin-2-one

To a solution of 140 mg (0.86 mmol) of carbonyldiimidazole in 1 ml of anhydrous THF is added at 0-5 ° C for 30 min in 4 portions 200 mg (0.72 mmol) of l- [3- (4-chloro-phenyl) -4.5 -dihydro- lH-pyrazol-4-yl] piperidin-2-one (preparation analogous to Example XTT) and stirred for 45 min at this temperature. The precipitate is filtered off, washed with methyl tert-butyl ether and dried in vacuo.

Yield: 138 mg (52% of theory) of solid

Concentration of the mother liquor and chromatography on silica gel (dichloromethane / methanol 40: 1) gives a further 114 mg (43% of theory) of product.

LC-MS (method 13): R _t = 1.80 min.

MS (ESI pos): m / z = 372 (M + Hf -NMR (300 MHz, DMSO-d ₆ ): δ = 1.5 (m, 2H), 1.7 (m, 2H), 2.25 (t, 2H), 2.82 (m, IH), 3.3 (m, IH), 4.13 (dd, IH), 4.32 (dd, IH), 6.43 (m, IH), 7.1 (m, IH), 7.59 (m, 2H), 7.75 (m, 2H), 7.87 (m, IH), 8.52 (m, IH)

Example 162

3- (4-chloro-phenyl) -4- (2-oxopiperidin-l-yl) -N- (2-phenylethyl) -4,5-dihydro-1H-pyrazole-1-carboxamide

13 mg (0.11 mmol) of phenethylamine are added to a solution of 40 mg (0.11 mmol) of the compound from Example 161 in 0.5 ml of THF at room temperature and the mixture is stirred at RT overnight. It is divided between 50 ml of ethyl acetate and saturated sodium chloride solution containing 1 ml of 1M acetic acid, the organic phase is washed again with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo.

Yield: 46 mg (89% of theory)

LC-MS (method 13): R _t = 2.52 min.

MS (ESI pos): m / z = 425 (M + H) ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.5 (m, 2H), 1.7 (m, 2H), 2.25 (t, 2H), 2.63 (, IH), 2.7 (m, 2H) , 3.1 (m, IH), 3.34 (m, 2H), 3.35 (dd, IH), 4.0 (dd, IH), 6.43 (m, IH), 7.25 (m, 5H), 7.59 (m, 2H), 7.52 (m, 2H), 7.72 (m, 2H), 8.52

Example 163

3- (4-Chlθφhenyl) -N-cyano-N- (2-cyclobutylethyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazol-1-carboximidamide

To a solution of 274 mg (0.67 mmol) phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) - 4,5-dihydro-lH-pyrazole-l-carboximidoate and 100 mg (1.01 mmol) of 2-cyclobutylethylamine in 3 ml of DMF, 0.28 ml (2.02 mmol) of triethylamine are added and the mixture is stirred at 70 ° C. for 24 h. The solution is then concentrated under vacuum, mixed with water and saturated sodium chloride solution and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by means of preparative HPLC. 79 mg (28% of theory) of the product are obtained.

LC-MS (method 14): R _t = 2.43 min.

MS (ESI pos): m / z = 413 (M + Hf, MS (ESI neg): m / z = 411 (M-HT

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.55-1.98 (m, 9H), 1.98-2.1 (m, 2H), 2.12-2.38 (, 3H), 2.75 (dt, IH), 3.25- 3.4 (m, 2H), 4.15-4.28 (, 2H), 6.0 (dd, IH), 7.55 (d, 2H), 7.79 (d, 2H), 7.9 (t, IH).

The compounds of Examples 164 to 404 are prepared analogously to the examples described above.

HO

Production method for example 393

3- (4-chlorophenyl) -N-cyano-4- (2-oxopynolidin-l-yl) -N- (3,3,3-trifluoropropyl) -4,5-dihydro-lH-pyrazole-l-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chloro-nyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.055 g ( 0.49 mmol) 3,3,3-trifluoropropane-l-amine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the precipitate is filtered off and washed several times with diethyl ether. 0.089 g (85% of theory) of the product are obtained.

LC-MS (method 13): R _t = 2.30 min,

MS (ESIpos): m / z = 427 (M + H) ⁴

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.77 (m, IH), 1.91 (m, IH), 2.23 (m, 2H), 2.61 (m, 2H), 2.71 (m, IH), 3.25 (m, IH), 3.58 (m, 2H), 4.27 (m, 2H), 6.05 (dd, IH), 7.58 (d, 2H), 7.76 (d, 2H), 8.04 (t, IH).

Production method for example 396

N-butyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-prazol-l-carboximidamide

0.1 g (0.245 mmol) phenyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.035 g (0.49 mmol) of n-butylamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added, the product precipitating. After filtration, it is washed several times with diethyl ether. 0.072 g (76% of theory) of the product are obtained. LC-MS (method 13): R _t = 2.44 min,

MS (ESIpos): mz = 387 (M + Hf

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.91 (t, 3H), 1.32 (m, 2H), 1.55 (m, 2H), 1.76 (m, IH), 1.91 (m, IH), 2.22 (m, 2H), 2.75 (m, IH), 3.29 (, IH), 3.39 (m, 2H), 4.19 (m, 2H), 6.01 (dd, IH), 7.51 (d, 2H), 7.77 ( d, 2H), 7.95 (t, IH).

Example 405

3- (4-chlorophenyl) -N-cyano-N- [2- (2,4-dichlorophenyl) -2-fluoroethyl] -4- (2-oxopyrrolidin-l-yl) -4,5- dihydro-lH- pyrazole-1-carboximidamide

Enantiomer removal from Example 354 by Method 17 yields the title compound as enantiomer 2 (> 98% ee).

HPLC (method 17): R _t = 5.90 min. (second fraction)

hi Analogy to the examples described above, the compounds of Examples 406 to 415 are prepared.

Example 416

3 - (4-Chloφhenyl) -N-cyano-N- (5-cyanopentyl) -4- (2-oxopyrrolidin- 1 -yl) -4,5 -dihydro-1 H-pyrazole-1 - carboximidamide

Enantiomer separation from Example 394 by Method 21 gives the title compound as enantiomer 1 (> 99.5% ee).

HPLC (method 21): R _t = 6.37 min

Example 417

N-butyl-3- (4-chloro-henyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidamide

Enantiomer separation of Example 396 by Method 22 gives the title compound as enantiomer 1 (> 99.5% ee).

HPLC (method 22): R _t = 5.32 min

Example 418

3 - (4-Chlorophenyl) -N-cyano-4- (2-oxopyrrolidin- 1 -yl) -N- (3, 3, 3-trifluoropropyl) -4,5-dihydro-1 H-pyrazole-1-carboximidamide

Enantiomer separation of Example 393 by Method 22 gives the title compound as enantiomer 1 (> 99% ee).

HPLC (method 22): R _t = 5.14 min

Example 419

3- (4-chloro-henyl) -N-cyano-N- (2-ethoxyethyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-l-carboximidamide

Enantiomer separation of Example 391 by Method 22 gives the title compound as Enantiomer 2 (> 99.5% ee).

HPLC (method 22): R _t = 11.35 min

Example 420

3- (4-chloro-phenyl) -N-cyano-N- (3-methoxybutyl) -4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidamide

Enantiomer separation from Example 410 according to Method 22 gives the title compound as enantiomer 1 / diastereomer 1 (> 99.5% ee).

HPLC (method 22): R _t = 5.11 min

Example 421

3 - (4-chloro-phenyl) -N-cyano-N- (3-methoxybutyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazole-1-carboximidamide

Enantiomer separation of Example 410 according to Method 22 gives the title compound as enantiomer 1 / diastereomer 2 (> 99.5% ee).

HPLC (method 22): R _t = 6.64 min

B) Assessment of physiological effectiveness

Abbreviations:

DMEM Dulbecco's Modified Eagle Medium

FCS Fetal Calf Serum

HEPES 4- (2-hydroxyethyl) -l-piperazineethanesulfonic acid

The suitability of the compounds according to the invention for the treatment of thromboembolic disorders can be shown in the following assay systems:

In vitro assays

a) Cellular, functional in vitro test

The identification of agonists of the human protease activated receptor 1 (PARI) and the quantification of the effectiveness of the substances described here is carried out using a recombinant cell line. The cell is originally derived from a human embryonic kidney cell (HEK293; ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell line consumatively expresses a modified form of the calcium-sensitive photoprotein aequorin, which after reconstitution with the co-factor coelenterazine emits light when the free calcium concentration in the inner mitochondrial compartment increases (Rizzuto R, Simpson AW, Brini M, Pozzan T .; Nature 1992, 358, 325-327). In addition, the cell stably expresses the endogenous human PARI receptor and the endogenous purinergic receptor P2Y2. The resulting PARI test cell responds to stimulation of the endogenous PARI or P2Y2 receptor with an intracellular release of calcium ions, which can be quantified by the resulting aequorin luminescence with a suitable luminometer (Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 1996, 17, 235-237).

To test the substance specificity, its effect after activation of the endogenous PAR1 receptor is compared with the effect after activation of the endogenous purinergic P2Y2 receptor, which uses the same intracellular signaling pathway.

Test procedure: The cells are placed in culture medium (DMEM F12, supplemented with 10% FCS, 2 mM glutamine, 20 mM HEPES, 1,4mM pyruvate, 0, lmg / ml gentamycin, two days (48 hours) before the test.

0.15% Na bicarbonate; BioWhittaker Cat. # BE04-687Q; B-4800 Verviers, Belgium) in 384 holes Plated microtitre plates and kept in a cell incubator (96% humidity, 5% v / v CO ₂ , 37 ° C). On the test day, the culture medium is replaced by a Tyrode solution (in M: 140 NaCl, 5 KC1, 1 MgCl ₂ , 2 CaCl ₂ , 20 glucose, 20 HEPES), which also contains the co-factor coelenterazine (25 μM) and glutathione (4 mM) contains, exchanged and then the Mikrotiteφlatte incubated for another 3-4 hours. Then the test substances are pipetted onto the microtiter plate and 5 minutes after transfer of the test substances into the wells of the microtiter plate, the plate is transferred to the luminometer, a PARl agonist concentration corresponding to EC ₅₀ is added and the resulting light signal is immediately measured in the luminometer. To differentiate an antagomst substance effect from a toxic effect, the endogenous purinergic receptor is activated with an agonist (ATP, 10 μM final concentration) and the resulting light signal is measured. The results are shown in Table A:

Table A:

b) platelet aggregation

To determine platelet aggregation, blood from healthy volunteers of both sexes who had not received any medication influencing platelet aggregation within the past ten days is used. The blood is taken up in monovettes (Sarstedt, Nümbrecht, Germany) which contain 3.8% sodium citrate as anticoagulant (1 part citrate + 9 parts blood). To obtain platelet-rich plasma, the whole citrate blood is centrifuged at 2500 rpm for 20 min at 4 ° C.

For the aggregation measurements, aliquots of the platelet-rich plasma with increasing concentrations of test substance are incubated for 10 min at 37 ° C. The aggregation is then triggered by adding a thrombin receptor agonist (SFLLRN) in an aggregometer and using the turbidimetric method according to Born (Born, GVR, Cross MJ, The Aggregation of Blood Platelets; J. Physiol. 1963, 168, 178-195 ) at 37 ° C. The SFLLRN concentration that leads to the maximum aggregation is determined individually for each donor.

To calculate the inhibitory effect, the increase in light transmission (amplitude of the aggregation curve in%) is determined 5 minutes after addition of the agonist in the presence and absence of test substance, and the inhibition is calculated. The concentration that inhibits aggregation by 50% is calculated from the inhibition curves. The results are shown in Table B:

Table B:

c) Stimulation of washed platelets and analysis in FACS (Fluorescence Associated Cell Sorter)

Isolation of washed platelets:

Human whole blood is obtained by venipuncture from voluntary donors and transferred to monovettes (Sarstedt, Nümbrecht, Germany) that contain sodium citrate as an anticoagulant (1 part sodium citrate 3.8% + 9 parts whole blood). The monovettes are centrifuged at 900 revolutions per minute and 4 ° C over a period of 20 minutes (Heraeus Instruments, Germany; Megafuge 1.0RS). The platelet-rich plasma is carefully removed and transferred to a 50 ml falcon tube. Now ACD buffer (44 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose) is added to the plasma. The volume of the ACD buffer corresponds to a quarter of the plasma volume. The platelets are sedimented by centrifugation at 2500 revolutions and 4 ° C. for ten minutes. The supernatant is then carefully decanted off and discarded. The precipitated platelets are first carefully washed with a milliliter of washing buffer (113 mM sodium chloride, 4 mM disodium hydrogen phosphate, 24 mM sodium dihydrogen phosphate, 4 mM potassium chloride, 0.2 mM ethylene glycol bis (2-aminoethyl) -N, N, NW tetraacetic acid, 0.1% glucose ) resuspended and then filled up with washing buffer to a volume which corresponds to that of the plasma amount. The washing process is carried out a second time. After the platelets have been precipitated by another centrifugation at 2500 revolutions and 4 ° C for ten minutes, they are carefully cautiously placed in a milliliter of incubation buffer (134 mM sodium chloride, 12 mM sodium hydrogen carbonate, 2.9 mM potassium chloride, 0.34 mM sodium dihydrogen carbonate, 5 mM HEPES, 5 mM glucose , 2 mM calcium chloride and 2 mM magnesium chloride) resuspended and adjusted to a concentration of 300,000 platelets per μl with incubation buffer.

FACS staining and stimulation of human platelets with human α-thrombin in the presence or absence of a PAR-1 antagonist:

The platelet suspension is preincubated with the substance to be tested or the corresponding solvent for 10 minutes at 37 ° C (Eppendorf, Germany; Thermomixer Comfort). By adding the agonist (0.5 μM or 1 μM α-thrombin; Kordia, Netherlands, 3281 NIH Units / mg; or 30μg / ml Thrombin receptor activating peptide (TRAP6); Bachern, Switzerland) at 37 ° and with shaking 500 revolutions platelet activation is triggered per minute. At the times 0, 1, 2.5, 5, 10 and 15 minutes, an aliquot of 50 μl is taken in each case and transferred to a milliliter of single-concentrated CellFix ™ solution (Becton Dick sonninocytometry Systems, USA). To fix the cells, they are incubated for 30 minutes at 4 ° C. in the dark. By a ten minute The platelets are precipitated by centrifugation at 600 g and 4 ° C. The supernatant is discarded and the platelets are resuspended in 400 μl CellWash ™ (Becton Dickinson nmunocytometry Systems, USA). An aliquot of 100 μl is transferred to a new FACS tube, 1 μl of the platelet-identifying antibody and 1 μl of the activation state-detecting antibody are filled up to a volume of 100 μl with CellWash ™. This antibody solution is then added to the platelet suspension and incubated for 20 minutes at 4 ° C. in the dark. After the staining, the batch volume is increased by adding another 400 μl CellWash ™.

To identify the platelets, a fluorescein-isothiocyanate-conjugated antibody is used which is directed against the human glycoprotein Ilb (CD41) (hnmunotech Coulter, France; Cat. No. 0649). With the help of the phycoerythrin-conjugated antibody, which is directed against the human glycoprotein P-selectin (hnmunotech Coulter, France; Cat. No. 1759), the activation state of the platelets can be determined. P-selectin (CD62P) is localized in the α-granules of resting platelets. However, it is translocalized to the outer plasma membrane after in vitro or in vivo stimulation.

FACS measurement and evaluation of FACS data:

The samples are measured in the FACSCalibur ™ Flow Cytometry System from Becton Dickinson nmunocytometry Systems, USA, and evaluated and graphically displayed using the CellQuest, Version 3.3 software (Becton Dickinson hnmunocytometry Systems, USA). The degree of platelet activation is determined by the percentage of CD62P positive platelets (CD41 positive events). 10,000 CD41 positive events are counted from each sample.

The inhibitory effect of the substances to be tested is calculated on the basis of the reduction in platelet activation, which relates to the activation by the agonist.

Ex vivo assay

Platelet aggregation (guinea pig)

Guinea pigs (strain: Dunkin Hartley) are treated orally, intravenously or intraperitoneally with test substances in a suitable formulation when awake or anesthetized. As a control, other guinea pigs are treated identically with the appropriate vehicle. Depending on the type of application, a different length of time is obtained from the deeply anesthetized animals by puncturing the heart or the aorta. The blood is collected in monovettes (Sarstedt, Nümbrecht, Germany) which are 3.8% anticoagulant sodium citrate (1st Part citrate solution + 9 parts blood) included. To obtain platelet-rich plasma, the citrate whole blood is centrifuged at 2500 rpm for 20 min at 4 ° C.

The aggregation is triggered by adding a thrombin receptor agonist (SFLLRN, 50 μg / ml) in an aggregometer and using the turbidimetric method according to Born (Born, GVR, Cross MJ, The Aggregation of Blood Platelets; J. Physiol. 1963, 168 , 178-195) at 37 ° C.

For the aggregation measurement, the increase in light transmission (amplitude of the aggregation curve in%) is determined 5 minutes after adding the agonist. The inhibitory effect of the administered test substances in the treated animals is calculated by reducing the aggregation, based on the mean value of the control animals.

In vivo assay

The compounds according to the invention can be investigated in thrombosis models in suitable animal species in which thrombin-induced platelet aggregation is mediated via the PAR-1 receptor. Suitable animal species are guinea pigs and especially primates (compare: Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kajiwara A, Hishinuma I, Circulation 2003, 108 Suppl. 17, IV-280; Derian CK, Damiano BP, Addo MF, Darrow AL, D'Andrea MR, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861).

C) Examples of pharmaceutical compositions

The substances according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Germany) and 2 mg magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of the compound of Example 1, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are dried with the magnesium stearate for 5 min. mixed. This mixture is veφresst with a conventional tablet press (format of the tablet see above).

Oral suspension:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum) (from FMC, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. The water is added with stirring. The mixture is stirred for about 6 hours until the swelling of the Rhodigel is complete. Solution that can be administered intravenously:

Composition:

1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injections.

production:

The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile filtered (pore diameter 0.22 μm) and filled into heat-sterilized infusion bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

Claims

Patentansprtiche

1. Compound of the formula

in which E represents methylene, NH, an oxygen atom or a sulfur atom, m represents 0, 1, 2 or 3, n represents 1, 2 or 3,

R ^{1 represents} halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl, alkylaminocarbonyl or -NH (C = 0) OR ⁹ , where

R ⁹ for (C, -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₇ ) cycloalkyl methyl or (C ₆ -Cι ₀ ) arylmethyl,

R ² for a group of the formula

stands where * stands for the connection point to the pyrazoline ring,

X represents R ³ or (C ₁ -C ₈ ) alkylene-R ⁴ , where alkylene can be substituted by 1 to 4 fluorine atoms,

Y represents R ³ or (C Cg) -alkylene-R ⁴ , where alkylene can be substituted by 1 to 4 fluorine atoms,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzo-dioxin, 2,2,4,4-tetrafluoro-4H-l, 3rd -benzodioxin, indanyl, 1,2,3,4-tetra-hydronaphthyl, (C ₆ -Cι ₀ ) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₆ ) - cycloal yl or 5- to 10 -linked heterocyclyl, where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy Tri-halomethoxy, alkyl, alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{4 is} hydrogen, 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-1 _. 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin, indanyl, 1,2,3,4-tetrahydronaphthyl, (C ₆ -Cιo) aryl, 5- to 10-membered heteroaryl , (C ₃ -C ₇ ) cycloalkyl, 5- to 10-membered heterocyclyl, hydroxy, cyano, trifluoromethyl, optionally fluorine-substituted alkylthio, -OR ⁵ , -C (= 0) R ⁶ or -NR ⁷ R ⁸ , where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxyl, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, tri halogen methoxy, alkyl, alkoxy optionally substituted with alkoxycarbonyl, alkylamino, aryl, benzyl, hydroxy carbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{5 represents} alkyl which is optionally substituted with fluorine, (C ₆ -C ₀ ) aryl, benzyl, (C ₃ -C ₇ ) cycloalkyl or alkylcarbonyl, where aryl, benzyl or cycloalkyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbon Alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl, R ^{6 represents} hydroxy, amino, alkyl, alkylamino, alkoxy, (C ₆ -C ₁₀ ) aryl, benzyloxy or 5- to 10-membered heterocyclyl, where aryl or benzyloxy can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalog enmethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl, R ^{7 represents} hydrogen, alkyl or benzyl,

R ^{8 represents} hydrogen, alkyl, phenyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylcarbonyl optionally substituted by alkyl or arylsulfonyl optionally substituted by alkyl, and their salts, their solvates and the solvates of their salts for the treatment and / or prophylaxis of diseases.

2. Compound of the formula

in which

E represents methylene, NH, an oxygen atom or a sulfur atom,

m represents 0, 1, 2 or 3,

n represents 1, 2 or 3,

R ^{1 represents} halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl, alkylaminocarbonyl or -NH (C = 0) OR ⁹ , where R ^{9 represents} (C _r C ₆ ) Alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₇ ) cycloalkylmethyl or (C6-Cιo) arylmethyl,

R ² for a group of the formula

stands where

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (CC ₈ ) alkylene-R ⁴ , where alkylene can be substituted with 1 to 4 fluorine atoms,

Y represents (CC _s ) alkylene-R ⁴ , where alkylene can be substituted by 1 to 4 fluorine atoms,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole ₅ 2,3-dihydro-1,4-benzo-dioxin, 2,2,4,4-tetrafluoro-4H-1,3 -benzodioxm, indanyl, 1,2,3,4-tetrahydronaphthyl, (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₆ ) cycloalkyl or 5- to 10- membered heterocyclyl, where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy , Alkyl, alkoxy, alkylamino, aryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{4 is} hydrogen, 1,3-benzodioxole, 2,2-difluoro-1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, 2,2,4,4-tetrafluoro-4H-1,3 -benzodioxin, indanyl, 1,2,3,4-tetrahydronaphthyl, (C ₆ -C ₁₀ ) aryl, 5- to 10-membered heteroaryl, (C ₃ -C ₇ ) cycloalkyl, 5- to 10-membered heterocyclyl , Hydroxy, cyano, trifluoromethyl, optionally fluorine-substituted alkylthio, -OR ⁵ , -C (= 0) R ⁶ or -NR ⁷ R ⁸ , where aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl optionally substituted with alkoxycarbonyl, Aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl, R ^{5 represents} , optionally substituted with fluorine, alkyl, (C ₆ -Cιo) aryl, benzyl, (C ₃ -C ₇ ) cycloalkyl or alkylcarbonyl, where aryl, benzyl or cycloalkyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl carbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{6 represents} hydroxy, amino, alkyl, alkylamino, alkoxy, (C6-Cι ₀ ) aryl, benzyloxy or 5- to 10-membered heterocyclyl, where aryl or benzyloxy can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxyl, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminylcarbonyl, Alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,

R ^{7 represents} hydrogen, alkyl or benzyl,

R ^{8 represents} hydrogen, alkyl, phenyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylcarbonyl optionally substituted by alkyl or arylsulfonyl optionally substituted by alkyl, and their salts, their solvates and the solvates of their salts.

3. A compound according to claim 2, in which

E represents methylene, NH or an oxygen atom, m represents 0, 1 or 2, n represents 1, 2 or 3,

R ^{1 represents} halogen, amino, cyano, nitro, trifluoromethyl, alkyl or alkoxy,

R ² for a group of the formula

stands where

* stands for the connection point to the pyrazoline ring,

X represents R ³ or (C ₁ -C ₈ ) alkylene-R ⁴ ,

Y represents (C _r C ₈ ) alkylene-R ⁴ , R ^{3 represents} 1,3-benzodioxole, 2,2-difluoro-1,3-benzodioxole, 2,3-dihydro-1,4-benzo-dioxin, 2,2,4,4-tetrafluoro-4H-1,3-benzodioxin, indanyl, 1,2,3,4-tetrahydronaphthyl, phenyl, 5- or 6-membered heteroaryl, (C ₃ -C ₆ ) - Cycloalkyl or 5- or 6-membered heterocyclyl, where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxyl, amino, halogen, cyano, nitro, trichloromethyl, Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (CC ₄ ) alkyl,

(-C-C) alkylamino, phenyl, hydroxycarbonyl, (-G -alkoxycarbonyl, aminocarbonyl, (Cι-C ₄ ) -alkylamino-carbonyl and (CC ₄ ) -alkylcarbonyl,

R ^{4 is} hydrogen, 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3 -benzodioxin, indanyl, 1,2,3,4-tetrahydronaphthyl, phenyl, naphthyl, 5- or 6-membered hetero- aryl, (C ₅ -C ₆ ) cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl, -OR ⁵ , -C (= O) R ⁶ or -NR ⁷ R ⁸ , where phenyl, naphthyl, heteroaryl , Cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently of one another, selected from the group consisting of hydroxyl, amino, halogen, cyano, nitro, oxo, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (CC ₄ ) - Alkyl, (CC ₄ ) -alkoxy, (CC ₄ ) -alkylamino, phenyl, hydroxycarbonyl, (Cι-C) -alkoxycarbonyl, aminocarbonyl, (Ci- C ₄ ) -alkylaminocarbonyl and (Cι-C ₄ ) -alkylcarbonyl,

R ^{5 represents} , optionally substituted with fluorine (-CC) alkyl, phenyl, benzyl or (CC ₄ ) alkylcarbonyl,

R ^{6 represents} (-O-alkoxy,

R ^{7 represents} hydrogen or (-CC ₄ ) -alkyl, R ^{8 represents} (C_-C ₄ ) -alkyl or phenylcarbonyl optionally substituted with (-C-C ₄ ) -alkyl, and their salts, their solvates and the solvates of their salts.

4. A compound according to claim 2 or 3, in which E represents methylene, NH or an oxygen atom, m represents 0, 1 or 2, n represents 1, 2 or 3,

R ^{1 represents} halogen, amino, cyano, trifluoromethyl, (CC) -allcyl or (-C-C ₄ ) alkoxy, R ^{2 represents} a group of the formula

stands where

* represents the point of attachment to the pyrazoline ring, X represents R ³ or (C, -C ₆ ) alkylene-R ⁴ ,

R ³ for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzo-dioxin, 2,2,4,4-tetrafluoro-4H-l, 3rd -benzodioxin, phenyl, 5- or 6-membered heteroaryl or (C ₃ -C ₆ ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 or 2 substituents, independently selected from the group consisting of halogen, cyano , Trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (C _r C ₄ ) alkyl and (CC ₄ ) alkoxy,

R ^{4 represents} hydrogen, phenyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl, -OR ⁵ or -NR ⁷ R ⁸ , where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano, oxo, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (CC) -alkyl and (Cι- C ₄ ) alkoxy,

R ^{5 represents} (CC) -alkyl which is optionally substituted with fluorine,

R ^{7 represents} hydrogen or (CC ₄ ) alkyl,

R ^{8 stands} for (-G -alkyl, and their salts, their solvates and the solvates of their salts.

5. Compounds according to one of claims 2 to 4, in which

E represents methylene,

m represents 1,

n stands for 1,

R ^{1 represents} halogen,

R ² for a group of the formula

stands, where * stands for the connection point to the pyrazoline ring,

X represents R ³ or (-CC ₆ ) alkylene-R ⁴ ,

R ^{3 represents} phenyl, 5- or 6-membered heteroaryl or (C ₅ -C ₆ ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano , Trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (CC ₄ ) alkyl and (CC ₄ ) alkoxy,

R ^{4 represents} hydrogen, phenyl, 5- or 6-membered heteroaryl, (C ₅ -C ₆ ) cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl or -OR ⁵ , where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl, monofluoromethoxy, difluoromethoxy, Trifluoromethyl, trifluoromethoxy, (-C-C ₄ ) alkyl and (C, -C ₄ ) - alkoxy,

R ^{5 represents} methyl or ethyl,

and their salts, their solvates and the solvates of their salts.

Process for the preparation of compounds of formula (I) as defined in claim 2, characterized in that compounds of formula

in which

R ¹ , E, m and n have the meaning given in claim 2,

either

[A] with compounds of the formula

in which

X has the meaning given in claim 2 and Z ^{1 represents} halogen, preferably chlorine or bromine, or hydroxy,

or

[B] with compounds of the formula Y - NGO (IV), in which

Y has the meaning given in claim 2, or

[C] with compounds of the formula Y-NCS (V), in which

Y has the meaning given in claim 2, or

[D] with compounds of the formula

in which

X has the meaning given in claim 2, or

[E] in two stages, first with diphenylcyanocarboimidate and then with compounds of the formula

X-NH ₂ (vπ), in which

X has the meaning given in claim 2, are implemented.

7. A compound of formula (T), as defined in any one of claims 2 to 4, for the treatment and / or prophylaxis of diseases.

8. Use of a compound of formula (I), as defined in one of claims 1 to 5, for the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular diseases.

9. Use of a compound of formula (I), as defined in one of claims 1 to 5, for the manufacture of a medicament for the treatment and / or prophylaxis of thromboembolic disorders.

10. A method for the treatment and / or prophylaxis of cardiovascular diseases using a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 5.

11. Medicament containing a compound of formula (I), as defined in one of claims 1 to 5, in combination with a further active ingredient.

12. Medicament containing a compound of formula (I), as defined in one of claims 1 to 5, in combination with an inert, non-toxic, pharmaceutically suitable excipient.