DE102004061748A1 - Azetidine-substituted pyrazolines - Google Patents

Abstract

The present invention relates to the field of blood clotting. In particular, the present invention relates to the use of azetidine-substituted pyrazolines as pharmaceuticals, to novel azetidine-substituted pyrazolines and to processes for their preparation and to their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases, preferably of thromboembolic disorders.

Description

The The present invention relates to the field of blood clotting. The in particular, the present invention relates to the use of azetidine-substituted ones Pyrazolines as drugs, new azetidine-substituted pyrazolines and process for their preparation and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, especially cardiovascular diseases, preferably thromboembolic Diseases.

platelet (Platelets) are an essential factor in both physiological hemostasis (hemostasis) as well as in thromboembolic diseases. Especially in the arterial System, platelets are central to the complex Interaction between blood components and vessel wall too. Unwanted platelet activation can be platelet-rich due to formation Thrombi to thromboembolic disorders and thrombotic complications with life-threatening conditions to lead.

one the most potent platelet activators is the clotting protease thrombin, which is formed on injured blood vessel walls and in addition to fibrin formation to activate platelets, Endothelial cells and mesenchymal cells (Vu TKH, Hung DT, Wheaton VI, Coughlin SR, Cell 1991, 64, 1057-1068). To platelets in In vitro and in animal models thrombin inhibitors inhibit platelet aggregation or formation platelet-rich Thrombi. In humans you can arterial thrombosis successful with inhibitors of platelet function and thrombin inhibitors (Bhatt DL, Topol EJ, Nat. Rev. Drug Discov. 2003, 2, 15-28). Therefore there is one high probability that antagonists of thrombin action on platelets the formation of thrombi and the appearance of clinical consequences like heart attack and stroke decrease. Further cellular thrombin effects, e.g. on vascular endothelium and smooth muscle cells, leukocytes and fibroblasts are possibly for inflammatory and proliferative diseases.

The cellular Effects of thrombin are at least partially via a family of G protein-coupled receptors (Protease Activated Receptors, PARs), their prototype the PAR-1-Rezepor represents. PAR-1 is produced by binding of thrombin and proteolytic Cleavage of its extracellular activated N-terminus activated. Proteolysis turns into a new one N-terminus with the amino acid sequence SFLLRN ... exposed as an agonist ("tethered ligand") to intramolecular Receptor activation and transmission intracellular Signals leads. From the tethered ligand Sequence derived peptides can be used as agonists of the receptor and perform Platelets for activation and aggregation.

Antibodies and other selective PAR-1 antagonists inhibit thrombin-induced Aggregation of platelets in vitro at low to medium levels Thrombin concentrations (Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR, J. Clin. Invest. 1999, 103, 879-887). One another thrombin receptor with possible Meaning of The pathophysiology of thrombotic processes, PAR-4, was based on human and animal platelets. In experimental thrombosis in animals with a similar human PAR expression pattern PAR-1 antagonists reduce the formation of platelet-rich thrombi (Derian CK, Damiano BP, Addo MF, Darrow AL, D'Andrea MR, Nedelman M, Zhang H-C, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861).

In In recent years, a variety of substances have been found to inhibit their platelet function Effect tested. In practice, only a few platelet function inhibitors have been proven. It There is therefore a need for pharmaceuticals that are specifically enhanced platelet response inhibit without significantly increasing the risk of bleeding and thus the risk of reduce thromboembolic complications. In contrast to the inhibition the protease activity of thrombin with direct thrombin inhibitors should be a blockade of the PAR-1 for the inhibition of platelet activation without reduction coagulation ability of the blood.

A The object of the present invention is therefore new PAR-1 antagonists for the treatment of cardiovascular diseases, e.g. thromboembolic Disease in humans and animals to provide.

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

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

in welcher
R¹ für eine Gruppe der Formel

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
X für NH, ein Sauerstoffatom oder ein Schwefelatom steht,
Y für NR⁷, ein Sauerstoffatom, ein Schwefelatom, S(=O) oder S(=O)₂ steht,
wobei
R⁷ für Wasserstoff, Methyl, Ethyl, 2-Hydroxyeth-1-yl, 2-Aminoethyl, Cyclopropyl oder Methylsufonyl steht,
o für 1, 2 oder 3 steht,
p für 1, 2 oder 3 steht,
q für 1, 2 oder 3 steht,
R⁴ für Wasserstoff, Amino, 2-Hydroxyeth-1-yl, (C₁-C₃)-Alkoxy oder (C₁-C₆)-Alkylamino steht,
R⁵ für Wasserstoff, Methyl, Ethyl, n-Propyl, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl oder 2,3-Dihydroxyprop-1-yl,
R⁶ für Wasserstoff, Methyl, Ethyl, n-Propyl, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl, 2,3-Dihydroxyprop-1-yl, Methylcarbonyl, Ethylcarbonyl, n-Propylcarbonyl, Methoxycarbonyl, Ethoxycarbonyl, n-Propoxycarbonyl oder Methylsulfonyl steht,
wobei Methylcarbonyl, Ethylcarbonyl und n-Propylcarbonyl substituiert sein können mit 1 bis 2 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Hydroxy, Amino, (C₁-C₃)-Alkoxy und (C₁-C₃)-Alkylcarbonyloxy,
R² für Methyl, (C₃-C₇)-Cycloalkyl, Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, Trifluormethyl, Trifluormethoxy und Difluormethoxy,
A für eine Bindung oder ein Sauerstoffatom steht,
m für 0, 1, 2 oder 3 steht,
n für 0, 1, 2 oder 3 steht,
R³ für eine Gruppe der Formel

steht;
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
R⁸ für Halogen, Cyano, Trifluormethyl, Trifluormethoxy oder Difluormethoxy steht,
R⁹ für Wasserstoff, Halogen, Methyl, Methoxy, Trifluormethyl, Trifluormethoxy oder Difluormethoxy steht,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.The present invention relates to compounds of the formula

in which
R ^{1 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
X is NH, an oxygen atom or a sulfur atom,
Y is NR ⁷ , an oxygen atom, a sulfur atom, S (= O) or S (= O) ₂ ,
in which
R ^{7 is} hydrogen, methyl, ethyl, 2-hydroxyeth-1-yl, 2-aminoethyl, cyclopropyl or methylsulfonyl,
o is 1, 2 or 3,
p is 1, 2 or 3,
q is 1, 2 or 3,
R ^{4 is} hydrogen, amino, 2-hydroxyeth-1-yl, (C ₁ -C ₃ ) -alkoxy or (C ₁ -C ₆ ) -alkylamino,
R ^{5 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop -1-yl,
R ^{6 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop 1-yl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or methylsulfonyl,
wherein methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₃ ) -alkoxy and (C ₁ -C ₃ ) -alkylcarbonyloxy,
R ^{2 is} methyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or 5- or 6-membered heteroaryl,
wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy .
A is a bond or an oxygen atom,
m is 0, 1, 2 or 3,
n is 0, 1, 2 or 3,
R ^{3 is} a group of the formula

stands;
in which
* represents the point of attachment to the pyrazoline ring,
R ^{8 is} halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
R ^{9 represents} hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
and their salts, their solvates, and the solvates of their salts.

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

The Compounds of the invention can dependent on of their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore includes the enantiomers or Diastereomers and their respective mixtures. From such mixtures enantiomers and / or diastereomers can be the stereoisomer isolate uniform components in a known manner.

The Compounds of the invention can as E and Z isomers at the C-N double bond of the cyanoguanidine group are present, preferred is the Z-isomer.

Provided the compounds of the invention can occur in tautomeric forms, For example, the present invention encompasses all tautomeric forms.

When Salts are physiologically acceptable in the context of the present invention Salts of the compounds of the invention prefers. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable but for example for insulation or cleaning the compounds of the invention can be used.

physiological Safe 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, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, naphthalenedisulfonic, Acetic acid, trifluoroacetic, propionic acid, Lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

physiological acceptable salts of the compounds of the invention also include Salts more usual Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, Diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, Dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

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

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl per se and "Alk" and "alkyl" in alkoxy, alkylamino and alkylcarbonyloxy are a linear or branched alkyl radical having 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert-butyl.

Alkoxy is exemplified and preferably methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.

Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N -diethylamino, N-ethyl-N-methylamino, N -methyl-Nn-propylamino, N-iso-propyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methyl-amino. C ₁ -C ₃ -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.

alkylcarbonyloxy is exemplary and preferably methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, iso -propylcarbonyloxy, n-butylcarbonyloxy and tert-butylcarbonyloxy.

cycloalkyl stands for a mono- or bicyclic cycloalkyl group with usually 3 to 7, preferably 5 or 6 carbon atoms, by way of example and by way of example for cycloalkyl may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Cycloheptyl.

heteroaryl stands for an aromatic monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 3 heteroatoms from the series S, O and N, by way of example and preferably for thienyl, furyl, pyrrolyl, Thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, Pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.

halogen stands for Fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

One Symbol # on a carbon atom means that the compound in terms of configuration at this carbon atom in enantiomerically pure Form is present, among which in the context of the present invention a enantiomeric excess (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 Remainders, unless otherwise specified, one or more times the same or substituted differently. A substitution with up to three identical or different substituents are preferred. All particularly preferred is substitution with a substituent.

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
X für NH oder ein Sauerstoffatom steht,
Y für NR⁷ oder ein Sauerstoffatom steht,
wobei
R⁷ für Wasserstoff, Methyl, Ethyl oder Cyclopropyl steht,
o für 1, 2 oder 3 steht,
p für 1, 2 oder 3 steht,
q für 1, 2 oder 3 steht,
R⁴ für Wasserstoff oder 2-Hydroxyeth-1-yl steht,
R⁵ für Wasserstoff, Methyl, Ethyl, n-Propyl, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl oder 2,3-Dihydroxyprop-1-yl steht,
R⁶ für Wasserstoff, Methyl, Ethyl, n-Propyl, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl, 2,3-Dihydroxyprop-1-yl, Methylcarbonyl, Ethylcarbonyl, n-Propylcarbonyl, Methoxycarbonyl, Ethoxycarbonyl, n-Propoxycarbonyl oder Methylsulfonyl steht,
wobei Methylcarbonyl, Ethylcarbonyl und n-Propylcarbonyl substituiert sein können mit 1 bis 2 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Hydroxy, Amino, (C₁-C₃)-Alkoxy und (C₁-C₃)-Alkylcarbonyloxy,
R² für Methyl, (C₃-C₇)-Cycloalkyl, Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, Trifluormethyl, Trifluormethoxy und Difluormethoxy,
A für eine Bindung oder ein Sauerstoffatom steht,
m für 0, 1, 2 oder 3 steht,
n für 0, 1, 2 oder 3 steht,
R³ für eine Gruppe der Formel

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
R⁸ für Halogen, Cyano, Trifluormethyl, Trifluormethoxy oder Difluormethoxy steht,
R⁹ für Wasserstoff oder Halogen steht,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.Preference is given to compounds of the formula (I)
in which
R ^{1 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
X is NH or an oxygen atom,
Y is NR ⁷ or an oxygen atom,
in which
R ^{7 is} hydrogen, methyl, ethyl or cyclopropyl,
o is 1, 2 or 3,
p is 1, 2 or 3,
q is 1, 2 or 3,
R ^{4 is} hydrogen or 2-hydroxyeth-1-yl,
R ^{5 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop -1-yl stands,
R ^{6 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop 1-yl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or methylsulfonyl,
wherein methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₃ ) -alkoxy and (C ₁ -C ₃ ) -alkylcarbonyloxy,
R ^{2 is} methyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or 5- or 6-membered heteroaryl,
wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy .
A is a bond or an oxygen atom,
m is 0, 1, 2 or 3,
n is 0, 1, 2 or 3,
R ^{3 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
R ^{8 is} halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
R ^{9 is} hydrogen or halogen,
and their salts, their solvates, and the solvates of their salts.

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
X für NH oder ein Sauerstoffatom steht,
Y für NR⁷ oder ein Sauerstoffatom steht,
wobei
R⁷ für Wasserstoff, Methyl, Ethyl oder Cyclopropyl steht,
o für 1, 2 oder 3 steht,
p für 1, 2 oder 3 steht,
q für 1, 2 oder 3 steht,
R⁴ für Wasserstoff oder 2-Hydroxyeth-1-yl steht,
R⁵ für Wasserstoff, Methyl, Ethyl, n-Propyl, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl oder 2,3-Dihydroxyprop-1-yl,
R⁶ für Wasserstoff, Methyl, Ethyl, n-Propyl, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl, 2,3-Dihydroxyprop-1-yl, Methylcarbonyl, Ethylcarbonyl, n-Propylcarbonyl, Methoxycarbonyl; Ethoxycarbonyl, n-Propoxycarbonyl oder Methylsulfonyl steht,
wobei Methylcarbonyl, Ethylcarbonyl und n-Propylcarbonyl substituiert sein können mit 1 bis 2 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Hydroxy, Amino, (C₁-C₃)-Alkoxy und (C₁-C₃)-Alkylcarbonyloxy,
R² für Methyl, Cyclopropyl, Cyclobutyl, Cyclopentyl, Phenyl, Thienyl, Pyrazolyl oder Pyridyl steht,
wobei Phenyl, Thienyl, Pyrazolyl und Pyridyl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Methyl, Ethyl, Methoxy, tert-Butyl, Trifluormethyl, Trifluormethoxy und Difluormethoxy,
A für eine Bindung oder ein Sauerstoffatom steht,
m für 0 oder 1 steht,
n für 0, 1 oder 2 steht,
R³ für eine Gruppe der Formel

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
R⁸ für Halogen, Cyano, Trifluormethyl, Trifluormethoxy oder Difluormethoxy steht,
R⁹ für Wasserstoff oder Halogen steht,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.Preference is also given to compounds of the formula (I)
in which
R ^{1 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
X is NH or an oxygen atom,
Y is NR ⁷ or an oxygen atom,
in which
R ^{7 is} hydrogen, methyl, ethyl or cyclopropyl,
o is 1, 2 or 3,
p is 1, 2 or 3,
q is 1, 2 or 3,
R ^{4 is} hydrogen or 2-hydroxyeth-1-yl,
R ^{5 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop -1-yl,
R ^{6 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop 1-yl, methylcarbonyl, ethylcarbonyl, n -propylcarbonyl, methoxycarbonyl; Ethoxycarbonyl, n-propoxycarbonyl or methylsulfonyl,
wherein methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₃ ) -alkoxy and (C ₁ -C ₃ ) -alkylcarbonyloxy,
R ^{2 is} methyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, thienyl, pyrazolyl or pyridyl,
where phenyl, thienyl, pyrazolyl and pyridyl can be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, methyl, ethyl, methoxy, tert-butyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
A is a bond or an oxygen atom,
m is 0 or 1,
n is 0, 1 or 2,
R ^{3 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
R ^{8 is} halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
R ^{9 is} hydrogen or halogen,
and their salts, their solvates, and the solvates of their salts.

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
Y für NR⁷ oder ein Sauerstoffatom steht,
wobei
R⁷ für Wasserstoff, Methyl, Ethyl oder Cyclopropyl steht,
p für 1 oder 2 steht,
R⁵ für Wasserstoff, Methyl, Ethyl oder 2-Hydroxyeth-1-yl steht,
R⁶ für Wasserstoff, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl, 2,3-Dihydroxyprop-1-yl oder Methylcarbonyl steht,
wobei Methylcarbonyl substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Hydroxy, Methoxy und Methylcarbonyloxy,
R² für Methyl, Cyclopropyl, Cyclobutyl, Phenyl, Thienyl, Pyrazolyl oder Pyridyl steht,
wobei Phenyl, Thienyl, Pyrazolyl und Pyridyl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Methyl, Ethyl, Methoxy, tert-Butyl, Trifluormethyl, Trifluormethoxy und Difluormethoxy,
A für eine Bindung oder ein Sauerstoffatom steht,
m für 0 oder 1 steht,
n für 0, 1 oder 2 steht,
R³ für eine Gruppe der Formel

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
R⁸ für Halogen steht,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.Preference is also given to compounds of the formula (I)
in which
R ^{1 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
Y is NR ⁷ or an oxygen atom,
in which
R ^{7 is} hydrogen, methyl, ethyl or cyclopropyl,
p stands for 1 or 2,
R ^{5 is} hydrogen, methyl, ethyl or 2-hydroxyeth-1-yl,
R ^{6 is} hydrogen, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop-1-yl or methylcarbonyl,
wherein methylcarbonyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and methylcarbonyloxy,
R ^{2 is} methyl, cyclopropyl, cyclobutyl, phenyl, thienyl, pyrazolyl or pyridyl,
where phenyl, thienyl, pyrazolyl and pyridyl can be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, methyl, ethyl, methoxy, tert-butyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
A is a bond or an oxygen atom,
m is 0 or 1,
n is 0, 1 or 2,
R ^{3 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
R ^{8 is} halogen,
and their salts, their solvates, and the solvates of their salts.

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
Y für NR⁷ oder ein Sauerstoffatom steht,
wobei
R⁷ für Wasserstoff steht,
p für 2 steht,
R⁵ für Wasserstoff, Methyl oder Ethyl steht,
R⁶ für Wasserstoff, 2-Hydroxyeth-1-yl, 2-Aminoeth-1-yl, 3-Hydroxyprop-1-yl, 3-Aminoprop-1-yl, 2,3-Dihydroxyprop-1-yl oder Methylcarbonyl steht,
wobei Methylcarbonyl substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Hydroxy, Methoxy und Methylcarbonyloxy,
R² für Methyl, Phenyl, Pyrazolyl oder Pyridyl steht,
wobei Phenyl, Pyrazolyl und Pyridyl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Methyl, Ethyl, Methoxy, tert-Butyl, Trifluormethyl, Trifluormethoxy und Difluormethoxy,
A für ein Sauerstoffatom steht,
m für 0 steht,
n für 0, 1 oder 2 steht,
R³ für eine Gruppe der Formel

steht,
wobei
* für die Anknüpfstelle an den Pyrazolinring steht,
R⁸ für Chlor oder Fluor steht,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.Preference is also given to compounds of the formula (I)
in which
R ^{1 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
Y is NR ⁷ or an oxygen atom,
in which
R ^{7 is} hydrogen,
p stands for 2,
R ^{5 is} hydrogen, methyl or ethyl,
R ^{6 is} hydrogen, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop-1-yl or methylcarbonyl,
wherein methylcarbonyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and methylcarbonyloxy,
R ^{2 is} methyl, phenyl, pyrazolyl or pyridyl,
where phenyl, pyrazolyl and pyridyl can be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, methyl, ethyl, methoxy, tert-butyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
A is an oxygen atom,
m stands for 0,
n is 0, 1 or 2,
R ^{3 is} a group of the formula

stands,
in which
* represents the point of attachment to the pyrazoline ring,
R ^{8 is} chlorine or fluorine,
and their salts, their solvates, and the solvates of their salts.

Preference is also given to compounds of the formula (I) in which R ^{1 is} 2-oxopyrrolidin-1-yl.

Prefers are also compounds of the formula (I) in which A represents an oxygen atom stands, m for 0 stands for and n for 0 stands.

Preference is also given to compounds of the formula (I) in which R ^{3 is} para-chlorophenyl.

in welcher
R¹ und R³ die oben angegebene Bedeutung aufweisen,
mit Verbindungen der Formel (III)

in welcher
A, m, n und R² die oben angegebene Bedeutung aufweisen,
umgesetzt werden.Another object of the present invention is a process for the preparation of the novel compounds of formula (I), wherein compounds of formula (II)

in which
R ¹ and R ^{3 have} the abovementioned meaning,
with compounds of the formula (III)

in which
A, m, n and R ^{2 have} the abovementioned meaning,
be implemented.

The Reaction is generally carried out in inert solvents, in the presence a base, preferably in a temperature range of 0 ° C until backflow the solvent at normal pressure.

inert solvent are, for example, halogenated hydrocarbons, such as methylene chloride, Trichloromethane or 1,2-dichloroethane, ethers such as dioxane, diethyl ether, Tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, 2-butanone or acetonitrile, preferred is dimethylformamide.

bases For example, alkali metal carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or DBU, DBN, pyridine, or mixtures the bases, preferred is diisopropylethylamine.

The Compounds of the formula (III) are optionally in the form of hydrohalides, prefers hydrochlorides, before.

in welcher
R¹ und R³ die oben angegebene Bedeutung aufweisen,
mit Diphenylcyanocarbonimidat umgesetzt werden.The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula (IV)

in which
R ¹ and R ^{3 have} the abovementioned meaning,
be reacted with Diphenylcyanocarbonimidat.

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

inert solvent are, for example, alcohols such as methanol, ethanol, n-propanol or iso-propanol, or other solvents such as tetrahydrofuran, dioxane, dimethylformamide or acetonitrile, preferred is isopropanol.

in welcher
R¹ und R³ die oben angegebene Bedeutung aufweisen,
in einem zweistufigen Verfahren zunächst mit Formaldehyd und anschließend mit Hydrazinhydrat umgesetzt werden.The compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula (V)

in which
R ¹ and R ^{3 have} the abovementioned meaning,
in a two-stage process first with formaldehyde and then reacted with hydrazine hydrate.

The Implementation in the first stage is generally carried out in inert solvents in the presence of a base, preferably in a temperature range of Room temperature to reflux of the solvent Normal pressure.

inert solvent are, for example, alcohols such as methanol, ethanol, n-propanol or iso-propanol, or other solvents such as tetrahydrofuran, or dimethylformamide, is preferred ethanol.

bases For example, organic bases such as amine bases, e.g. piperidine, Triethylamine, diisopropylethylamine or DBU, preferred is piperidine.

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

inert solvent are, for example, alcohols such as methanol, ethanol, n-propanol or iso-propanol, or other solvents such as tetrahydrofuran or dimethylformamide, ethanol is preferred.

The Connections can optionally isolated after the first stage and subsequently after a purification step to be implemented.

in welcher
R³ die oben angegebene Bedeutung aufweist,
mit Verbindungen der Formel (VII)

in welcher
R¹ die oben angegebene Bedeutung aufweist,
umgesetzt werden.The compounds of the formula (V) are known or can be prepared by reacting compounds of the formula (VI)

in which
R ^{3 has} the meaning indicated above,
with compounds of the formula (VII)

in which
R ^{1 has} the meaning indicated above,
be implemented.

The Reaction is generally carried out in inert solvents, if appropriate in the presence of a base, optionally with the addition of potassium iodide, preferably in a temperature range from room temperature to backflow of the solvent at normal pressure.

inert solvent 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, preferred is dimethylformamide or tetrahydrofuran.

Examples of bases are alkali metal hydroxides such as sodium, potassium or lithium hydroxide, or alkali metal bonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide 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, preferred is sodium hydride.

in welcher
R¹ und R³ die oben angegebene Bedeutung aufweisen,
oxidiert werden.In an alternative process, the compounds of the formula (V) can be prepared by reacting compounds of the formula (VIII)

in which
R ¹ and R ^{3 have} the abovementioned meaning,
be oxidized.

The Reaction is generally carried out in inert solvents, in the presence an oxidizing agent, preferably in a temperature range of -78 ° C to 50 ° C at atmospheric pressure.

inert solvent For example, mixtures of water with dioxane, benzene or Acetone, preferred is a mixture of water and dioxane.

oxidant For example, ozone, potassium osmate, potassium permanganate or osmium tetroxide in the presence of sodium or potassium periodate, preferred is potassium osmate with sodium periodate.

in welcher
R³ die oben angegebene Bedeutung aufweist,
mit Verbindungen der Formel (VII) umgesetzt werden.The compounds of the formula (VIII) are known or can be prepared by reacting compounds of the formula (IX)

in which
R ^{3 has} the meaning indicated above,
be reacted with compounds of formula (VII).

The Implementation takes place in accordance with the implementation of compounds of Formula (VI) with compounds of the formula (VII).

In an alternative process, instead of the compounds of the formula (VII), their imino ethers or imino esters which contain the radical R ¹ can also be reacted with compounds of the formula (VI) or (IX).

The Compounds of formulas (III), (VI), (VII) and (IX) are known or can be prepared by known methods from the corresponding Synthesize starting compounds.

The Preparation of the starting compounds and the compounds of the formula (I) can be illustrated by the following synthesis schemes.

Scheme 1:

Scheme 2:

Scheme 3:

Scheme 4:

Scheme 5:

Scheme 6:

The Compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic spectrum of activity. These are selective Antagonists of the PAR-1 receptor, in particular as a platelet aggregation inhibitor Act.

she are therefore suitable for use as a medicament for treatment and / or prophylaxis of diseases in humans and animals.

Another The present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of thromboembolic disorders and / or thromboembolic Complications.

Among the "thromboembolic diseases" in the context of the present invention include in particular diseases such as heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenosis after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, peripheral arterial occlusive diseases , Pulmonary embolism, deep venous thrombosis and renal vein thrombosis, transient ischemic attacks as well as thrombotic and thromboembolic stroke.

The Substances are therefore also suitable for the prevention and treatment of Cardiogenic thromboembolism, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as Atrial fibrillation, and those undergoing cardioversion, also in patients with valvular diseases or with artificial Heart valves. About that In addition, the compounds of the invention suitable for the treatment of disseminated intravascular coagulation (DIC).

thromboembolic Complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits, like hemodialysis, and heart valve prostheses.

Besides, come the compounds of the invention also for influencing wound healing, for prophylaxis and / or treatment of atherosclerotic vascular disease and inflammatory Diseases such as rheumatic diseases of the musculoskeletal system, coronary heart disease, heart failure, high blood pressure, of inflammatory Diseases such as Asthma, inflammatory lung disease, Glomerulonephritis and inflammatory Beyond bowel disease, beyond that also for prophylaxis and / or treatment of Alzheimer's disease. In addition, the compounds of the invention to inhibit tumor growth and metastasis Microangiopathies, age-related macular degeneration, diabetic Retinopathy, diabetic nephropathy and other microvascular diseases as well as for prevention and treatment of thromboembolic complications, such as venous Thromboembolism, in tumor patients, especially those who are larger surgical Have surgery or undergo chemo- or radiotherapy become.

The Compounds of the invention can about that also used to prevent coagulation ex vivo be, e.g. for the preservation of blood and plasma products, for Cleaning / pretreatment of catheters and other medical Aids and devices, for coating artificial surfaces of in vivo or ex vivo used medical aids and devices or biological samples containing platelets.

Another The present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another The present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another The subject of the present invention is a method of treatment and / or prophylaxis of diseases, in particular those mentioned above Diseases using a therapeutically effective amount a compound of the invention.

Another The present invention relates to medicaments containing a compound of the invention and one or more other active ingredients.

Another The present invention is a method for preventing the blood coagulation in vitro, especially in blood or biological samples, the platelets contain, which is characterized by being an anticoagulant effective amount of the compound of the invention added becomes.

Of the Active substance, the compound according to the invention, can be systemic and / or local. For this purpose he can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otically or as an implant or stent.

For this Application routes, the active ingredient in suitable forms of administration be administered.

For the oral Application are functioning according to the prior art rapidly and / or modifies the compounds according to the invention donating Application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, e.g. Tablets (uncoated or coated Tablets, for example, with enteric, delayed-dissolving or insoluble coatings that control the release of the compounds of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, capsules, dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or Solutions.

The Parenteral administration can bypass a resorption step happen (intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or under intervention absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates and sterile powders.

Prefers is the oral application.

For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), nasal drops / solutions, sprays; lingual, sublingual or buccal tablets or capsules to be applied, suppositories, Ear and eye preparations, Vaginal capsules, watery Suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, milk, pastes, scattering powders, Stents or implants.

The Compounds of the invention can be converted in a conventional manner in the mentioned application forms. This is done using inert, non-toxic, pharmaceutical suitable adjuvants. Which includes et al excipients (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 flavor and / or Odors.

Another The present invention relates to medicaments which are at least a compound of the invention, preferably together with one or more inert nontoxic, containing pharmaceutically suitable excipient, as well as their use for the purposes mentioned above.

in the In general, it has proven to be beneficial in parenteral Application amounts of about 5 to 250 mg per 24 hours to achieve to deliver effective results. For oral administration, the amount is about 5 to 100 mg per 24 hours.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on of body weight, Route of administration, individual behavior towards the active substance, type of Preparation and time or interval to which the application he follows.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each on the volume. The term "w / v" means "weight / volume". For example, "10% means w / v ": 100 ml solution or Suspension contain 10 g of substance.

A) Examples

Abbreviations:

Boc

tert-butoxycarbonyl

CDCl ₃

deuterochloroform

CO ₂

carbon dioxide

d

Day

DIEA

N, N-diisopropylethylamine

DMAP

4-N, N-dimethylaminopyridine

DMF

dimethylformamide

DMSO

dimethyl sulfoxide

theory

the theory

EDC

N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl

eq.

equivalent to

IT I

Electrospray ionization (in MS)

ges.

saturated

H

hour

HOBt

1-hydroxy-1H-benzotriazole × H ₂ O

HPLC

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

LC-MS

Liquid chromatography-coupled mass spectroscopy

minute

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

R _t

Retention time (at HPLC)

TEA

triethylamine

THF

tetrahydrofuran

HPLC and LC-MS methods:

• Method 1 (HPLC, enantiomer separation): Chiral silica gel selector KBD 5326 (250 mm × 30 mm) based on the selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 25 ml / min; UV detection: 280 nm.
• Method 2 (HPLC): Chiral silica gel selector KBD 5326 (250 mm × 4.6 mm) based on the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 2.0 ml / min; UV detection: 280 nm.
• Method 3 (HPLC, enantiomer separation): Chiral silica gel selector SYFO 7266 (250 mm × 30 mm) based on the selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 50 ml / min; UV detection: 280 nm.
• Method 4 (HPLC): Chiral silica gel selector SYFO 7266 (250 mm × 4.6 mm) based on the selector poly (N-methacryloyl-D-leucine dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 2 ml / min; UV detection: 280 nm.
• Method 5 (GC-MS): Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30m × 250μm × 0.25μm; constant Flow with helium: 0.88ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (0.30 min.), 50 ° C / min → 120 ° C, 16 ° C / min → 250 ° C, 30 ° C / min → 300 ° C (1.7 min hold).
• Method 6 (LC-MS): Device Type MS: Micromass ZQ; device type HPLC: HP 1100 Series; UV DAD; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter 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 7 (LC-MS): Device Type MS: Micromass ZQ; device type HPLC: Waters Alliance 2795; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm × 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 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 8 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 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 9 (LC-MS): Instrument MS: Micromass TOF (LCT); instrument HPLC: 2-column circuit, Waters2690; Pillar: YMC-ODS-AQ, 50 mm × 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.

Starting Compounds:

Example 1A 5-Methoxy-3,4-dihydro-2H-pyrrole

20 g (235 mmol) of pyrrolidin-2-one are added to 22.2 ml (235 mmol) of dimethyl sulfate and the resulting mixture is stirred at 60 ° C for 16 h. After cooling, is added to 200 ml of saturated 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 removal of the solvent is purified by distillation (70 mbar). This gives 10.2 g (44% of theory) of the desired product.
GC-MS (Method 5): R _t = 2.57 min
MS (ESIpos): m / z = 99 (M + H) ^+
1 H-NMR (200 MHz, CDCl _3): δ = 1.95-2.12 (m, 2H) 2.46 (dd, 2H), 3.66 (tt, 2H), 3.81 (s, 3H).

Example 2A 5-Methoxy-3,6-dihydro-2H-1,4-oxazine

A mixture of 20 g (198 mmol) of morpholin-3-one and 24.95 g (198 mmol) of dimethyl sulfate is stirred at 60 ° C. for 20 h. The remaining oil is poured into 320 ml of saturated potassium carbonate solution and stirred vigorously for 1 h. It is extracted three times with tert-butyl methyl ether, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo at a bath temperature of 20.degree. 14.25 g (63% of theory) of the desired product are obtained as an oil.
¹ H-NMR (300 MHz, CDCl _3): δ = 3:55 (m, 2H), 3.63 (m, 2H), 3.68 (s, 3H), 4:05 (s, 2H).

Example 3A tert -Butyl 3-oxopiperazine-1-carboxylate

10.44 g (47.80 mmol) of di-tert-butyl-dicarbonate are added in small portions to a suspension of 4.36 g (43.5 mmol) of piperazinone in 60 ml of dichloromethane at 0 ° C. The solution is stirred at RT for 3 h and then cautiously mixed with water. The organic phase is separated, washed with 1M hydrochloric acid and saturated sodium chloride solution, dried and concentrated. Without further purification, 9.26 g (99% of theory) of the desired product are obtained.
LC-MS (Method 6): R _t = 1.36 min.
MS (ESI pos): m / z = 201 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.41 (s, 9H), 3.17 (m, 2H), 3.46 (t, 2H), 3.82 (s, 2H), 7.98 (br, 1H) ,

Example 4A 1- [2- (4-Chlorophenyl) -2-oxoethyl] pyrrolidin-2-one

29.44 g (126.09 mmol) of 4-chlorophenacyl bromide are heated overnight at 50 ° C. with 15 g (151.31 mmol) of 5-methoxy-3,4-dihydro-2H-pyrrole (Example 1A) 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 7): R _t = 1.65 min,
MS (ESIpos): m / z = 238 (M + H) ^+
1 H-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).

In Analogous to Example 4A, the compounds of Examples 5A and 6A.

Example 7A 1- [2- (5-Chloro-2-thienyl) -2-oxoethyl] pyrrolidin-2-one

Analogous to the preparation procedure for Example 4A, from 78 g (117 mmol) of crude (36%) 2-bromo-1- (5-chloro-2-thienyl) ethanone (JB Bagli, E. Ferdinand, Can. Chem. 1975, 53, 2598) and 20.9 g (221 mmol) of 5-methoxy-3,4-dihydro-2H-pyrrole (Example 1A) (DMF, 18 h, RT) 27.8 g (97% of theory) of the product.
LC-MS (Method 8): R _t = 1.81 min.
MS (ESIpos): m / z = 244 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.00 (m, 2H), 2.29 (t, 2H), 3.38 (t, 2H), 4.7 (s, 2H), 7.35 (d, 1H) , 7.99 (d, 1H).

Example 8A 4- [2- (4-Chlorophenyl) -2-oxoethyl] morpholin-3-one

A solution of 10.0 g (86.9 mmol) of 5-methoxy-3,6-dihydro-2H-1,4-oxazine (Example 2A) in 40 ml of DMF is treated with 169 g (233.5 mmol) of 2-bromo-1- (4 -chlorophenyl) -2-ethanone and stirred for 2 days at RT. The reaction mixture is stirred into water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on 300 g of silica gel (mobile phase: isohexane / ethyl acetate 5: 1 → 1: 1). 11.8 g (64% of theory) of the product are obtained as crystals.
LC-MS (Method 6): R _t = 1.67 min.
MS (ESIpos): m / z = 254 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 3.4 (m, 2H), 3.9 (t, 2H), 4.1 (s, 2H), 4.9 (s, 2H), 7.63 (m, 2H) , 8.02 (m, 2H).

Example 9A 1- [1- (Bromomethyl) vinyl] -4-chlorobenzene

A mixture of 18.51 g (104.02 mmol) of N-bromosuccinimide and 81 mg (0.45 mmol) of 2,2'-azobisis is added at 95 ° C. to a solution of 15.12 g (99.07 mmol) of 4-chloromethylstyrene in 14 ml of tetrachloromethane. 2-methylpropanenitrile (AIBN) was added firmly in small portions. The mixture is stirred for 12 h at 95 ° C, then cooled to RT and filtered. The filtrate is concentrated and the residue is chromatographed on 100 g of silica gel with petroleum ether. 9.5 g (41% of theory) of the desired product are obtained as an oil.
¹ H-NMR (400 MHz, CDCl _3): δ = 4.65 (s, 2H), 5.61 (s, 1H), 5.65 (s, 1H), 7:46 (d, 2H), 7:59 (d, 2H).

Example 10A tert -Butyl 4- [2- (4-chlorophenyl) prop-2-en-1-yl] piperazine-1-carboxylate

To a solution of 3 g (14.98 mmol) of tert-butyl-3-oxo-piperazine-1-carboxylate (Example 3A) in 60 ml of DMF are added 659 mg (16.48 mmol) of a dispersion of 60% sodium hydride in mineral oil and the suspension Stirred for 1 h at RT. The resulting solution is then mixed at 0 ° C. with 3.64 g (15.73 mmol) of 1- [1- (bromomethyl) vinyl] -4-chlorobenzene (Example 9A) and stirred at RT for 4 h. The mixture is concentrated and the residue taken up in water and ethyl acetate. The organic phase is separated and the aqueous extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. Without further purification, 9.26 g (99% of theory) of the desired product are obtained.
LC-MS (Method 7): R _t = 2.37 min.
MS (ESI pos): m / z = 351 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.47 (s, 9H), 3.18 (t, 2H), 3.44 (t, 2H), 3.90 (s, 2H), 4.41 (s, 2H) , 5.22 (s, 1H), 5.58 (s, 1H), 7.41 (d, 2H), 7.48 (s, 2H).

Example 11A tert -Butyl 4- [2- (4-chlorophenyl) -2-oxoethyl] piperazine-1-carboxylate

To a solution of 9.78 g (26.2 mmol) of tert-butyl 4- [2- (4-chlorophenyl) prop-2-en-1-yl] piperazine-1-carboxylate (Example 10A) in 172 ml of dioxane becomes a solution of 14.02 g (65.53 mmol) of sodium periodate in 86 ml of water. Then 87 mg (0.26 mmol) of potassium osmate are added and the solution is stirred at RT for 18 h. The mixture is mixed with saturated sodium chloride solution and extracted with tert-butyl methyl ether and ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. 9 g (71% of theory) of the desired product are obtained. The product is used without purification.
LC-MS (Method 8): R _t = 2.29 min.
MS (ESI pos): m / z = 297 (M + H -tBu) ⁺
MS (ESI neg): m / z = 351 (M-H) ^-
1 H-NMR (400 MHz, CDCl _3): δ = 1:49 (s, 9H), 3:42 (t, 2H), 3.74 (t, 2H), 4.18 (s, 2H), 4.82 (s, 2H), 7:47 (d, 2H), 7.90 (s, 2H).

Example 12A Allyl [2- (4-chlorophenyl) -2-oxoethyl] carbamate

44.13 g (214.14 mmol) of 2-amino-1- (4-chlorophenyl) ethanone hydrochloride are added to a solution of 62.15 g (449.69 mmol) of potassium hydroxide in 11 water and briefly heated until an almost clear solution is formed. Under ice cooling then 25.00 ml (235.55 mmol) of allyl chloroformate are added dropwise, whereby a precipitate precipitates. The suspension is stirred overnight at room temperature, diluted with dichloromethane and washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and concentrated. This gives 42.09 g (77% of theory) of the product as crystals.
LC-MS (Method 6): R _t = 2.20 min.
MS (ESI pos): m / z = 254 (M + H) ⁺

Example 13A 1- [1- (4-Chlorobenzoyl) vinyl] pyrrolidin-2-one

13 g (54.69 mmol) of 1- [2- (4-chlorophenyl) -2-oxo-ethyl] pyrrolidin-2-one (Example 4A) are treated with 6.65 g (82.04 mmol) of aqueous formaldehyde solution (37% strength). submitted in 150 ml of ethanol and heated with 6.98 g (82.04 mmol) of piperidine overnight at 70 ° C. After cooling to room temperature, the solvent is removed in vacuo and the product is reacted further without further purification.
LC-MS (Method 6): R _t = 1.97 min,
MS (ESIpos): m / z = 249 (M + H) ⁺

In Analogous to Example 13A, the compounds of Examples 14A and 15A.

Example 16A 1- {1 - [(5-Chloro-2-thienyl) carbonyl] vinyl} pynolidin-2-one

Analogously to the process of Example 18A, from 27.8 g (114 mmol) of the compound from Example 7A, 115.7 g (1.425 mol) of aqueous formaldehyde solution (37% strength) and 12.14 g (142.6 mmol) of piperidine (DMF, 18 h, 70 ° C) 7.26 g (25% of theory) of the title compound.
LC-MS (Method 6): R _t = 1.99 min.
MS (ESI pos): m / z = 256 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.1 (m, 2H), 2.85 (t, 2H), 3.7 (t, 2H), 5.08 (s, 1H), 5.18 (s, 1H) , 7.25 (d, 1H), 7.57 (d, 1H).

Example 17A 4- [1- (4-Chlorobenzoyl) vinyl] morpholin-3-one

To a solution of 15.4 g (60.7 mmol) of 4- [2- (4-chlorophenyl) -2-oxoethyl] morpholin-3-one (Example 8A) and 24.6 g (303.5 mmol) of aqueous formaldehyde solution (37% strength by weight) ) in 150 ml of THF are added dropwise 3 ml (30.4 mmol) of piperidine. It is stirred for 3 h at 70 ° C. Then another 14.8 g (182.1 mmol) of aqueous formaldehyde solution (37% strength) and 1.8 ml (18.2 mmol) of piperidine are added and stirring is continued overnight at 70.degree. The reaction solution is applied in vacuo to 75 g of silica gel and chromatographed on 275 g of silica gel with toluene / ethyl acetate (3: 1) → (2: 3). This gives 13.46 g (83% of theory) of the product as crystals.
LC-MS (Method 8): R _t = 1.92 min.
MS (ESIpos): m / z = 266 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 3.77 (m, 2H), 3.98 (m, 2H), 4.05 (s, 2H), 5.25 (d, 1H), 5.6 (d, 1H) , 7.56 (m, 2H), 7.77 (m, 2H).

Example 18A tert -Butyl 4- [2- (4-chlorobenzoyl) vinyl] piperazine-1-carboxylate

To a solution of 3.57 g (9.21 mmol) of tert-butyl 4- [2- (4-chlorophenyl) -2-oxoethyl] piperazine-1-carboxylate (Example 11A) in 50 ml of THF are added 13.8 ml (184.2 mmol) of aqueous Formaldehyde solution (37%) and 0.91 ml (9.21 mmol) of piperidine. The solution is stirred for 24 h at 60.degree. The batch is mixed with tert-butyl methyl ether and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed over 50 g of silica gel (0-20% ethyl acetate / dichloromethane). 3.48 g (98% of theory) of the desired product are obtained.
LC-MS (Method 7): R _t = 2.21 min.
MS (ESI pos): m / z = 365 (M + H) ^+
1 H-NMR (400 MHz, CDCl _3): δ = 1:49 (s, 9H), 3.71 (t, 2H), 3.81 (t, 2H), 4.12 (s, 2H), 5:35 (s, 1H), 5:52 (s, 1H), 7.42 (d, 2H), 7.86 (s, 2H).

Example 19A Allyl [1- (4-chlorobenzoyl) vinyl] carbamate

To a solution from 42.09 g (165.92 mmol) of allyl [2- (4-chlorophenyl) -2-oxoethyl] carbamate (Example 12A) and 18.65 ml (248.87 mmol) of aqueous formaldehyde solution (37%) in 500 ml of ethanol at room temperature 24.61 ml (248.87 mmol) Dropped piperidine and the mixture heated for 30 minutes under reflux. The Mixture is concentrated and further reacted directly.

Example 20A 1- [3- (4-Chloro-phenyl) -4,5-dihydro-1H-pyrazol-4-yl] -pyrrolidin-2-one

17.58 g (70.40 mmol) of 1- [1- (4-chlorobenzoyl) vinyl] pyrrolidin-2-one (Example 13A) are dissolved in 100 ml of ethanol and 12.33 g (246.4 mmol) of hydrazine hydrate at 100 ° C. under argon for one hour heated. After cooling to room temperature, the precipitated product is filtered off and washed twice with a little ethanol. There are obtained 7.05 g (44% of theory) of product.
LC-MS (Method 6): R _t = 1.72 min,
MS (ESIpos): m / z = 264 (M + H) ^+
1 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 (m, 2H), 7.55 (d, 2H), 7.61 (m, 1H).

In Analogous to Example 20A, the compounds of Examples 21A and 22A.

Example 23A 1- [3- (5-Chloro-2-thienyl) -4,5-dihydro-1H-pyrazol-4-yl] pyrrolidin-2-one

Analogously to the procedure of Example 25A, 35.7 g (139.6 mmol) of the compound from Example 16A and 14.26 g (279 mmol) of hydrazine hydrate (750 ml of DMF, overnight, RT) give 51.2 g (quant.) Of product, which is further reacted crude becomes.
LC-MS (Method 8): R _t = 1.80 min.
MS (ESI pos): m / z = 270 (M + H) ⁺

Example 24A 4- [3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] morpholin-3-one

To a suspension of 13.4 g (50.4 mmol) of 4- [1- (4-chlorobenzoyl) vinyl] morpholin-3-one (Example 17A) in 66 ml of ethanol are added 5.15 g (100.9 mmol) of hydrazine hydrate and stirred for 1.5 h at RT , where after 5 min, a solution is formed and precipitates after about 20 min a precipitate. This is filtered off and washed twice with 10 ml of ethanol. After drying in a high vacuum, 12.06 g (70% of theory) of the product are obtained as a solid.
LC-MS (Method 6): R _t = 1.72 min
MS (ESIpos): m / z = 280 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.77 (m, 1H), 3.2 (m, 1H), 3.6 (m, 3H), 3.78 (m, 1H), 4.07 (m, 2H) , 6.2 (m, 1H), 7.43 (m, 2H), 7.58 (m, 2H), 7.7 (d, 1H).

Example 25A tert -Butyl 4- [3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] -3-oxopiperazine-1-carboxylate

A solution of 3.54 g (9.7 mmol) of tert-butyl 4- [2- (4-chlorobenzoyl) vinyl] piperazine-1-carboxylate (Example 18A) in 50 ml of ethanol is treated with 0.52 ml (10.66 mmol) of hydrazine hydrate and 18 Stirred at RT. The solution is concentrated, the residue dissolved in a little diethyl ether, mixed with n-hexane and concentrated. After drying the residue under reduced pressure, 3.6 g (58% of theory) of the desired product are obtained. The product is used without purification.
LC-MS (method 7): R _t = 2.07 min.
MS (ESI pos): m / z = 379 (M + H) ⁺

Example 26A Allyl [3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] carbamate

To a solution from 44.08 g (165.92 mmol) of allyl [1- (4-chlorobenzoyl) vinyl] carbamate (Example 19A) in 500 ml of ethanol under argon 29.07 g (580.72 mmol) of hydrazine hydrate and the resulting mixture for one hour stirred under reflux. Of the Approach is concentrated and the residue in a mixture of ice-water, saturated ammonium chloride solution and ethyl acetate given. The organic phase is separated, with saturated Sodium chloride solution washed over Dried magnesium sulfate, over a glass frit is filtered off with suction and concentrated. This resulted in 45.95 g (99% of theory) product as crystals.

Example 27A Phenyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazole-1-carboximidoate

10 g (37.91 mmol) of 1- [3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] -pyrrolidin-2-one (Example 20A) are combined with 9 g (37.91 mmol) of diphenylcyanocarbonimidate Argon in 180 ml of 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 8): R _t = 2.29 min.
MS (ESI pos): m / z = 408 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.85 (m, 2H), 2.24 (m, 2H), 2.80 (m, 1H), 3.49 (m, 1H), 4.44 (m, 2H) , 6.10 (dd, 1H), 7.31 (m, 3H), 7.47 (d, 2H), 7.62 (m, 2H), 7.71 (m, 2H).

In Analogous to Example 27A, the compounds of Examples 28A produced up to 29A.

Example 30A Phenyl-3- (5-chloro-2-thienyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazole-1-carboximidoate

5 g (18.5 mmol) of 1- [3- (5-chloro-2-thienyl) -4,5-dihydro-1H-pyrazol-4-yl] -pyrrolidin-2-one (Example 23A) are treated with 5.3 g (22.24 mmol) of diphenylcyanocarbonimidate under argon in 50 ml of 2-propanol heated to reflux overnight. After cooling to room temperature, the precipitate is filtered off and chromatographed on silica gel with isohexane / ethyl acetate (0 to 80%). After stirring with ethyl acetate, 0.83 g (11% of theory) of a solid are obtained.
LC-MS (Method 8): R _t = 2.08 min.
MS (ESI pos): m / z = 414 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ): δ = 2.05 (m, 2H), 2.4 (m, 2H), 3.1 (m, 1H), 3.4 (m, 1H), 4.2 (dd, 1H), 4.35 (dd, 1H), 6.13 (dd, 1H), 6.88 (d, 1H), 7.15 (m, 2H), 7.23 (d, 1H), 7.3 (m, 1H), 7.42 (m, 2H).

Example 31A Phenyl-3- (4-chlorophenyl) -N-cyano-4- (3-oxomorpholin-4-yl) -4,5-dihydro-1H-pyrazole-1-carboximidoate

A suspension of 7.5 g (22 mmol) of 4- [3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] morpholin-3-one (Example 24A) in 150 ml of isopropanol heated to reflux with 6.29 g (26.4 mmol) of diphenylcyanocarbonimidate under argon overnight. First, dissolution occurs, then the precipitation of a precipitate. After cooling in an ice bath, the precipitate is filtered off and washed twice with isohexane. 5.44 g (58% of theory) of a solid are obtained.
LC-MS (Method 6): R _t = 2.26 min.
MS (ESI pos): m / z = 424 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.9 (m, 1H), 3.5 (m, 1H), 3.73 (m, 1H), 3.82 (m, 1H), 4.1 (s, 2H) , 4.37 (dd, 1H), 4.5 (dd, 1H), 6.5 (m, 1H), 7.3 (m, 3H), 7.48 (m, 2H), 7.62 (m, 2H), 7.7 (m, 2H).

Example 32A tert -Butyl 4- {3- (4-chlorophenyl) -1 - [(cyanimino) (phenoxy) methyl] -4,5-dihydro-1H-pyrazol-4-yl} -3-oxopiperazine-1 carboxylate

A solution of 2.5 g (6.6 mmol) tert-butyl 4- [3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] -3-oxopiperazine-1-carboxylate (Example 25A). in 50 ml of isopropanol is mixed with 3.14 g (13.2 mmol) of diphenylcyanocarbonimidate and stirred at 100 ° C for 5 h. The solution is concentrated and the residue is chromatographed on silica gel (0-20% ethyl acetate / dichloromethane). 1.96 g (50% of theory) of the desired product are obtained.
LC-MS (Method 7): R _t = 2.41 min.
MS (ESI pos): m / z = 523 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.35 (s, 9H), 2.90 (m, 1H), 3.38 (m, 1H), 3.50 (m, 2H), 3.96 (m, 2H) , 4.36 (dd, 1H), 4.49 (t, 1H), 6.48 (br, 1H), 7.32 (m, 3H), 7.48 (t, 2H), 7.61 (d, 2H), 7.71 (m, 2H).

Example 33A Phenyl-4 - {[(allyloxy) carbonyl] amino} -3- (4-chlorophenyl) -N-cyano-4,5-dihydro-1H-pyrazole-1-carboximidoate

A solution of 45.95 g (164.27 mmol) of allyl [3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] carbamate (Example 26A) and 39.14 g (164.27 mmol) of diphenyl cyanocarbonimidate in 500 ml 2-propanol is stirred for one hour under reflux. The mixture is concentrated and the precipitated crystals slurried in diethyl ether, filtered with suction through a glass frit and dried. This results in 31.47 g (45% of theory) of crystals.
LC-MS (Method 8): R _t = 2.51 min.
MS (ESI pos): m / z = 424 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 4.10.16 (m, 1H), 4.51 (t, 3H), 5.13-5.23 (m, 2H), 5.58-5.65 (m, 1H), 5.82-5.92 (m, 1H), 7.24 (d, 2H), 7.30-7.35 (m, 1H), 7.45-7.50 (m, 2H), 7.57-7.65 (m, 2H), 7.78-7.89 (m, 2H ), 8.19 (d, 1H).

Example 34A 1- (Diphenylmethyl) azetidin-3-one

To a solution of 5 g (20.89 mmol) of 1- (diphenylmethyl) azetidin-3-ol (Anderson, Lok, J. Org. Chem. 1972, 37, 3953) and 29.12 ml (208.93 mmol) of triethylamine in 100 ml of DMSO a solution of 19.95 g (125.36 mmol) of sulfur trioxide-pyridine complex in 80 ml of DMSO was added dropwise. The mixture is stirred for 30 min at 50 ° C and poured after cooling to RT on ice water. The mixture is extracted twice with ethyl acetate, the organic phase washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed over 60 g of silica gel (0-20% ethyl acetate / cyclohexane). 3.43 g (69% of theory) of the desired product are obtained.
LC-MS (Method 8): R _t = 1.30 min.
MS (ESI pos): m / z = 256 (M + H ₂ O + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 3.99 (s, 4H), 4.82 (s, 1H), 7.19 (t, 2H), 7.30 (t, 4H), 7.50 (d, 4H) ,

Example 35A 1- (Diphenylmethyl) -3-propylideneacetidine

2.63 ml (4.21 mmol) of a 1.6M solution of n-butyllithium in hexane are added dropwise at 0 ° C. to a solution of 1.62 g (4.21 mmol) of n-propyltriphenylphosphonium bromide in 10 ml of absolute THF under argon. The resulting suspension is stirred at RT for 15 min and then a solution of 500 mg (2.11 mmol) of 1- (diphenylmethyl) azetidin-3-one (Example 34A) in 5 ml of absolute THF at RT is added dropwise. The mixture is stirred for 16 h at RT, then treated with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. For purification, the residue is filtered through silica gel (mobile phase: cyclohexane / ethyl acetate = 1/1), the filtrate is concentrated and then chromatographed over 20 g of silica gel (0-10% ethyl acetate / cyclohexane) for fine purification. 520 mg (87% of theory) of the product are obtained.
LC-MS (Method 8): R _t = 1.64 min.
MS (ESI pos): m / z = 264 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.88 (t, 3H), 1.83 (m, 2H), 3.64 (d, 4H), 4.55 (s, 1H), 5.17 (m, 1H) , 7.17 (m, 2H), 7.28 (t, 4H), 7.43 (d, 4H).

In Analogous to Example 35A, the compounds of Examples 36A produced up to 38A.

Example 39A 1- (diphenylmethyl) -3-propoxyazetidine

To a solution of 500 mg (2.089 mmol) of 1- (diphenylmethyl) azetidin-3-ol (Anderson, Lok, J. Org. Chem. 1972, 37, 3953) in 7.5 ml of THF at 0 ° C 6.27 ml (6.27 mmol) of a 1M solution of potassium tert-butoxide in THF was added dropwise. The solution is stirred for 1 h at RT and then treated at 0 ° C with 1.77 g (10.45 mmol) of 1-iodopropane. The mixture is stirred for 18 h at RT, then treated with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. After separation of the residue by preparative HPLC, 390 mg (66% of theory) of the desired product are obtained.
LC-MS (Method 8): R _t = 1.41 min.
MS (ESI pos): m / z = 282 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.83 (t, 3H), 1.45 (m, 2H), 2.75 (m, 2H), 3.22 (t, 2H), 3.34 (m, 2H) , 4.05 (m, 1H), 4.40 (s, 1H), 7.18 (t, 2H), 7.28, t, 4H), 7.41 (d, 4H).

In Analogous to Example 39A, the compounds of Examples 40A produced up to 43A.

Example 44A 1- (diphenylmethyl) azetidin-3-yl methanesulfonate

To a solution of 2 g (8.36 mmol) of 1- (diphenylmethyl) azetidin-3-ol (Anderson, Lok, J. Org. Chem. 1972, 37, 3953) in 20 ml of pyridine at -20 ° C 0.97 ml ( 12.5 mmol) of methanesulfonyl chloride was added dropwise. The solution is stirred for 1 h at -20 ° C and then allowed to stand for 3 days at 4 ° C. Subsequently, the batch is poured onto ice water, the precipitate filtered off with suction and washed with water. After drying in a high vacuum, 2.56 g (74% of theory) of the desired product are obtained.
LC-MS (Method 6): R _t = 1.80 min.
MS (ESI pos): m / z = 318 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 3.10 (m, 2H), 3.18 (m, 3H), 3.52 (t, 2H), 4.53 (s, 1H), 5.10 (m, 1H) , 7.18 (t, 2H), 7.29 (t, 4H), 7.42 (d, 4H).

Example 45A 2-Chloro-5 - {[1- (diphenylmethyl) azetidin-3-yl] oxy} pyridine

To a solution of 385 mg (1.21 mmol) of 2-chloro-5-hydroxypyridine in 3 ml of DMF is added 73 mg (1.82 mmol) of sodium hydride (60% dispersion in mineral oil) at 0 ° C. After 15 minutes, 385 mg (1.21 mmol) of 1- (diphenylmethyl) azetidin-3-yl methanesulfonate (Example 44A) are added and the mixture is heated to 80 ° C. The mixture is concentrated and separated by preparative HPLC. 220 mg (47% of theory) of the product are obtained.
LC-MS (Method 7): R _t = 1.77 min.
MS (ESI pos): m / z = 351 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 3.01 (m, 2H), 3.63 (m, 2H), 4.53 (s, 1H), 4.92 (m, 1H), 7.18 (t, 2H) , 7.29 (t, 4H), 7.48 (s, 2H), 7.42 (d, 4H).

Example 46A [1- (Diphenylmethyl) azetidin-3-yl] methanol

To a suspension of 2.04 g (7.25 mmol) of 1- (diphenylmethyl) azetidine-3-carboxylic acid (Anderson, Lok, J. Org. Chem. 1972, 37, 3953) in 30 ml of dry THF at 0 ° C 14.5 ml ( 14.5 mmol) of a 1 M solution of lithium aluminum hydride in THF was added dropwise. The clear solution is stirred for 16 h at RT and then treated dropwise with 15 ml of a 1 M sodium hydroxide solution. The resulting precipitate is filtered off, the filtrate is concentrated, diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gives 1.8 g (98% of theory) of the desired product.
LC-MS (Method 8): R _t = 1.25 min.
MS (ESI pos): m / z = 254 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.43 (m, 1H), 2.78 (t, 2H), 3.08 (t, 2H), 3.50 (t, 2H), 4.38 (s, 1H) , 4.55 (t, 1H), 7.15 (t, 2H), 7.26 (t, 4H), 7.40 (d, 4H).

Example 47A 1- (Diphenylmethyl) -3- (propoxymethyl) azetidine

To a solution of 205 mg (0.81 mmol) of [1- (diphenylmethyl) azetidin-3-yl] methanol (Example 46A) in 5 ml of THF at 0 ° C 1.21 ml (1.21 mmol) of a 1M solution of potassium tert-butoxide in THF added dropwise. The solution is stirred for 1 h at RT and then treated at 0 ° C with 0.16 ml (1.62 mmol) of 1-iodopropane and stirred for 18 h at RT. At intervals of 24 h, 1.21 ml (1.21 mmol) of a 1M solution of potassium tert-butoxide in THF and 0.16 ml (1.62 mmol) of 1-iodopropane are added twice more. After 3 days at RT, the mixture is heated at 45 ° C. for 3 h, then treated with water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC gives 138 mg (58% of theory) of the desired product.
LC-MS (Method 8): R _t = 1.82 min.
MS (ESI pos): m / z = 296 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.85 (t, 3H), 1.47 (m, 2H), 2.57 (m, 1H), 2.77 (t, 2H), 3.14 (t, 2H) , 3.31 (t, 2H), 3.49 (d, 2H), 4.39 (s, 1H), 7.16 (t, 2H), 7.26 (t, 4H), 7.40 (d, 4H).

In Analogous to Example 47A, the compounds of Examples 48A and 49A produced.

Example 50A 3-propylazetidine

A solution of 520 mg (1.97 mmol) of 1- (diphenylmethyl) -3-propylideneacetidine (Example 35A) in 20 ml of methanol is treated with 0.16 ml (4.34 mmol) of formic acid and 416 mg (0.59 mmol) of palladium (II) hydroxide (20% on activated charcoal) and shaken for 2 days at 3 bar under hydrogen in a Parr apparatus. Subsequently, will the mixture over Diatomaceous earth filtered. The crude product in solution is without purification implemented further.

In Analogous to Example 50A, the compounds of Examples 51A produced up to 53A.

Example 54A 3-propoxyazetidinium chloride

A solution of 385 mg (1.37 mmol) of 1- (diphenylmethyl) -3-propoxyazetidine (Example 39A) in 6 ml of dichloroethane is treated with 254 mg (1.78 mmol) of 1-chloroethylchloroformate mixed and 1.5 h at 70 ° C. touched. Subsequently 6 ml of methanol are added at RT and the mixture at 1.5 h at 70 ° C stirred. The solution is concentrated and the crude product is further reacted without purification.

Example 55A 3 - [(2-Chloropyridin-5-yl) oxy] azetidinium chloride

To a solution of 215 mg (0.61 mmol) of 2-chloro-5 - {[1- (diphenylmethyl) azetidin-3-yl] oxy} pyridine (Example 45A) in 4 ml of dichloroethane, 263 mg (1.84 mmol) of 1-chloroethylchloroformate added and the solution 18 h at 70 ° C touched. Subsequently 4 ml of methanol are added at RT and stirred at 70 ° C for a further 24 h. The solution is concentrated and the crude product is further reacted without purification.

Example 56A 3- (Propoxymethyl) azetidinium chloride

To a solution of 100 mg (0.338 mmol) of 1- (diphenylmethyl) -3- (methoxymethyl) azetidine (Example 47A) in 3 ml of dichloroethane at RT 0.11 ml (1.02 mmol) of 1-chloroethyl chloroformate and the mixture 18 h at 70 ° C stirred. Then be 3 ml of methanol were added at RT and the mixture was stirred at 70 ° C. for a further 24 h. The solution is concentrated and the crude product is further reacted without purification.

In Analogous to Example 56A, the compounds of Examples 57A produced up to 62A.

Example 63A [[3- (4-chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3-hydroxyazetidin-1-yl) methylene] cyanamide

A solution of 837 mg (2.05 mmol) of phenyl 3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazole-1-carboximidoate (Example 27A), 300 mg (4.1 mmol) of azetidin-3-ol and 1.14 ml (8.21 mmol) of triethylamine in 10 ml of ethanol is stirred at 70 ° C for 3 h. The mixture is mixed with saturated ammonium chloride solution and extracted six times with ethyl acetate. The combined organic phases are dried and concentrated. The residue is combined with methanol and ethyl acetate and the precipitate is filtered off. The filtrate is concentrated and chromatographed on silica gel (ethyl acetate / toluene = 1/1). After precipitation and chromatography, 438 mg (54% of theory) of the desired product are obtained.
LC-MS (Method 7): R _t = 1.63 min.
MS (ESI pos): m / z = 387 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.74 (m, 1H), 3.30 (m, 1H) , 4.1 (m, 2H), 4.26 (m, 2H), 4.5 (br, 1H), 4.76 (m, 2H), 5.84 (br, 1H), 5.89 (dd, 1H), 7.53 (d, 2H), 7.66 (d, 2H).

Example 64A Allyl [1- [[3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] carbamate

A solution from 750 mg (1.77 mmol) phenyl-4 - {[(allyloxy) carbonyl] amino} -3- (4-chlorophenyl) -N-cyano-4,5-dihydro-1H-pyrazole-1-carboximidoate (Example 33A), 778 mg (3.54 mmol) of 3- (4-chlorophenoxy) azetidine and 0.74 ml (5.31 mmol) triethylamine in 40 ml of ethanol is stirred at 70 ° C for 3 h. Of the Approach becomes semi-saturated Ammonium chloride solution and ethyl acetate poured, the organic phase separated, with saturated Sodium chloride solution washed over Dried magnesium sulfate, filtered and concentrated. The obtained Product continues to be used raw.

Example 65A tert -Butyl 4- [1 - [[3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazole 4-yl] -3-oxopiperazin-1-carboxylate

A solution of 84 mg (0.38 mmol) 4-chlorophenyl-3-azetidinium chloride, 200 mg (0.38 mmol) tert-butyl 4- {3- (4-chlorophenyl) -1 - [(cyanoimino) (phenoxy) methyl] - 4,5-dihydro-1H-pyrazol-4-yl} -3-oxopiperazine-1-carboxylate (Example 32A) and 0.08 ml (0.57 mmol) of triethylamine in 5 ml of DMF is stirred at RT for 18 h. The mixture is diluted with DMSO, filtered and the filtrate is treated with methanol. The resulting precipitate is filtered off, washed with methanol and dried. After purification of the resulting solid by preparative HPLC, 84 mg (36% of theory) of the desired product are obtained.
LC-MS (Method 8): R _t = 3.00 min.
MS (ESI pos): m / z = 612 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.34 (s, 9H), 2.80 (m, 1H), 3.29 (m, 2H), 3.49 (m, 1H), 3.93 (s, 2H) , 4.12 (dd, 1H), 4.21 (t, 1H), 4.49 (m, 2H), 5.04 (m, 3H), 6.32 (br, 1H), 6.93 (d, 2H), 7.39 (d, 2H), 7.54 (d, 2H), 7.64 (d, 2H).

EXAMPLES

Example 1 [[3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3-propylazetidin-1-yl) methylene] cyanamide

A solution of 1.31 mmol of 3-propylazetidine (Example 50A) in 14 ml of methanol is treated with 100 mg (0.245 mmol) of phenyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) - 4,5-dihydro-1H-pyrazole-1-carboximidoate (Example 27A) and 0.64 ml (0.368 mmol) of DIEA and stirred at 40 ° C for 16 h. The solution is concentrated, mixed with water and extracted three times with ethyl acetate: The combined organic phases are dried over sodium sulfate, filtered and concentrated. After purification of the residue by preparative HPLC, 73 mg (72% of theory) of the product are obtained.
LC-MS (Method 6): R _t = 2.63 min.
MS (ESI pos): m / z = 413 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.89 (t, 3H), 1.27 (m, 2H), 1.59 (q, 2H), 1.75 (m, 1H), 1.90 (m, 1H) , 2.20 (m, 2H), 2.64 (m, 1H), 2.73 (m, 1H), 3.30 (m, 1H), 4.14 (m, 4H), 4.63 (m, 2H), 5.89 (dd, 1H), 7.53 (d, 2H), 7.66 (d, 2H).

Example 2 [[3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3-propoxyazetidin-1-yl) methylene] cyanamide

A solution of 1.2 mmol 3-propoxyazetidinium chloride (Example 54A), 245 mg (0.6 mmol) phenyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl) -4,5-dihydro 1H-pyrazole-1-carboximidoate (Example 27A) and 0.21 ml (1.2 mmol) of DIEA in 6 ml of DMF is stirred at RT for 16 h. After separation of the reaction mixture by preparative HPLC, 258 mg (92% of theory) of the desired product are obtained.
LC-MS (Method 8): R _t = 2.45 min.
MS (ESI pos): m / z = 428 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.89 (t, 3H), 1.55 (m, 2H), 1.75 (m, 1H), 1.91 (m, 1H), 2.22 (m, 2H) , 2.64 (m, 1H), 2.75 (m, 1H), 3.36 (m, 1H), 4.11 (m, 2H), 4.31 (m, 2H), 4.75 (m, 2H), 5.90 (dd, 1H), 7.53 (d, 2H), 7.68 (d, 2H).

Example 3 ([3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] {3 - [(2-chloropyridin-5-yl ) oxy] azetidin-1-yl} methylene) cyanamide

A solution of 130 mg (0.59 mmol) of 3 - [(2-chloropyridin-5-yl) oxy] azetidinium chloride (Example 55A), 120 mg (0.29 mmol) of phenyl-3- (4-chlorophenyl) -N-cyano -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazole-1-carboximidoate (Example 27A) and 0.13 ml (0.74 mmol) DIEA in 4 ml DMF is stirred at RT for 18 h. The batch is concentrated and, after separation of the reaction mixture by preparative HPLC, 120 mg (78% of theory) of the desired product are obtained.
LC-MS (Method 6): R _t = 2.51 min.
MS (ESI pos): m / z = 498/500 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.75 (m, 1H), 1.91 (m, 1H), 2.21 (m, 2H), 2.77 (m, 1H), 3.32 (m, 1H) , 4.12 (m, 2H), 4.51 (m, 2H), 5.04 (m, 2H), 5.18 (m, 1H), 5.93 (dd, 1H), 7.49 (s, 2H), 7.54 (d, 2H), 7.69 (d, 2H), 8.12 (s, 1H).

Example 4 {[3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] [3- (methoxymethyl) azetidin-1-yl] methylene} cyanamide

A solution of 55 mg (0.33 mmol) of 3- (propoxymethyl) azetidinium chloride (Example 56A), 80 mg (0.196 mmol) of phenyl-3- (4-chlorophenyl) -N-cyano-4- (2-oxopyrrolidin-1-yl ) -4,5-dihydro-1H-pyrazole-1-carboximidoate (Example 27A) and 0.068 ml (0.40 mmol) DIEA in 3 ml DMF is stirred at RT for 18 h. The batch is concentrated and, after separation via preparative HPLC, 36 mg (41% of theory) of the desired product are obtained.
LC-MS (Method 6): R _t = 2.56 min.
MS (ESI pos): m / z = 443 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.88 (t, 3H), 1.55 (m, 2H), 1.75 (m, 1H), 1.91 (m, 1H), 2.22 (m, 2H) , 2.74 (m, 1H), 2.89 (m, 1H), 3.31 (m, 1H), 3.39 (t, 2H), 3.58 (d, 2H) 4.08 (m, 2H), 4.29 (m, 2H), 4.61 (m, 2H), 5.89 (dd, 1H), 7.54 (d, 2H), 7.66 (d, 2H).

In Analogously to Example 4, the compounds of Examples 5 to 26 produced.

Example 27 {[3- (4-Chlorophenoxy) azetidin-1-yl] [3- (4-chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazole-1] yl] methylene} cyanamide

Example 15 is separated by method 1 into the enantiomers. The active enantiomer elutes second.
HPLC (Method 2, flow: 3.0 ml / min): R _t = 11.61 min.

Example 28 [[3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3-propylazetidin-1-yl) methylene] cyanamide

Example 1 is separated by method 3 into the enantiomers. The active enantiomer elutes first (99% ee).
HPLC (Method 4): R _t = 2.04 min.

Example 29 [[3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3-propoxyazetidin-1-yl) methylene] cyanamide

example 2 is separated by method 1 into the enantiomers. The active enantiomer elutes second.

Example 30 {[3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] [3- (pyridin-2-yloxy) -azetidine] 1-yl] methylene} cyanamide

Example 9 is separated by method 1 into the enantiomers. The active enantiomer elutes second (98.6% ee).
HPLC (method 2): R _t = 13.69 min.

Example 31 {[3- (4-Chlorophenoxy) azetidin-1-yl] [3- (4-chlorophenyl) -4- (2-oxopiperazin-1-yl) -4,5-dihydro-1H-pyrazole-1] yl] methylene} cyanamide

To a solution of 54 mg (0.09 mmol) tert-butyl 4- [1 - [(Z) - [3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl ) -4,5-dihydro-1H-pyr azol-4-yl] -3-oxopiperazine-1-carboxylate (Example 65A) in 5 ml of dichloromethane is added 99 mg (0.44 mmol) of dry zinc bromide. The mixture is stirred for 3 days at RT, then diluted with methanol and DMSO and separated by preparative HPLC. 39 mg (86% of theory) of the desired product are obtained.
LC-MS (Method 8): R _t = 1.91 min.
MS (ESI pos): m / z = 512 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.68, (m, 2H), 2.85 (m, 1H), 3.16 (m, 1H), 3.28 (s, 2H), 4.06 (dd, 1H ), 4.23 (t, 1H), 4.47 (m, 2H), 5.03 (m, 3H), 6.37 (br, 1H), 6.93 (d, 2H), 7.39 (d, 2H), 7.54 (d, 2H) , 7.65 (d, 2H).

Example 32 ([3- (4-chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] {3 - [(4-fluorobenzyl) oxy] azetidine -1-yl} methylene) cyanamide

To a suspension of 250 mg (0.65 mmol) of [[3- (4-chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3-hydroxyazetidine -1-yl) methylene] cyanamide (Example 63A) in 5 ml of absolute THF are added at 0 ° C 145 mg of potassium tert-butoxide and the mixture stirred for 30 min. Then 244 mg (1.29 mmol) of 4-fluorobenzyl bromide are added and the mixture is stirred at RT for 3 days. The mixture is mixed with saturated sodium chloride solution and extracted four times with ethyl acetate. The combined organic phases are dried and concentrated. After separation of the residue by preparative HPLC, 12 mg (3.6% of theory) of the desired product are obtained.
LC-MS (Method 7): R _t = 2.35 min.
MS (ESI pos): m / z = 495 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.75 (m, 1H), 1.91 (m, 1H), 2.22 (m, 2H), 2.74 (m, 1H), 3.31 (m, 1H) , 4.11 (m, 2H), 4.34 (m, 2H), 4.43 (m, 1H), 4.50 (s, 2H), 4.72 (m, 2H), 5.89 (dd, 1H), 7.21 (t, 2H), 7.45 (m, 2H), 7.54 (d, 2H), 7.66 (d, 2H).

Example 33 [[3- (4-Chlorophenyl) -4- (2-oxopyrrolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3 - {[4- (difluoromethoxy) benzyl] oxy} azetidin-1-yl) methylene] cyanamide

Analogously to the instructions for Example 32, 250 mg (0.65 mmol) of [[3- (4-chlorophenyl) -4- (2-oxopyr rolidin-1-yl) -4,5-dihydro-1H-pyrazol-1-yl] (3-hydroxyazetidin-1-yl) methylene] cyanamide (Example 63A) and 306 mg (1.29 mmol) of 4- (difluoromethoxy) - Benzylbromid after silica gel chromatography with isohexane / ethyl acetate (40-100%) and trituration with ethanol 31.9 mg (9% of theory) of the product as a solid.
LC-MS (Method 7): R _t = 2.38 min.
MS (ESI pos): m / z = 543 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.75 (m, 1H), 1.91 (m, 1H), 2.22 (m, 2H), 2.74 (m, 1H), 3.31 (m, 1H) , 4.11 (m, 2H), 4.36 (m, 2H), 4.45 (m, 1H), 4.51 (s, 2H), 4.75 (m, 2H), 5.90 (dd, 1H), 7.19 (d, 2H), 7.26 (t, 1H), 7.45 (d, 2H), 7.54 (d, 2H), 7.65 (d, 2H).

Example 34 {[4-Amino-3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-1-yl] [3- (4-chlorophenoxy) azetidin-1-yl] methylene} cyanamide

A solution of 1903 mg (3.71 mmol) of allyl [1 - [[3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl) -4,5-dihydro-1H pyrazol-4-yl] carbamate (Example 64A), 3897 mg (27.80 mmol) of dimedone and 214 mg (0.19 mmol) of tetrakis (triphenylphosphine) palladium (0) in 80 ml of tetrahydrofuran are stirred under argon for 2 h at room temperature. The batch is poured into 300 ml of saturated sodium bicarbonate solution and, after separation of the phases, extracted three times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography on silica gel 60 (mobile phase ethyl acetate → ethyl acetate: methanol = 1: 1). The product obtained is then further purified by RP-HPLC. The resulting product is treated with methanol in an ultrasonic bath. The precipitated solid is separated on a glass frit and dried. This results in 288 mg (17% of theory) of the product as a solid.
LC-MS (Method 6): R _t = 2.00 min.
MS (ESI pos): m / z = 429 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.22-2.40 (m, 2H), 3.79 (dd, 1H), 4.13 (dd, 1H), 4.34.46 (m, 2H), 4.62 ( d, 1H), 4.89-5.10 (m, 3H), 6.93 (d, 2H), 7.38 (d, 2H), 7.51 (d, 2H), 7.91 (d, 2H).

Example 35 {[3- (4-Chlorophenoxy) azetidin-1-yl] [3- (4-chlorophenyl) -4- (ethylamino) -4,5-dihydro-1H-pyrazol-1-yl] methylene} cyanamide

To a solution of 150 mg (0.35 mmol) of {[4-amino-3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-1-yl] [3- (4-chlorophenoxy) azetidine-1] yl] methylene} cyanamide (Example 34) in 5 ml of methanol, 0.023 ml (0.42 mmol) of acetaldehyde are added and the mixture is stirred for 2 h at room temperature. The after about 30 Mi Nuts precipitated solid is filtered off with suction through a glass frit, washed with methanol and dried. This results in 123 mg (78% of theory) of the product as a solid.
LC-MS (Method 8): R _t = 2.21 min.
MS (ESI pos): m / z = 457 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.94 (t, 3H), 2.29-2.55 (m, 2H), 3.94-4.08 (m, 2H), 4.34-4.48 (m, 2H), 4.62.70 (m, 1H), 4.88-5.11 (m, 3H), 6.93 (d, 2H), 7.48 (d, 2H), 7.51 (d, 2H), 7.90 (d, 2H).

Example 36 N- [1 - [[3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] -N-ethyl-2-methoxy-

To a solution of 750 mg (1.77 mmol) of {[3- (4-chlorophenoxy) azetidin-1-yl] [3- (4-chlorophenyl) -4- (ethylamino) -4,5-dihydro-1H-pyrazole] 1-yl] methylene} cyanamide (Example 35) in 5 ml dichloromethane are added 0.016 ml (0.115 mmol) triethylamine, 0.009 ml (0.115 mmol) methoxyacetyl chloride and 0.67 mg (0.005 mmol) dimethylaminopyridine and the mixture is stirred for 20 h at room temperature. The mixture is concentrated and the residue is purified by RP-HPLC. The product obtained is then purified by silica gel chromatography on silica gel 60 (mobile phase toluene → toluene: ethyl acetate = 1: 1). This results in 9 mg (16% of theory) of the product as a solid.
LC-MS (Method 7): R _t = 2.56 min.
MS (ESI pos): m / z = 529 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.94-1.04 (bs, 3H), 3.18 (s, 2H), 3.90-4.13 (m, 3H), 4.28 (t, 1H), 4.42- 4.51 (m, 2H), 4.96-5.12 (m, 3H), 5.70-5.92 (m, 1H), 6.93 (d, 2H), 7.48 (d, 2H), 7.52 (d, 2H), 7.64 (d, 2H).

Example 37 2 - [[1 - [[3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl ] (ethyl) amino] -2-oxoethyl acetate

To a solution of 100 mg (0.22 mmol) of {[3- (4-chlorophenoxy) azetidin-1-yl] [3- (4-chlorophenyl) -4- (ethylamino) -4,5-dihydro-1H-pyrazole] 1-yl] methylene} cyanamide (Example 35) in 5 ml of dichloromethane are added 0.032 ml (0.23 mmol) of triethylamine, 0.022 ml (0.23 mmol) of acetoxyacetyl chloride and 1.34 mg (0.01 mmol) of dimethylaminopyridine and the mixture is stirred for 20 h at room temperature. The mixture is concentrated and the residue is purified by RP-HPLC. The product obtained is treated with methanol and diethyl ether in an ultrasonic bath. This results in 11 mg (9% of theory) of the product as crystals.
LC-MS (Method 8): R _t = 2.75 min.
MS (ESI pos): m / z = 557 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.01 (bs, 3H), 2.05 (s, 3H), 3.15-3.30 (m, 2H), 3.86-3.94 (m, 1H), 4.25 ( t, 1H), 4.39-4.50 (m, 2H), 4.67-4.76 (m, 2H), 4.96-5.10 (m, 3H), 5.70-5.93 (m, 1H), 6.93 (d, 2H), 7.47 ( d, 2H), 7.51 (d, 2H), 7.64 (d, 2H).

Example 38 N- [1 - [[3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl) -4,5-dihydro-1H-pyrazol-4-yl] -N-ethyl-2-hydroxyacetamide

A solution of 30 mg (0.054 mmol) of 2 - [[1- [[3- (4-chlorophenoxy) azetidin-1-yl] (cyanoimino) methyl] -3- (4-chlorophenyl) -4,5-dihydro- 1H-pyrazol-4-yl] (ethyl) amino] -2-oxoethylacetate (Example 37) and 11 mg (0.081 mmol) of potassium carbonate in 2 ml of methanol and 0.2 ml of water are stirred at room temperature overnight. The mixture is concentrated and the residue is purified by RP-HPLC. This results in 13 mg (47% of theory) of the product as a solid.
LC-MS (Method 6): R _t = 2.66 min.
MS (ESI pos): m / z = 515 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.02 (bs, 3H), 3.12-3.26 (m, 2H), 3.39-4.12 (m, 4H), 4.26 (t, 1H), 4.39- 4.50 (m, 2H), 4.65-4.72 (m, 1H), 4.95-5.12 (m, 3H), 5.60-5.93 (m, 1H), 6.92 (d, 2H), 7.46 (d, 2H), 7.51 ( d, 2H), 7.66 (d, 2H).

B) Assessment of physiological effectiveness

Abbreviations:

DMEM

Dulbecco's Modified Eagle medium

FCS

Fetal Calf Serum

HEPES

4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

The Suitability of the compounds of the invention for the treatment of thromboembolic disorders may be mentioned in the following Assay systems are shown:

In vitro assays

a) Cellular, more functional in vitro test

The identification of agonists of the human Protease Activated Receptor 1 (PAR1) as well as the quantification of the efficacy of the substances described herein is carried out with the aid of 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 constitutively expresses a modified form of the calcium-sensitive photoprotein aequorin which, upon reconstitution with co-factor coelenterazine, emits light upon increases in free calcium concentration in the inner mitochondrial compartment (Rizzuto R, Simpson AW, Brini M, Pozzan T .; Nature 1992, 358, 325-327). In addition, the cell stably expresses the endogenous human PAR1 receptor as well as the endogenous purinergic receptor P2Y2. The resulting PAR1 test cell responds to stimulation of the endogenous PAR1 or P2Y2 receptor with intracellular release of calcium ions, which can be quantitated by the resulting aequorin luminescence with a suitable luminometer (Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 1996, 17, 235-237).

For the exam of Substance-specificity its effect is after activation of the endogenous PAR1 receptor with the effect after activation of the endogenous P2Y2 purinergic receptor comparing the same intracellular signaling pathway.

Test Procedure: Cells are cultured (DMEM F12 supplemented with 10% FCS, 2mM glutamine, 20mM HEPES, 1.4mM pyruvate, 0.1mg / ml gentamycin, 0.15%) for 2 days (48 hrs.) Prior to assay % Na bicarbonate; BioWhittaker Cat. # BE04-687Q; B-4800 Verviers, Belgium) in 384-well microtiter plates and maintained in a cell incubator (96% humidity, 5% v / v CO ₂ , 37 ° C). On the test day the culture medium is passed through a Tyrodel solution (in mM: 140 NaCl, 5 KCl, 1 MgCl ₂ , 2 CaCl ₂ , 20 glucose, 20 HEPES), which additionally contains the co-factor coelenterazine (25 μM) and glutathione (4 mM). contains, exchanged and the microtiter plate then incubated for a further 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 PAR1 agonist concentration corresponding to EC ₅₀ , and immediately measured the resulting light signal in the luminometer. To distinguish an antagonist substance effect from a toxic effect, the endogenous purinergic receptor with agonist is activated immediately afterwards (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 Determination of platelet aggregation will be blood from healthy volunteers both sexes, which within the last ten days no had received medications influencing platelet aggregation, used. The blood is used in monovettes (Sarstedt, Nümbrecht, Germany) serving as anticoagulant sodium citrate 3.8% (1 part citrate + 9 parts of blood) included. To obtain platelet-rich Plasma, the citrated whole blood is centrifuged at 2500 rpm for 20 min at 4 ° C.

For the aggregation measurements, aliquots of the platelet-rich plasma are incubated with ascending concentrations of test substance at 37 ° C. for 10 min. The aggregation is then triggered by addition of a thrombin receptor agonist (SFLLRN) in an aggregometer and by the turbidimetric Born method (Born, GVR, Cross MJ, The Aggregation of Blood Platelets, J. Physiol 1963, 168, 178-195 ) at 37 ° C. The SFLLRN concentration, which leads to the maximum aggregation, becomes respectively 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. From the inhibition curves the concentration is calculated, which inhibits the aggregation to 50%. The results are shown in Table B: TABLE B

c) stimulation washed Platelets and Analysis in FACS (Fluorescence Associated Cell Sorter)

Insulation washed platelets:

human Whole blood is obtained by venipuncture from volunteer donors and in monovettes (Sarstedt, Nümbrecht, Germany), the as anticoagulant sodium citrate (1 part sodium citrate 3.8% + 9 parts whole blood). The Monovettes are at 900 revolutions per minute and 4 ° C over a period of time centrifuged for 20 minutes (Heraeus Instruments, Germany; Megafuge 1.0RS). The platelet rich Plasma is gently removed and transferred to a 50 ml Falcon tube. Now The plasma is mixed with ACD buffer (44 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose). The volume of the ACD buffer is one Quarter of the plasma volume. By centrifugation at 2500 for ten minutes Revolutions and 4 ° C the platelets are sedimented. After that, the supernatant carefully decanted and discarded. The precipitated platelets become first carefully with one 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, N ', N'-tetraacetic acid, 0.1% Glucose) and then with washing buffer to a volume filled, which corresponds to the amount of plasma. The washing process becomes a second one Time performed. After the platelets by another ten minute centrifugation at 2500 revolutions and 4 ° C precipitated Be careful in one milliliter of incubation buffer (134 mM sodium chloride, 12 mM sodium bicarbonate, 2.9 mM potassium chloride, 0.34 mM sodium dihydrogencarbonate, 5 mM HEPES, 5 mM glucose, 2 mM Calcium chloride and 2 mM magnesium chloride) and resuspended Incubation buffer to a concentration of 300,000 platelets adjusted per μl.

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

The platelet suspension is preincubated with the substance 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 30 μg / ml thrombin receptor activating peptide (TRAP6), Bachem, Switzerland) at 37 ° and shaking 500 revolutions Thrombocyte activation is triggered per minute. An aliquot of 50μl is withdrawn at time points 0, 1, 2.5, 5, 10 and 15 minutes and transferred to one milliliter of single-concentrated CellFix ^™ solution (Becton Dickinson Immunocytometry Systems, USA). To fix the cells they are incubated for 30 minutes at 4 ° C in the dark. Ten minutes of centrifugation at 600 g and 4 ° C precipitate the platelets. The supernatant is discarded and the platelets are resuspended in 400 μl CellWash ^™ (Becton Dickinson Immunocytometry 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 made up to a volume of 100 μl with CellWash ^™ . This anti body fluid is then added to the platelet suspension and incubated for 20 minutes at 4 ° C in the dark. Following staining, the batch volume is increased by adding an additional 400 μl of CellWash ^™ .

to Identification of the platelets becomes a fluorescein-isothiocyanate-conjugated antibody used, directed against the human glycoprotein IIb (CD41) (Immunotech Coulter, France, Cat No. 0649). With the help of phycoerythrin-conjugated antibody, against the human glycoprotein P-selectin (Immunotech Coulter, France; Cat. No. 1759), the activation state can be determined determine the platelets. P-selectin (CD62P) is more dormant in the α-granules Platelets localized. However, it becomes in response to in vitro or in vivo stimulation to the outer plasma membrane translocated.

FACS measurement and evaluation the FACS data:

Samples are measured in the FACSCalibur ^™ Flow Cytometry System from Becton Dickinson Immunocytometry Systems, USA, and analyzed and graphed using CellQuest, Version 3.3 (Becton Dickinson Immunocytometry Systems, USA) software. The level of platelet activation is determined by the percentage of CD62P-positive platelets (CD41-positive events). There are 10,000 CD41 positive events from each sample.

The inhibitory effect of the test to be tested Substance is determined by the reduction of platelet activation calculated, which refers to the activation by the agonist.

Ex vivo assay

platelet aggregation (Guinea pig)

Guinea pig (Strain: Dunkin Hartley) are in an alert or anesthetized state oral, intravenous or intraperitoneally with test substances treated in appropriate formulation. As a control, others will Guinea pigs in identical manner with the appropriate vehicle treated. Depending on the type of application of different lengths of time becomes from the deeply anaesthetized animals blood by puncture of the Heart or aorta won. The blood is used in monovettes (Sarstedt, Nümbrecht, Germany) as anticoagulant sodium citrate 3.8% (1 part citrate solution + 9 Parts of blood) included. To obtain platelet-rich Plasma, the citrated whole blood is centrifuged at 2500 rpm for 20 min at 4 ° C.

The Aggregation is agonist by adding a thrombin receptor (SFLLRN, 50 μg / ml) triggered in an aggregometer and by the turbidimetric Born method (Born, G.V.R., Cross M.J., The Aggregation of Blood Platelets; J. Physiol. 1963 168, 178-195) at 37 ° C certainly.

to Aggregation measurement is the increase in light transmission (amplitude the aggregation curve in%) 5 minutes after addition of the agonist determined. The inhibitory effect of the administered test substances in the treated animals is reduced by the reduction of aggregation, calculated on the mean of the control animals.

In vivo assay

The Compounds of the invention can in thrombosis models in suitable animal species in which the thrombin-induced Platelet aggregation over the PAR-1 receptor is mediated. As animal species guinea pigs and in particular primates are suitable (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 H-C, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861).

C) exemplary embodiments for pharmaceutical compositions

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

Tablet:

Composition:

• 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg cornstarch, 10 mg polyvinylpyrolidone (PVP 25) (BASF, Germany) and 2 mg of 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 with a 5% solution (m / m) of the PVP in water granulated. The granules will dry after drying with the magnesium stearate for 5 minute mixed. This mixture is compressed 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 rhodigel (xanthan gum) (FMC, USA) and 99 g water.
• A single dose of 100 mg of the compound of the invention correspond to 10 ml of oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of the example 1 is added to the suspension. While stirring the addition of the water takes place. Until the completion of the swelling of the Rhodigels is stirred for about 6h.

Intravenously administrable Solution:

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

Claims (13)

Compound of the formula (I)

in which R ^{1 is} a group of the formula

where * is the point of attachment to the pyrazoline ring, X is NH, an oxygen atom or a sulfur atom, Y is NR ⁷ , an oxygen atom, a sulfur atom, S (= O) or S (= O) ₂ , where R ^{7 is} hydrogen, methyl, ethyl, 2-hydroxyeth-1-yl, 2-aminoethyl, cyclopropyl or methylsulfonyl, o is 1, 2 or 3, p is 1, 2 or 3, q is 1, 2 or 3 R ^{4 is} hydrogen, amino, 2-hydroxyeth-1-yl, (C ₁ -C ₃ ) -alkoxy or (C ₁ -C ₆ ) -alkylamino, R ^{5 is} hydrogen, methyl, ethyl, n-propyl , 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop-1-yl, R ^{6 is} hydrogen, methyl, Ethyl, n -propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop-1-yl, methylcarbonyl, Ethylcarbonyl, n-propylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or methylsulfonyl, wherein methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted n having 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₃ ) alkoxy and (C ₁ -C ₃ ) alkylcarbonyloxy, R ^{2 is} methyl, (C ₃ -C ₇ ) -Cycloalkyl, phenyl or 5- or 6-membered heteroaryl, where phenyl and heteroaryl may be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) alkoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy, A is a bond or an oxygen atom, m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, R ^{3 is} a group of the formula

where * is the point of attachment to the pyrazoline ring, R ^{8 is} halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy, R ^{9 is} hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy, and their salts, their solvates and the solvates of their salts. A compound of the formula (I) according to claim 1, in which R ^{1 represents} a group of the formula

where * is the point of attachment to the pyrazoline ring, X is NH or an oxygen atom, Y is NR ⁷ or an oxygen atom, where R ^{7 is} hydrogen, methyl, ethyl or cyclopropyl, o is 1, 2 or 3 , p is 1, 2 or 3, q is 1, 2 or 3, R ^{4 is} hydrogen or 2-hydroxyeth-1-yl, R ^{5 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth- 1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop-1-yl, R ^{6 is} hydrogen, methyl, ethyl, n- Propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop-1-yl, methylcarbonyl, ethylcarbonyl, n- Propylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or methylsulfonyl, wherein methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₃ ) - Alkoxy and (C ₁ -C ₃ ) -A alkylcarbonyloxy, R ^{2 is} methyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen , Cyano, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy, A is a bond or an oxygen atom, m is 0, 1, 2 or 3, n is 0, 1, 2 or 3, R ^{3 is} a group of the formula

where * is the point of attachment to the pyrazoline ring, R ^{8 is} halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy, R ^{9 is} hydrogen or halogen, and their salts, their solvates and the solvates of their salts. A compound of the formula (I) according to claim 1, in which R ^{1 represents} a group of the formula

where * is the point of attachment to the pyrazoline ring, X is NH or an oxygen atom, Y is NR ⁷ or an oxygen atom, where R ^{7 is} hydrogen, methyl, ethyl or cyclopropyl, o is 1, 2 or 3 , p is 1, 2 or 3, q is 1, 2 or 3, R ^{4 is} hydrogen or 2-hydroxyeth-1-yl, R ^{5 is} hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth- 1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop-1-yl, R ^{6 is} hydrogen, methyl, ethyl, n-propyl , 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop-1-yl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl , Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or methylsulfonyl, wherein methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₃ ) alkoxy and (C ₁ -C ₃ ) alkylca rbyloxy, R ^{2 is} methyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, thienyl, pyrazolyl or pyridyl, wherein phenyl, thienyl, pyrazolyl and pyridyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano Methyl, ethyl, methoxy, tert-butyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy, A is a bond or an oxygen atom, m is 0 or 1, n is 0, 1 or 2, R ^{3 is} a group of the formula

where * is the point of attachment to the pyrazoline ring, R ^{8 is} halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy, R ^{9 is} hydrogen or halogen, and their salts, their solvates and the solvates of their salts. A compound of the formula (I) according to claim 1, in which R ^{1 represents} a group of the formula

where * is the point of attachment to the pyrazoline ring, Y is NR ⁷ or an oxygen atom, wherein R ^{7 is} hydrogen, methyl, ethyl or cyclopropyl, p is 1 or 2, R ^{5 is} hydrogen, methyl, ethyl or 2-hydroxyeth-1-yl, R ^{6 is} hydrogen, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3- Dihydroxyprop-1-yl or methylcarbonyl, where methylcarbonyl may be substituted by a substituent selected from the group consisting of hydroxy, methoxy and methylcarbonyloxy, R ^{2 is} methyl, cyclopropyl, cyclobutyl, phenyl, thienyl, pyrazolyl or pyridyl, where phenyl, Thienyl, pyrazolyl and pyridyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, methyl, ethyl, methoxy, tert-butyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy, A is a bond or an oxygen atom , m is 0 or 1, n is 0, 1 or 2, R ^{3 is} a group of the formula

where * is the point of attachment to the pyrazoline ring, R ^{8 is} halogen, and their salts, their solvates and the solvates of their salts. A compound of the formula (I) according to claim 1, in which R ^{1 represents} a group of the formula

where * is the point of attachment to the pyrazoline ring, Y is NH or an oxygen atom, p is 2, R ^{5 is} hydrogen, methyl or ethyl, R ^{6 is} hydrogen, 2-hydroxyeth-1-yl, 2- Aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop-1-yl or methylcarbonyl, wherein methylcarbonyl may be substituted with one substituent selected from the group consisting of hydroxy , Methoxy and methylcarbonyloxy, R ^{2 is} methyl, phenyl, pyrazolyl or pyridyl, wherein phenyl, pyrazolyl and pyridyl may be substituted with 1 to 3 substituents independently of one another which is selected from the group consisting of halogen, methyl, ethyl, methoxy, tert-butyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy, A is an oxygen atom, m is 0, n is 0, 1 or 2, R ^{3 is} a group the formula

where * is the point of attachment to the pyrazoline ring, R ^{8 is} chlorine or fluorine, and their salts, their solvates and the solvates of their salts. Process for the preparation of compounds of the formula (I) as defined in claim 1, characterized in that compounds of the formula (II)

in which R ¹ and R ^{3 have} the meaning given in claim 1, with compounds of the formula (III)

in which A, m, n and R ^{2 have} the meaning given in claim reacted. A compound of the formula (I) as claimed in any one of claims 1 to 5 defines, for the treatment and / or prophylaxis of diseases. Use of a compound of formula (I) as in one of the claims 1 to 5 for the manufacture of a medicament for treatment and / or prophylaxis of cardiovascular diseases. Use of a compound of formula (I) as in one of the claims 1 to 5 for the manufacture of a medicament for treatment and / or prophylaxis of thromboembolic disorders. Method for the treatment and / or prophylaxis of Cardiovascular diseases using a therapeutic effective amount of a compound of formula (I) as in any of claims 1 to 5 defined. Medicament containing a compound of the formula (I) as in any of the claims 1 to 5, in combination with another active ingredient. Medicament containing a compound of the formula (I) as in any of the claims 1 to 5, in combination with an inert, non-toxic, pharmaceutically suitable excipient. Method for preventing blood coagulation in in vitro, characterized in that an anticoagulatory effective Amount of a compound of formula (I) as in any of claims 1 to 5 defined, is added.