EP1907363A1

EP1907363A1 - Phenyl substituted piperazine-derivatives as inhibitors of plaminogenic activator inhibitors-i (pai-i)

Info

Publication number: EP1907363A1
Application number: EP06762520A
Authority: EP
Inventors: Andreas Wilmen; Julia Strassburger; Mark Jean Gnoth; Christoph Gerdes; Britta-Nicole FRÖHLEN; Stephan Siegel
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2005-07-16
Filing date: 2006-07-11
Publication date: 2008-04-09
Also published as: JP2009501740A; WO2007009635A1; DE102005033371A1; CA2614939A1

Abstract

The invention relates to substituted pyridocarboxamides, to a method for the production thereof and to the use thereof in the production of medicaments for the treatment and/or prophylaxis of illnesses in humans and animals, in particular thrombotic diseases.

Description

PHENYL SUBSTITUTED PIPERAZINE DERIVATIVES AS INHIBITORS FROM THE PLAMINOGEN ACTIVATOR

INHIBITOR-I (PAI-I)

The invention relates to substituted pyridocarboxamides, a process for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases in humans and animals, in particular thrombotic diseases.

Plasminogen Activator Inhibitor-1 (PAI-I) is the major regulatory component of the plasminogen plasmin system. The fibrinolytic system encloses the proenzyme plasminogen, which is converted by the two plasminogen activators tPA and uPA into the active enzyme plasmin. PAI-I is the major physiological inhibitor of both tissue-specific plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). One of the main tasks of plasmin in the fibrino-1 system is the breakdown of fibrin at the site of vascular injury. However, the fibrinolytic system is not only responsible for the removal of fibrin from the circulation but is also involved in various other processes including ovulation, embryogenesis, intimal proliferation, angiogenesis, tumorigenesis and atherosclerosis.

Increased plasma levels of PAI-I are associated with a variety of conditions and conditions that interfere with the fibrinolytic system. So are z. For example, elevated plasmatic PAI-I levels are associated with thrombotic disorders characterized, for example, by the formation of a thrombus that locally impairs or detaches and vascularizes vascular blood flow to block downstream blood flow (Krishnamurti, Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigations, 92, 2756 (1993); Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis, 24, 243 (1994 )). Neutralizing antibodies of PAI-I activity result in an acceleration of endogenous fibrinolysis and perfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation, 85, 305 (1992)).

An object of the present invention is therefore to provide new PAI-I inhibitors for the treatment of thrombotic diseases in humans and animals.

Structures similar to the compounds of the invention are disclosed in WO 03/080060 and WO 03/080564 as PAI-I inhibitors for the treatment of thrombotic disorders. WO 95/33750 discloses inter alia substituted pyridocarboxamides as corticotropin releasing factor (CRF) antagonists for the treatment of diseases of the central nervous system and WO 03/061387 discloses methods for controlling algae using substituted pyridinecarboxamides. The present invention relates to compounds of the formula

in which

X for a group of the formula

stands,

in which

the point of attachment to the carbonyl group is,

# is the point of attachment to the oxygen atom,

and

R ^2, R ^3, R ⁴ and R ^{5 are} independently hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C] -C ₄ alkyl, C _r C ₄ alkoxy, Ci-C ₆ -alkylamino, Q is C ₄ -alkoxycarbonyl or C 1 -C 6 -alkylaminocarbonyl,

is phenyl or pyridyl,

wherein phenyl and pyridyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ₆ alkyl, Ci _C6 alkoxy, Ci-Cβ alkylamino, Ci-C ₆ alkylcarbonyl, C _r C ₆ alkoxycarbonyl and Ci-C _δ alkylaminocarbonyl,

n is a number 0, 1, 2 or 3, R ^{1 is} phenyl or 5- or 6-membered heteroaryl,

wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, CpCe-alkyl, Ci-C ₆ -alkoxy, C _ö alkylamino, Ci-C ₆ alkylcarbonyl, Q

C ₆ alkoxycarbonyl, Ci-Cβ-alkylaminocarbonyl and Ci-C _ö alkylsulfonylamino,

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

Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts; the compounds of the formula (I) below and the salts, solvates and solvates of the salts thereof and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the of formula (I), compounds mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

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

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

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

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, Alkylcarbonvh alkylaminocarbonyl, alkoxycarbonyl and alkylsulfonylamino stand for a linear or branched alkyl radical having usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is, by way of example and by way of preference, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino is 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, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl N-methylamino. C 1 -C ₄ -alkylamino is, for example, a monoalkylamino radical having 1 to 4 carbon atoms or a dialkylamino radical having 1 to 4 carbon atoms per alkyl substituent.

Alkylcarbonyl is by way of example and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents. (C ₁ -C ₃ ) -Alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkyl aminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent. Examples which may be mentioned by way of example and by way of example: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl- N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl is by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, terf-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylsulfonylamino is by way of example and preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.

Heteroaryl represents 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 Ν, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, Pyrimidyl and pyridazinyl.

Halogen is fluorine, chlorine, bromine and iodine.

In the formula of the group which stands for X, the end point of the line next to each of which a * or # stands, is not a carbon atom or a CK ^ group, but is part of the bond to the carbonyl group or to the Oxygen atom to which X is bonded.

If radicals are substituted in the compounds according to the invention, the radicals may, unless otherwise specified, be mono- or polysubstituted or differently substituted. Substitution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

Preference is given to compounds of the formula (I) in which

X for a group of the formula

stands,

in which

the point of attachment to the carbonyl group is,

the point of attachment to the oxygen atom is,

and

R ^2, R ^3, R ⁴ and R ^{5 are} independently hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, _Ci-C4-alkyl, Ci-C ₄ alkoxy, _Ci-C6 alkylamino, Q C ₄ alkoxycarbonyl or C 1 -C 6 -alkylaminocarbonyl,

Y is phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C _r C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ -alkylamino, Ci-C ₆ alkylcarbonyl, Ci-Cβ alkoxycarbonyl, and Ci-C _ö alkylaminocarbonyl,

n stands for a number 0,

R ^{1 is} phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl,

Aminocarbonyl, Ci-C ₆ alkyl, Ci-C ₆ alkoxy, C] _-C6 alkylamino, Ci-C ₆ alkylcarbonyl, C _r C ₆ alkoxycarbonyl, Ci-C ₆ -alkylaminocarbonyl and C-C ₆ - alkylsulfonylamino,

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

Preference is also given to compounds of the formula (I) in which X for a group of the formula

stands,

in which

the point of attachment to the carbonyl group is,

# is the point of attachment to the oxygen atom,

and

R ² , R ³ , R ⁴ and R ^{5 are} hydrogen,

Y is phenyl,

wherein phenyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen and C _r C ₄ alkoxy,

n stands for a number 0,

R ^{1 is} phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, methyl, methoxy and methylsulfonylamino,

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

Preference is also given to compounds of the formula (I) in which

X for a group of the formula

stands,

in which

* is the point of attachment to the carbonyl group,

# is the point of attachment to the oxygen atom,

and

R ² and R ^{3 are} hydrogen.

Preference is also given to compounds of the formula (I) in which R ² and R ^{3 are} hydrogen.

Preference is also given to compounds of the formula (I) in which R ⁴ and R ^{5 are} hydrogen.

Preference is also given to compounds of the formula (I) in which Y is phenyl.

Preference is also given to compounds of the formula (I) in which n is the number zero.

Preference is also given to compounds of the formula (I) in which R ^{1 is} phenyl, where phenyl is substituted once by trifluoromethyl.

Another object of the present invention is a process for the preparation of the compounds of formula (I), characterized in that compounds of the formula

in which,

X and R ^{1 have} the abovementioned meaning,

with compounds of the formula

in which

X and n have the abovementioned meaning,

be implemented.

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

Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or acetonitrile, dimethyl sulfoxide being preferred.

Examples of bases are alcoholates such as 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 organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride or DBU, sodium hydride is preferred.

The compounds of the formula (H) are known or can be prepared by reacting compounds of the formula

in which,

R ^{1 has} the meaning indicated above,

with compounds of the formula

O

HcA _χ - ^{F (V)} ' in which,

X has the meaning indicated above,

be implemented.

The reaction is generally carried out in inert solvents, in the presence of a dehydrating reagent, if appropriate in the presence of a base, preferably in a temperature range from -3O ⁰ C to 5O ⁰ C at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g. N, N-diethyl, N, N-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl Polystyrene (PS carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride, or O- (benzotriazole-1 -yl) -NNN ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) -1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O- (benzotriazol-1-yl) -NNN ', N'-tetramethyluronium tetrafluoroborate (TBTU) or O- (7-azabenzotriazol-1-yl) -NN N'.N'-tetramethyluronium hexafluorophosphate (HATU), or 1 - Hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino no) -phosphonium hexafluorophosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or N-hydroxysuccinimide, or mixtures thereof, with bases.

Preferably, the condensation is carried out with TBTU in the presence of diisopropylethylamine. The compounds of the formulas (III), (IV) and (V) are known per se to the person skilled in the art or can be prepared by customary processes known from the literature.

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes.

Scheme 1:

Scheme 2:

The compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum.

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

The pharmaceutical activity of the compounds according to the invention can be explained by their action as PAI-1 inhibitors.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably thrombotic diseases.

The compounds of the invention are useful in the prophylaxis and / or treatment of thrombotic disorders such as venous and arterial thrombosis, pulmonary thrombosis, cerebral thrombosis, thromboembolism and deep venous thrombosis, or coronary heart disease, atrial fibrillation, pulmonary fibrosis, cystic fibrosis, thromboembolic complications, or stroke z. As thrombotic stroke and thromboembolic stroke, or transient ischemic attacks, reocclusion and restenosis after Coronary interventions (reocclusion and restenosis after percutaneous coronary interventions, reocclusion and restenosis after coronary bypass surgery), disseminated intravascular coagulation, or surgical intervention such as pulmonary embolism, apoplexy, vascular surgery, vascular graft, stent patency, organ, tissue and cell implantation and transplantation, or cardiovascular Diseases such as myocardial infarction, atherosclerotic plaque formation, myocardial infarction, stable angina pectoris and unstable angina pectoris, or chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, Alzheimers disease, bone loss induced by estrogen deficiency, diabetes, obesity, chronic periodontitis, lymphomas, diseases in conjunction with accumulation of extracellular matrix, inflammatory diseases such. As asthma, septic shock, kidney disease, obesity, insulin resistance, diseases associated with angiogenesis, or cancer such. As leukemias, malignant tumors or vascular damage with infections and diseases associated with increased uPA levels such as breast and ovarian cancer.

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

The compounds of the present invention may also be used to treat blood and blood products used for dialysis and storage of blood in the liquid phase, particularly for ex vivo platelet aggregation. The present compounds may also be added to human plasma during chemical blood analysis under hospital conditions to determine fibrinolytic capacity.

The compounds of the present invention may also be used in combination with pro- thrombolytic, fibrinolytic and anticoagulant agents.

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

Another object of the present invention is a method for the prophylaxis and / or treatment of diseases, in particular the aforementioned diseases, using a cardiovascular effective amount of the compound of the invention.

Another object of the present invention are pharmaceutical compositions containing a compound of the invention in combination with one or more other active ingredients, in particular for the prophylaxis and / or treatment of the aforementioned diseases.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration are, for example inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, and their use for the purposes mentioned above.

In general, it has proven to be advantageous both in human and in veterinary medicine, the compound of the invention in total amounts of about 0.01 to about 700, preferably 0.01 to 100 mg / kg body weight per 24 hours, optionally in the form of several single doses Achieve the desired results. A single dose contains the compound of the invention preferably in amounts of about 0.1 to about 80, in particular 0.1 to 30 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. So it may be sufficient to manage with less than the abovementioned ^'minimum amount in some cases, while in other cases the upper limit mentioned must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. A. Examples

Abbreviations:

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DCM dichloromethane

DIEA N, N-diisopropylethylamine

DMA N, N-dimethylacetamide

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory

EE ethyl acetate (ethyl acetate)

EI electron impact ionization (in MS)

ESI electrospray ionization (in MS)

Mp melting point sat. saturated h hour

HATU 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

TBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

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

HPLC high pressure, high performance liquid chromatography conc. concentrated

LC-MS liquid chromatography-coupled mass spectrometry

LDA lithium diisopropylamide min

MPLC medium pressure, medium performance liquid chromatography

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy org. organic proc. percent quant. quantitatively

RF reflux

RF retention factor (in DC)

RP-HPLC reverse phase HPLC

RT room temperature R. Retention time (by HPLC)

TFA trifluoroacetic acid

THF tetrahydrofuran

starting compounds

Example IA

l - [(2-fluoropyridin-3-yl) carbonyl] -4- [3- (trifluoromethyl) phenyl] piperazine

300 mg (2.06 mmol) of 2-fluoronicotinic acid in 10 ml of dichloromethane are introduced into a round bottom flask and 993 mg (3.09 mmol) of TBTTJ are added. After dropwise addition of 0.539 ml (3.09 mmol) of diisopropylethylamine is stirred for 10 min at RT and then 532.96 mg (2.27 mmol) of 3-piperazino-benzotrifluoride are added. The mixture is stirred at RT for 16 h and the solvent is removed completely. Purification by preparative HPLC gives 652 mg (89% of theory) of product.

MS (ESIpos): m / z = 354 (M + H) ⁺ .

¹ H NMR (400MHz, DMSOd ₆ ): δ = 8.37 (d, IH), 8.08 (t, IH), 7.49 (t, IH), 7.43 (d, IH), 7.24 (d, IH), 7.21 ( s, IH), 7.11 (d, IH), 3.80 (t, 2H), 3.34-3.40 (m, 4H), 3.23 (t, 2H).

Example 2A

1 - (2-Fluoroisonicotinoyl) -4- [3- (trifluoromethyl) phenyl] piperazine

150 mg (1.04 mmol) of 2-fluoro-4-pyridinecarboxylic acid in 10 ml of dichloromethane are introduced into a round bottom flask and 502 mg (1.56 mmol) of TBTU are added. After dropwise addition of 0.272 ml (1.56 mmol) of diisopropylethylamine is stirred for 10 min at RT and then be Added 367 mg (1.56 mmol) of 3-piperazino-benzotrifluoride. The mixture is stirred at RT for 16 h and the solvent is removed completely. After purification by preparative HPLC, 272 mg (74% of theory) of product are obtained.

MS (ESIpos): m / z = 354 (M + H) ⁺ .

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 7.4-7.69 (m, 2H), 7.30 (s, IH), 7.24 (d, IH), 7.19 (s, IH ), 7.1 1 (d, IH), 3.78 (m, 2H), 3.39 (m, 4H), 3.26 (m, 2H).

Example 3A

l - [(2-fluoropyridin-3-yl) carbonyl] -4- [4- (trifluoromethyl) phenyl] piperazine

100 mg (0.71 mmol) of 2-fluoronicotinic acid in 8 ml of dichloromethane are introduced into a round bottom flask and 331 mg (1.03 mmol) of TBTU are added. After dropwise addition of 0.18 ml (1.03 mmol) of diisopropylethylamine, the mixture is stirred at RT for 10 min and then 174.1 mg (0.756 mmol) of 1- (4-trifluoromethylphenyl) -piperazine are added. The mixture is stirred at RT for 16 h and the solvent is removed completely. Purification by preparative HPLC gives 228 mg (94% of theory) of product as a solid.

MS (DCI, NH _3): m / z = 371 (M + NH,) ^+.

¹ H-NMR (400MHz ₅ DMSO-Cl ₆ ): δ = 8.36 (d, IH), 8.08 (dt, IH), 7.53 (d, 2H), 7.48-7.51 (m, IH), 7.08 (d, 2H ), 3.80 (t, 2H), 3.39-3.43 (m, 4H), 3.30 (s, 2H).

Example 4A

l- (3,4-dichlorophenyl) -4 - [(2-fluoropyridin-3-yl) carbonyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 175 mg (0.756 mmol) of 1- (3,4-dichlorophenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 236 mg (97% of theory) of product as a solid.

MS (ESIpos): m / z = 354 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, IH), 8.07 (dt, IH), 7.47-7.51 (m, IH), 7.42 (d, IH), 7.16 (d, IH ), 6.95 (dd, IH), 3.77 (t, 2H), 3.35-3.39 (m, 4H), 3.15-3.21 (m, 2H).

Example 5A

1 - [3, 5 -Bis (trifluoromethyl) phenyl] 4 - [(2-fluoropyridine-3-yl) carbonyl] -piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 225 mg (0.756 mmol) of 1- [3,5-bis (trifluoromethyl) phenyl] piperazine to give the corresponding amide. Purification by preparative HPLC gives 215 mg (74% of theory) of product as a solid.

MS (ESIpos): m / z = 422 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSOd ₆ ): δ = 8.36 (d, IH), 8.08 (dt, IH), 7.47-7.53 (m, 3H), 7.36 (s, IH), 3.80 (t, 2H), 3.50 (m, 2H), 3.35-3.42 (m, 4H). Example 6A

l- (2-chlorophenyl) -4 - [(2-fluoφyridin-3-yl) carbonyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 148.7 mg (0.756 mmol) of 1- (2-chlorophenyl) piperazine to give the corresponding amide. After purification via preparative HPLC, 208 mg (95% of theory) of product are obtained as an oil.

MS (ESIpos): m / z = 320 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 8.08 (dt, IH), 7.49 (m, IH), 7.43 (dd, IH), 7.32 (t, IH), 7.18 (dd, IH), 7.08 (t, IH), 3.82 (t, 2H), 3.41 (t, 2H), 3.05 (t, 2H), 2.95 (t, 2H).

Example 7A

4- {4 - [(2-Fluoφyridin-3-yl) carbonyl] piperazin-l-yl} -benzonitrile

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 141.6 mg (0.756 mmol) of 4-piperazin-1-yl-benzonitrile to give the corresponding amide. After purification via preparative HPLC, 201 mg (94% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 31 1 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, IH), 8.08 (dt, IH), 7.61 (d, 2H), 7.46-7.52 (m, IH), 7.03 (d, 2H ), 3.78 (t, 2H), 3.48 (t, 2H), 3.35-3.41 (m, 4H). Example 8A

l- (4-chlorophenyl) -4 - [(2-fluoropyridin-3-yl) carbonyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 148.7 mg (0.756 mmol) of 1- (4-chlorophenyl) piperazine to give the corresponding amide. After purification via preparative HPLC, 190 mg (86% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 320 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO- (I ₆ ): δ = 8.35 (d, IH), 8.07 (dt, IH), 7.48 (m, IH), 7.25 (d, 2H), 6.97 (d, 2H) , 3.79 (t, 2H), 3.38 (t, 2H), 3.24 (t, 2H), 3.12 (t, 2H).

Example 9A

l- (3,5-dichlorophenyl) -4 - [(2-fluoropyridin-3-yl) carbonyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 174.8 mg (0.756 mmol) of 1- (3,5-dichlorophenyl) piperazine to give the corresponding amide. After purification by preparative HPLC, 207 mg (85% of theory) of product are obtained as solid.

MS (DCI, NH _3): m / z = 371 (M + NHL) ^*. ¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 8.07 (dt, IH), 7.49 (m, IH), 6.97 (s, 2H), 6.91 (s, IH), 3.76 (t, 2H), 3.34-3.39 (m, 4H), 3.21-3.26 (m, 2H).

Example IQA

l- (2,3-dichlorophenyl) -4 - [(2-fluoropyridin-3-yl) carbonyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 174.8 mg (0.756 mmol) of 1- (2,3-dichlorophenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 218 mg (90% of theory) of product as a solid.

MS (ESIpos): m / z = 354 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 8.08 (dt, IH), 7.47-7.51 (m, IH), 7.30-7.36 (m, 2H), 7.15-7.20 (m, IH), 3.83 (t, 2H), 3.42 (t, 2H), 3.07 (t, 2H), 3.96 (t, 2H).

Example IIA

l - [(2-fluoropyridin-3-yl) carbonyl] -4- [2- (trifluoromethyl) phenyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 174.1 mg (0.756 mmol) of 1- [2- (trifluoromethyl) phenyl] piperazine to give the corresponding amide. Purification by preparative HPLC gives 223 mg (92% of theory) of product as a solid.

MS (ESIpos): m / z = 354 (M + H) ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 8.09 (dt, IH), 7.68 (t, 2H), 7.59 (d, IH), 7.47-7.51 (m, IH ), 7.38 (t, IH), 3.78 (m, 2H), 3.34-3.39 (m, 2H), 2.95 (t, 2H), 2.84 (t, 2H).

Example 12A

l - [(2-fluoropyridin-3-yl) carbonyl] -4- (4-methoxyphenyl) piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 145.4 mg (0.756 mmol) of 1- (4-methoxyphenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 148 mg (67% of theory) of product as a solid.

MS (ESIpos): m / z = 316 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 8.07 (dt, IH), 7.48 (m, IH), 6.92 (d, 2H), 6.83 (d, 2H), 3.79 (t, 2H), 3.38 (t, 2H), 3.09 (t, 2H), 3.97 (t, 2H).

Example 13A

3- {4 - [(2-Fluoφyridin-3-yl) carbonyl] piperazin-l-yl} -benzonitrile

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 169.2 mg (0.756 mmol) of 3-piperazin-1-yl-benzonitrile hydrochloride to give the corresponding amide. However, 3 equivalents of diisopropylethylamine are used as base addition. After purification via preparative HPLC, 201 mg (93% of theory) of product are obtained as solid. MS (ESIpos): m / z = 311 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.36 (d, IH), 8.08 (dt, IH), 7.49 (m, IH), 7.41 (t, IH), 7.37 (s, IH), 7.29 (dd, IH), 7.20 (d, IH), 3.79 (t, 2H), 3.30-3.41 (m, 4H), 3.23 (t, 2H).

Example 14A

1 - [(2-fluoropyridin-3-yl) carbonyl] -4- (4-methylphenyl) piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 188.4 mg (0.756 mmol) of 1- (4-methylphenyl) piperazine dihydrochloride to give the corresponding amide. However, 4.5 equivalents of diisopropylethylamine are used as base addition. Purification by preparative HPLC gives 179 mg (87% of theory) of product as a solid.

MS (ESIpos): m / z = 300 (M + H) ⁺ .

¹ H NMR (400MHz, DMSOd ₆ ): δ = 8.36 (d, IH), 8.07 (dt, IH), 7.49 (m, IH), 7.04 (d, 2H), 6.86 (d, 2H), 3.79 ( t, 2H), 3.33-3.40 (m, 2H), 3.16 (t, 2H), 3.04 (t, 2H).

Example 15A

l - [(2-Fluoφyridin-3-yl) carbonyl] -4- (2-methoxyphenyl) piperazine

Analogously to the instructions for the preparation of Example 3 A, 100 mg (0.71 mmol) of 2

Fluornicotinic acid with 173 mg (0.756 mmol) of 1- (2-methoxyphenyl) piperazine hydrochloride to the corresponding amide reacted. However, 3 equivalents of diisopropylethylamine are used as a base addition. After purification via preparative HPLC, 190 mg (88% of theory) of product are obtained as a resin.

MS (ESIpos): m / z = 316 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 8.07 (m, IH), 7.48 (m, IH), 6.93-7.02 (m, 2H), 6.85-6.92 (m , 2H), 3.78-3.81 (m, 2H), 3.78 (s, 3H), 3.38 (t, 2H), 3.03 (t, 2H), 2.92 (t, 2H).

Example 16A

N- (2- {4 - [(2-fluoropyridin-3-yl) carbonyl] piperazin-l-yl} phenyl) methanesulfonamide

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 248.2 mg (0.756 mmol) of N- (2-piperazin-1-ylphenyl) methanesulphonamide dihydrochloride to give the corresponding amide. However, 4.5 equivalents of diisopropylethylamine are used as base addition. Purification by preparative HPLC gives 98 mg (27% of theory) of product as a solid.

MS (ESIpos): m / z = 379 (M + H) ⁺ .

Example 17A

l - [(2-Fluoφyridin-3-yl) carbonyl] -4- (3-methoxyphenyl) piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid with 149.9 mg (0.78 mmol) of 1- (3-methoxyphenyl) piperazine to the corresponding Amide implemented. Purification by preparative HPLC gives 157 mg (68% of theory) of product as a resin.

MS (ESIpos): m / z = 316 (M + H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.36 (d, IH), 8.07 (dt, IH), 7.49 (hept, IH), 7.13 (t, IH), 6.54 (dd, IH), 6.48 (t, IH), 6.41 (dd, IH), 3.78 (t, 2H), 3.71 (s, 3H), 3.37 (t, 2H), 3.23 (t, 2H), 3.11 (t, 2H).

Example 18A

l- (4-Fluoφhenyl) -4 - [(2-fluoropyridin-3-yl) carbonyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 180.23 mg (0.78 mmol) of 1- (4-fluorophenyl) piperazine to give the corresponding amide. Purification by preparative HPLC gives 199 mg (92% of theory) of product as an oil.

MS (ESIpos): m / z = 304 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.35 (d, IH), 8.06 (hept, IH), 7.49 (hept, IH), 7.07 (d, 2H), 6.99 (d, IH), 6.98 (d, IH), 3.79 (t, 2H), 3.38 (t, 2H), 3.17 (t, 2H), 3.05 (t, 2H).

Example 19A

l- [4-chloro-3- (trifluoromethyl) phenyl] -4 - [(2-fluoφyridin-3-yl) carbonyl] piperazine

Analogously to the instructions for the preparation of Example 3A, 100 mg (0.71 mmol) of 2-fluoronicotinic acid are reacted with 206.34 mg (0.78 mmol) of 1- [4-chloro-3- (trifluoromethyl) phenyl] piperazine to give the corresponding amide. After purification by preparative HPLC, 271 mg (99% of theory) of product are obtained as a resin.

MS (ESIpos): m / z = 388 (M + H) ⁺ .

¹ H NMR (400MHz, DMSOd ₆ ): δ = 8.37 (d, IH), 8.08 (hept, IH), 7.52 (d, IH), 7.49 (hept, IH), 7.29 (d, IH), 7.23 ( dd, IH), 3.79 (t, 2H), 3.38 (m, 4H), 3.24 (t, 2H).

embodiments

example 1

4 - {[3 - ({4- [3- (trifluoromethyl) phenyl] piperazin-l-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

37.53 mg (0.272 mmol) of 4-hydroxybenzoic acid are initially charged in 4 ml of dry DMSO and 22.64 mg (0.57 mmol) of sodium hydride (60%) are added. The mixture is stirred for 10 min under argon at RT and then 80 mg (0.226 mmol) of the 2-Fluornicotinsäureamids from Example IA added. It is heated for 1 h at 80 ⁰ C and a further 16 h at 120 ⁰ C, since there was still starting material. It is carefully added about 1 ml of water. After purification via preparative HPLC, 36 mg (34% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 472 (M + H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.25 (dd, IH), 7.97 (d, 2H), 7.94 (dd, IH), 7.44 (t, IH), 7.31 (dd, IH), 7.25 (d, 2H), 7.19 (d, 2H), 7.10 (d, IH), 3.80 (t, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.15 (m, 2H).

Example 2

4- {[4- ({4- [3- (Trifluoromethyl) phenyl] piperazine-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

46.9 mg (0.34 mmol) of 4-hydroxybenzoic acid are initially charged in 4 ml of dry DMSO and 28.3 mg (0.71 mmol) of sodium hydride (60% strength) are added. The mixture is stirred for 10 min under argon at RT and then 100 mg (0.28 mmol) of the isonicotinic acid amide from Example 2A are added. It will be 16 h heated at 130 ⁰ C and neutralized after cooling with IN hydrochloric acid. After purification via preparative HPLC, 57 mg (43% of theory) of product are obtained.

MS (ESIpos): m / z = 472 (M + H) ⁺ .

¹ H NMR (300MHz ₅ DMSOd ₆ ): δ = 12.88 (s, broad, IH), 8.28 (d, IH), 7.99 (d, 2H), 7.45 (t, IH), 7.08-7.29 (m, 7H ), 3.78 (m, 2H), 3.47 (m, 2H), 3.37 (m, 4H).

Example 3

4- {[3- ({4- [4- (trifluoromethyl) phenyl] piperazine-1-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

37.18 mg (0.255 mmol) of 4-hydroxybenzoic acid are initially charged in 6 ml of dry DMSO and 28.5 mg (0.713 mmol) of sodium hydride (60%) are added. The mixture is stirred for 10 min under argon at RT and then 60 mg (0.17 mmol) of 2-Fluornicotinsäureamids from Example 3 A is added. It is heated at 12O ⁰ C for 16 h. About 1 ml of 2N hydrochloric acid is carefully added until the pH is slightly acidic. Purification by preparative HPLC gives 58 mg (72% of theory) of product as a solid.

MS (ESIpos): m / z = 472 (M + H) ⁺ .

¹ H NMR (400MHz, DMSOd ₆ ): δ = 8.24 (dd, IH), 7.97 (d, 2H), 7.94 (dd, IH), 7.52 (d, 2H), 7.30 (dd, IH), 7.24 ( d, 2H), 7.06 (d, 2H), 3.79 (t, 2H), 3.48 (m, 2H), 3.34 (m, 4H).

Example 4

4 - [(3 - {[4- (3,4-Dichlθφhenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.226 mmol) of the 2-fluoronicotinamide from Example 4A are reacted with 46.79 mg (0.339 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 77 mg (72% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 472 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSOd ₆ ): δ = 12.93 (s, broad, IH), 8.24 (dd, IH), 7.98 (d, 2H), 7.94 (dd, IH), 7.41 (d, 2H), 7.30 (dd, IH), 7.14 (d, 2H), 6.93 (dd, IH), 3.76 (t, 2H), 3.45 (m, 2H), 3.28 (m, 2H), 3.19 (m, 2H).

Example 5

4 - {[3 - ({4- [3,5-bis (trifluoromethyl) phenyl] piperazin-l-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.19 mmol) of the 2-fluoronicotinamide from Example 5A are reacted with 39.34 mg (0.285 mmol) 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 75 mg (73% of theory) of product as a solid.

MS (ESIpos): m / z = 540 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSOd ₆ ): δ = 12.92 (s, broad, IH), 8.25 (dd, IH), 7.98 (d, 2H), 7.95 (dd, IH), 7.48 (s, 2H), 7.34 (s, IH), 7.31 (dd, IH), 7.25 (d, 2H), 3.80 (m, 2H), 3.47 (m, 4H), 3.37 (m, 2H).

Example 6

4 - [(3 - {[4- (2-chlorophenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.25 mmol) of the 2-fluoronicotinamide from Example 6A are reacted with 51.8 mg (0.375 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 78 mg (71% of theory) of product as a solid.

MS (ESIpos): m / z = 438 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.93 (s, broad, IH), 8.24 (dd, IH), 7.98 (d, 2H), 7.94 (dd, IH), 7.42 (dd, IH ), 7.30 (dd, IH), 7.27 (d, IH), 7.26 (d, 2H), 7.11 (dd, IH), 7.07 (dt, IH), 3.81 (m, 2H), 3.49 (m, 2H) , 3.0 (m, 4H).

Example 7

4 - [(3 - {[4- (4-cyanophenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.258 mmol) of the 2-fluoronicotinamide from Example 7A are reacted with 53.41 mg (0.387 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 71 mg (64% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 429 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSOd ₆ ): δ = 12.94 (s, broad, IH), 8.25 (dd, IH), 7.97 (d, 2H), 7.95 (dd, IH), 7.60 (d, 2H), 7.30 (dd, IH), 7.25 (d, 2H), 7.01 (d, 2H), 3.77 (t, 2H), 3.46 (m, 4H), 3.35 (m, 2H).

Example 8

4 - [(3 - {[4- (4-chlorophenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.25 mmol) of the 2-fluoronicotinamide from Example 8A are reacted with 51.83 mg (0.375 mmol) 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 84 mg (77% of theory) of product as a solid.

MS (ESIpos): m / z = 438 (M + H) ⁺ .

¹ H NMR (400MHz, DMSOd ₆ ): δ = 12.95 (s, broad, IH), 8.24 (dd, IH), 7.97 (d, 2H), 7.94 (dd, IH), 7.30 (dd, IH), 7.24 (dd, 4H), 6.94 (d, 2H), 3.78 (t, 2H), 3.46 (m, 2H), 3.21 (m, 2H), 3.12 (m, 2H).

Example 9

4 - [(3 - {[4- (3,5-Dichlorophenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.266 mmol) of the 2-fluoronicotinamide from Example 9A are reacted with 46.8 mg (0.339 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification by preparative HPLC, 70 mg (66% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 472 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.94 (s, broad, IH), 8.25 (dd, IH), 7.98 (d, 2H), 7.94 (dd, IH),

7.30 (dd, IH), 7.24 (d, 2H), 6.95 (d, 2H), 6.90 (t, IH), 3.75 (t, 2H), 3.43 (m, 2H), 3.33 (m, 2H),

3.31 (m, 2H).

Example 10

4 - [(3 - {[4- (2,3-Dichlorophenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.266 mmol) of the 2-fluoronicotinamide from Example 10A are reacted with 46.8 mg (0.339 mmol) 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 73 mg (68% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 472 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO- (I ₆ ): δ = 12.94 (s, broad, IH), 8.24 (dd, IH), 7.98 (d, 2H), 7.94 (dd, IH), 7.22-7.36 ( m, 5H), 7.11 (dd, IH), 3.82 (m, 2H), 3.50 (m, 2H), 2.9-3.1 (m, 4H).

Example 11

4 - {[3 - ({4- [2- (trifluoromethyl) phenyl] piperazin-l-yl} carbonyl) pyridin-2-yl] oxy} benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.226 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 46.91 mg (0.34 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 51 mg (48% of theory) of product as a solid.

MS (ESIpos): m / z = 472 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSOd ₆ ): δ = 12.94 (s, broad, IH), 8.24 (dd, IH), 7.99 (d, 2H), 7.95 (dd, IH), 7.65 (dd, 2H), 7.49 (d, IH), 7.36 (t, IH), 7.31 (dd, IH), 7.26 (d, 2H), 3.77 (m, 2H), 3.44 (t, 2H), 2.73-2.98 (m, 4H) ,

Example 12

4 - [(3 - {[4- (4-methoxyphenyl) -piperazine-1-yl] carbonyl] pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.254 mmol) of the 2-fluoronicotinamide from Example 12A are reacted with 52.56 mg (0.381 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 63 mg (54% of theory) of product as a solid.

MS (ESIpos): m / z = 434 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, IH), 8.24 (dd, IH), 7.98 (d, 2H), 7.93 (dd, IH), 7.30 (dd, IH ), 7.24 (d, 2H), 6.89 (d, 2H), 6.81 (d, 2H), 3.78 (m, 2H), 3.68 (s, 3H), 3.45 (m, 2H), 2.90-3.1 (m, 4H).

Example 13

4 - [(3 - {[4- (3-cyanophenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.258 mmol) of the 2-fluoronicotinamide from Example 13A are reacted with 53.41 mg (0.387 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 66 mg (60% of theory) of product are obtained as solid.

MS (DCI, NH _3): m / z = 446 (M + NH,) ^+.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.93 (s, broad, IH), 8.25 (dd, IH), 7.98 (d, 2H), 7.94 (dd, IH), 7.40 (t, IH ), 7.26-7.36 (m, 5H), 7.19 (d, IH), 3.78 (t, 2H), 3.46 (m, 2H), 3.30 (m, 2H), 3.24 (m, 2H).

Example 14

4 - [(3 - {[4- (4-methylphenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.267 mmol) of the 2-fluoronicotinamide from Example 14A are reacted with 55.37 mg (0.4 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification by preparative HPLC, 76 mg (68% of theory) of product are obtained as solid.

MS (DCI, NH _3): m / z = 418 (M + H) ^+.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, IH), 8.23 (d, IH), 7.97 (d, 2H), 7.93 (d, IH), 7.30 (dd, IH ), 7.24 (d, 2H), 7.02 (d, 2H), 6.83 (d, 2H), 3.78 (m, 2H), 3.45 (m, 2H), 3.23-3.18 (m, 4H), 2.19 (s, 3H).

Example 15

4 - [(3 - {[4- (2-methoxyphenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.254 mmol) of the 2-fluoronicotinamide from Example 15A are reacted with 52.56 mg (0.381 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 2 mg (2% of theory) of product as a solid.

MS (ESIpos): m / z = 434 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-Cl ₆ ): δ = 12.92 (s, broad), 8.36 (dd), 8.24 (dd), 8.07 (t), 7.98 (d), 7.93 (d), 7.48 (t ), 7.30 (dd), 7.25 (d), 6.92-7.01 (m), 6.81-6.91 (m), 3.77 (s), 3.45 (m), 3.39 (m,), 3.03 (m), 2.92 (m ). Example 16

4- ({3 - [(4- {2 - [(Methylsulfonyl) amino] phenyl} piperazine-1-yl) carbonyl] pyridin-2-yl} oxy) benzoic acid

Analogously to the instructions for the preparation of Example 3, 40 mg (0.106 mmol) of the 2-fluoronicotinamide from Example 16A are reacted with 21.9 mg (0.159 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 27 mg (49% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 497 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, IH), 8.6 (s, IH), 8.24 (dd, IH), 7.99 (d, 2H), 7.96 (m, IH ), 7.37 (dd, IH), 7.30 (dd, IH), 7.45 (d, 2H), 7.08-7.19 (m, 3H), 3.86 (m, 2H), 3.53 (m, IH), 3.45 (m, IH), 3.1 (s, 3H), 2.83-2.94 (m, 2H), 2.70-2.82 (m, 2H).

Example 17

4 - [(3- {[4- (3-Methoxyphenyl) piperazine-1-yl] carbonyl) 1-pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 46 mg (0.146 mmol) of the 2-fluoronicotinamide from Example 17A are reacted with 30.22 mg (0.219 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 17 mg (25% of theory) of product are obtained as solid.

MS (ESIpos): m / z = 434 (M + H) ⁺ . ¹ H-NMR (400MHz, DMSOd ₆ ): δ = 12.91 (s, broad, IH), 8.24 (dd, IH), 7.97 (d, 2H), 7.94 (dd, IH), 7.30 (dd, IH), 7.24 (d, 2H), 7.12 (t, IH), 6.51 (dd, IH), 6.45 (t, IH), 6.39 (dd, IH), 3.77 (t, 2H), 3.70 (s, 3H), 3.45 (m, 2H), 3.20 (m, 2H), 3.11 (m, 2H).

Example 18

4 - [(3 - {[4- (4-fluorophenyl) piperazin-l-yl] carbonyl} pyridin-2-yl) oxy] benzoic acid

Analogously to the instructions for the preparation of Example 3, 46 mg (0.152 mmol) of the 2-fluoronicotinamide from Example 18A are reacted with 31.42 mg (0.227 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification via preparative HPLC, 47 mg (74% of theory) of product are obtained.

MS (ESIpos): m / z = 422 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, IH), 8.24 (dd, IH), 7.97 (d, 2H), 7.94 (dd, IH), 7.30 (dd, IH ), 7.24 (d, 2H), 7.06 (t, 2H), 6.97 (d, IH), 6.95 (dd, IH), 3.78 (t, 2H), 3.46 (m, 2H), 3.13 (m, 2H) , 3.05 (m, 2H).

Example 19

4 - {[3 - ({4- [4-chloro-3 - (trifluoromethyl) phenyl] piperazine-1-yl} carbonyl} pyridin-2-yl] oxy} benzoic acid

Analogously to the instructions for the preparation of Example 3, 80 mg (0.21 mmol) of the 2-fluoronicotinamide from Example 19A are reacted with 42.7 mg (0.31 mmol) of 4-hydroxybenzoic acid to give the corresponding ether. After purification by preparative HPLC gives 100 ^"mg (96% d. Th.) Product as a solid. MS (ESIpos): m / z = 506 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.94 (s, broad, IH), 8.25 (dd, IH), 7.97 (d, 2H), 7.94 (dd, IH), 7.51 (d, IH ), 7.30 (d, IH), 7.27 (d, IH), 7.25 (d, 2H), 7.21 (dd, IH), 3.78 (t, 2H), 3.47 (m, 2H), 3.30 (m, 2H) , 3.24 (m, 2H).

Example 20

3-Fluoro-4- {[3 - ({4- [3- (trifluoromethyl) -phenyl] -piperazine-1-yl} carbonyl} pyridin-2-yl] oxy} -benzoic acid

Analogously to the instructions for the preparation of Example 3, 40 mg (0.11 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 26.5 mg (0.17 mmol) of 3-fluoro-4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 15 mg (26% of theory) of product as a solid.

MS (ESIpos): m / z = 490 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSOd ₆ ): δ = 13.28 (s, broad, IH), 8.20 (dd, IH), 7.96 (dd, IH), 7.84 (s, IH), 7.81 (d, IH), 7.48 (t, IH), 7.44 (t, IH), 7.30 (dd, IH), 7.23 (d, IH), 7.20 (s, IH), 7.10 (d, IH), 3.82 (t, 2H), 3.47 (m, 2H), 3.33 (m, 2H), 3.27 (m, 2H).

Example 21

3-Chloro-4- {[3- ({4- [3- (trifluoromethyl) phenyl] piperazine-1-yl} carbonyl) pyridin-2-yl] oxy} -benzoic acid

Analogously to the instructions for the preparation of Example 3, 40 mg (0.113 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 29.3 mg (0.17 mmol) of 3-chloro-4-hydroxybenzoic acid to give the corresponding ether. Purification by preparative HPLC gives 18 mg (31% of theory) of product as a resin.

MS (ESIpos): m / z = 506 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 13.31 (s, broad, IH), 8.19 (dd, IH), 8.04 (dd, IH), 7.95 (dt, 2H), 7.44 (d, 2H ), 7.30 (dd, IH), 7.23 (d, IH), 7.20 (s, IH), 7.10 (d, IH), 3.82 (t, 2H), 3.51 (m, 2H), 3.36 (m, 2H) , 3.28 (m, 2H).

Example 22

3-Methoxy-4 - {[3 - ({4- [3- (trifluoromethyl) phenyl] piperazin-1-yl} carbonyl) pyridin-2-yl] oxy} -benzoic acid

Analogously to the instructions for the preparation of Example 3, 40 mg (0.113 mmol) of the 2-fluoronicotinamide from Example IA are reacted with 28.6 mg (0.17 mmol) of vannilic acid to give the corresponding ether. After purification via preparative HPLC, 12 mg (21% of theory) of product are obtained as an oil.

MS (ESIpos): m / z = 501 (M + H) ⁺ .

¹ H-NMR (400MHz, DMSOd ₆ ): δ = 13.01 (s, broad, IH), 8.12 (dd, IH), 8.08 (t, IH), 7.89 (dd, IH), 7.61 (m, IH), 7.49 (hept, IH), 7.44 (d, IH), 7.25 (m, 2H), 7.20 (s, IH), 7.11 (t, IH), 3.8 (t, 2H), 3.75 (s, 3H), 3.38 (m, 2H), 3.35 (m, 2H), 3.22 (m, 2H). B. Evaluation of physiological activity

Abbreviations:

HEPES 4- (2-Hydroxyethy) piperazine-1-ethanesulfonic acid tPA Tissue Plasminogen Activator

NaCl sodium chloride

PEG 6000 polyethylene glycol 6000

RT room temperature

The in vitro effect of the compounds according to the invention can be shown in the following assays:

1. Plasma fibrinolysis test

The identification of inhibitors of the plasminogen activator inhibitor-1 (PAI-I) of the rat and the quantification of the effectiveness of the substances described herein is carried out using a plasma-based fibrinolysis. The inhibition of the fibrinolytic system can take place either at the level of plasmin by α ₂ -antiplasmin or α ₂ -macroglobulin or at the level of the plasminogen activators by PAI-I.

The addition of human α-thrombin leads via several intermediates to form a Fibrinnetzes with three-dimensional structure. The degradation of this fibrin network is carried out by means of the serine protease plasmin, which is previously formed by the plasminogen activator tPA from the inactive proenzyme plasminogen. The activity of tPA is regulated by the plasminogen activator inhibitor-1 PAI-I. The inhibition of PAI-I leads to accelerated lysis of the fibrin network.

Test Procedure: The rat recombinant plasminogen activator inhibitor-1 (PAI-1, Molecular Innovations Inc., MI, USA) (final concentration: 8.25 nM, 50 mM HEPES, pH 6.2, 50 mM NaCl, 0.1% PEG 6000) was incubated with the substance to be tested in a concentration range of 100 μM to 10 nM or the corresponding solvent for three minutes at room temperature in a 96-well microtiter plate. Human platelet-poor plasma (Blood Donor Service German Red Cross, Hagen, Germany) is diluted 1: 3 with buffer (150 mM NaCl, 20 mM HEPES, pH 7.4). 183 μl of the plasma / buffer mixture are added per batch to the protein / substance mixture. Subsequently, 8 μl of a mixture of calcium chloride (final concentration: 10 mM), human tissue plasminogen activator (tPA, final concentration: 7.5 nM, Chromogenix, Mölndal, Sweden) and α-thrombin (final concentration: 25 nM, Kordia, Leiden, The Netherlands) were added, mixed and transferred twice each 80 ul in a 384-well microtiter plate. The formation of a fibrin clot and its subsequent lysis are monitored by absorbance measurement at a wavelength of 405 nm. The measurement of the kinetics is performed over at least 3 hours at intervals of two minutes at 37 ⁰ C (Tecan Saphire, Tecan Germany GmbH, Crailsheim, Germany).

Interpretation of data: The clot lysis time (CLT) is the time at which absorption reached half the absorbance value between maximum and minimum absorbance The determined CLT value in the absence of PAI-I is reported as "0% PAI -I activity "and defined as" 100% activity "in the presence of 8.25 nM The CLT ₅₀ value represents the concentration of test substance in which the clot lysis time was reduced by half.

Representative in vitro activity data for the compounds according to the invention are given in Table A:

Table A:

2. Selectivity comparison with other serine proteases

2.1 plasminogen activators t-PA and urokinase

Test procedure: The substances are characterized with regard to their effect on tPA (tissue plasminogen activator) and urokinase. For this purpose, the PAI-I inhibitors with human tPA (Sigma Aldrich Chemie GmbH, Taufkirchen, Germany, final concentration: 1 nM) or human urokinase (Sigma Aldrich Chemie GmbH, Taufkirchen, Germany, final concentration: 2.5 nM) in a buffer with 50 mM TRIS pH 7.5, 140 mM NaCl and 0.1% PEG 6000 incubated for 10 min at RT. The enzyme activities are measured as fluorescence increase by cleavage of specific peptide substrates (final concentration 10 μM, 444XF for tPA and 244XF for urokinase, American Diagnostica) in a SPECTRA Fluor Plus (Tecan, Männedorf, Switzerland). The highest substance concentration is 10 μM.

Evaluation: The fluorescence values achieved without substance addition are set as 100%, all other values then related to this 100%. From the percentages are under Using the GraphPad Prism Computer Program Dose-response curves and IC ₅₀ values calculated.

2.2. Coagulation factors FX, FXa. FDCass, FVIIa, FXIa and serine proteases plasmin and trypsin

Test procedure: The coagulation factors Factor X (FX), Factor Xa (FXa), Factor IXass (FIXass), Factor VIIa (FVIIa), Factor XIa (FXlA) and thrombin as well as the serine proteases plasmin and trypsin are used for the tests. The generic fluorogenic substrates are the substrates designated 1-1 100 (Boc-Ile-Glu-Gly-Arg-AMC), I-1575 (Boc-Glu (OBzl) -Ala-Arg-AMC HCl ), 1-1560 (Boc-Asp (OBzl) -Pro-Arg-AMC HCl), and I-1275 (MeOSuc-Ala-Phe-Lys-AMC TFA). These substrates are all commercially available from Bachern (Bubendorf, Switzerland). All experiments are performed in 50 millimolar (mM) Tris, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% BSA, at pH 7.4 and at room temperature. The final volume in all experiments is 100 microliter (μl) -

For each assay, 10 nM FXa with 5 μM substrate I-1100, 0.3 nM FXIa with 5 μM 1-1575, 0.1 nM trypsin with 5 μM 1-1100, 0.002 nM thrombin with 5 μM 1-1560, and 0.012 nM Plasmin spiked with 50 μM 1-1275. For the coupled assay systems, 8.8 nM FDCass or 1 pM FVIIa are mixed with 9.5 nM FXa and 50 μM substrate 1-1100, respectively. The test compounds are prepared as 10 millimolar (mM) solutions in dimethyl sulfoxide (DMSO). These 1 OmM stock solutions are first diluted 1: 5 in DMSO and then 1: 100 in the test medium. From this 20 .mu.M solution, an eight-stage dilution series is used, the respective following concentration corresponds to 1/3 of the initial concentration. 30 μl of these individual dilution mixtures are added to the 30 μl cells so that in this mixture the enzyme / substance has the highest substance concentration 10 μM, the following corresponding 3.3 μM, 1.1 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.012 μM and 0.004 Set μM. These so diluted test substances are added to the individual enzyme test systems. After a 60-minute incubation, the amidolytic activity of the enzymes is determined in a SPECTRA Fluor Plus (Tecan, Maennedorf, Switzerland) at the wavelengths 360 nm (absorbance) and 465 nm (emission).

Evaluation: The fluorescence values achieved without substance addition are set as 100%, all other values then related to this 100%. This allows experiments to be performed on different days, ^"are compared., From the percentages are calculated using the GraphPad Prism program computer dose-response curves and ICso-values. 2.3 Inhibition of serine proteases

2.3.1 Qo-antiplasmin

The serine protease inhibitor α ₂ -antiplasmin is able, in addition to α ₂ -macroglobulin, to inhibit the serine protease plasmin.

Test procedure: In a volume of ten microliters, human ct ₂ -antiplasmin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany, final concentration: 50 nM, 50 mM TrisHCl pH 7.3, 200 mM NaCl, 0.2% BSA) with the substance to be tested in a concentration range of 100 to 10 μM or the corresponding solvent for five minutes at room temperature in a 96-well microtiter plate. 20 μl of human plasmin (Merck Biosciences, Schwalbach / Taunus, Germany, final concentration: 5 nM) are added per batch to the α ₂ -antiplasmin / substance mixture and incubated for 15 minutes at 37 ° C. Subsequently, 20 μl of the fluorogenic piasmium substrate 11275 (Bachern, Weil am Rhein, Germany, final concentration: 15 μM, 50 mM TRIS pH 7.3, 200 mM NaCl, 0.02% BSA) are added. (Gain 50; 465 nm Tecan Saphire, Tecan Germany GmbH, Crailsheim, Germany;::; Absorbance 360 nm emission) after 40 minutes of incubation at a temperature of 37 ⁰ C is the fluorescence signal.

Evaluation of the data: The determined fluorescence value (emission at 465 nm) in the absence of α ₂ -antiplasmin is defined as "0% inhibition" and that in the presence of 50 nM as "100% inhibition". The IC ₅₀ value represents the concentration of test substance in which the emitted fluorescence was reduced by half.

2.3.2 ct-antitrypsin

The serine protease inhibitor oci-antitrypsin is able to inhibit the serine protease trypsin.

Test Procedure: In a volume of ten microliters, human oci-antitrypsin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 2 μM; 50 mM TrisHCl pH 7.3; 100 mM NaCl; 5 mM calcium chloride; 0.5% BSA) with the test substance in a concentration range of 100 to 10 uM or the corresponding solvent for five minutes at room temperature in a 96-well microtiter plate incubated. 20 ul human trypsin (Sigma-Aldrich, Taufkirchen, Germany; final concentration: 500 nM) are added per batch for .alpha..sub.i-antitrypsin / substance mixture and incubated for 15 minutes at 37 ⁰ C. Subsequently, 20 μl of the fluorogenic trypsin substrate Il 100 (Bachern, Weil am Rhein, Germany, final concentration: 1 μM, 50 mM TRIS pH 7.3, 200 mM NaCl, 0.02% BSA) are added. After 40- (Gain 50; 465 nm Tecan Saphire, Tecan Germany GmbH, Crailsheim, Germany;::; Absorbance 360 nm emission) minutes of incubation at a temperature of 37 ⁰ C is the fluorescence signal.

Evaluation of the data: The determined fluorescence value. (Emission at 465 nm). in the absence of oti-antitrypsin is defined as "0% inhibition" and that in the presence of 2 μM as "100% inhibition". The IC ₅₀ value represents the concentration of test substance in which the emitted fluorescence was reduced by half.

The suitability of the compounds according to the invention for the treatment of thrombotic diseases can be demonstrated in the following animal models:

The compounds of the present invention can be tested in thrombosis models in which fibrinolysis is mediated via a PAI-I dependent mechanism (see: Clozel, J Cardiovasc Pharmacol 12: 520-5 (1998); Levi, Circulation 85: 305-12 ( Biemond, Circulation 91: 1175-81 (1995); Friederich, Circulation 96: 916-21 (1997)). Furthermore, it is possible to characterize the compounds of the present invention with respect to their inhibition or reduction of PAI-I activity in vivo (compare: Crandall, BBRC 311: 904-908 (2003)).

The half-life of the compounds of the invention can be demonstrated in the following assay:

To determine the apparent half-life in vivo, the test substances are mixed in various formulating agents (e.g., plasma, ethanol, DMSO, PEG400, etc.) or mixtures thereof

Solubilizers were dissolved and administered intravenously to male Wistar rats. The applied

Doses are in the range of 0.1 to 1 mg / kg. Blood samples are taken by means of a catheter or as

Killing plasma taken at different time points over an interval of up to 26 h. The quantitative determination of the substances in the test samples is carried out in plasma on calibration samples which are adjusted in plasma. Proteins contained in the plasma are removed by precipitation with acetonitrile. Subsequently, the samples are analyzed by HPLC on a 2300 HTLC

Plant (Cohesive Technologies, Franklin, MA, USA) using reversed phase

Columns separated. The HPLC system is connected to a triple via a Turbo Ion Spray Interface

Quadropole mass spectrometer API 3000 (Applied Biosystems, Darmstadt, Germany) coupled. The evaluation of the plasma concentration time course is carried out using a validated kinetics evaluation program. C. Embodiments of Pharmaceutical Compositions

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

Tablet:

Composition:

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

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

production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules, after drying with the magnesium stearate for 5 min. mixed. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

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

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

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels swirling is stirred for about 6 hours. Intravenous solution:

Composition:

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

production:

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

Claims

claims

1. Compound of the formula

in which

X for a group of the formula

stands,

in which

the point of attachment to the carbonyl group is,

# is the point of attachment to the oxygen atom,

and

R ² , R ³ , R ⁴ and R ⁵ independently of one another are hydrogen, halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, C 1 -C 6 -alkylamino, C 1 -C ₄ Alkoxycarbonyl or Ci-Cβ-alkylaminocarbonyl,

is phenyl or pyridyl,

wherein phenyl and pyridyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, Cyaήo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C _r C ₆ alkyl, Ci -Cβ alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl and CpC ₆ -alkylaminocarbonyl,

n is a number 0, 1, 2 or 3,

R ^{1 is} phenyl or 5- or 6-membered heteroaryl,

wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ₆ alkyl, Ci -C ₆ -alkoxy, C ₆ -Alkylaniino, Ci-C ₆ alkylcarbonyl, Ci-C ₆ alkoxycarbonyl, C) -C ₆ - alkylaminocarbonyl, and Ci-Cβ-alkylsulfonylamino,

or one of its salts, its solvates or the solvates of its salts.

2. A compound according to claim 1, characterized in that

X for a group of the formula

stands,

in which

the point of attachment to the carbonyl group is,

# is the point of attachment to the oxygen atom,

and

R ^2, R ^3, R ⁴ and R ⁵ independently represent hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C _r C ₄ alkyl, Ci-C ₄ alkoxy, C _r C ₆ - alkylamino, C C ₄ alkoxycarbonyl or C 1 -C ₆ -alkylaminocarbonyl, Y is phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C _ö alkylamino, C] _-C6 alkylcarbonyl, C] _-C6 alkoxycarbonyl and CpC ₆ - alkylaminocarbonyl,

n stands for a number 0,

R ^{1 is} phenyl,

where phenyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkyl, QC ₆ - -alkoxy, C _r C ₆ alkylamino, Ci-Q-alkylcarbonyl, Ci-C ₆ alkoxycarbonyl, C _r C ₆ - alkylaminocarbonyl and Ci-C ₆ alkylsulfonylamino,

or one of its salts, its solvates or the solvates of its salts.

3. A compound according to claim 1 or 2, characterized in that

X for a group of the formula

stands,

in which

the point of attachment to the carbonyl group is,

the point of attachment to the oxygen atom is,

and R ² , R ³ , R ⁴ and R ^{5 are} hydrogen,

Y is phenyl,

where phenyl can be substituted by 1 to 2 substituents, where the substituents are selected independently of one another from the group consisting of halogen and C 1 -C ₄ -alkoxy,

n stands for a number 0,

R ^{1 is} phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the

Substituents independently of one another are selected from the group consisting of halogen, cyano, trifluoromethyl, methyl, methoxy and methylsulfonylamino,

or one of its salts, its solvates or the solvates of its salts.

4. A process for preparing a compound of formula (I) according to claim 1 or one of its salts, solvates or the solvates of their salts, characterized in that a compound of formula

in which,

X and R ^{1 have} the meaning given in claim 1,

with a compound of the formula

H _U , O>. H JrXγl .OH _(ffl) , °

in which

X and n have the meaning given in claim 1, is implemented.

5. A compound according to any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

6. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases

7. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of thrombotic diseases

8. A medicament containing at least one compound according to any one of claims 1 to 3 in combination with another active ingredient.

9. A pharmaceutical composition containing at least one compound according to any one of claims 1 to 3 in combination with at least one inert, non-toxic, pharmaceutically suitable excipient.

10. Medicament according to claim 8 or 9 for the treatment and / or prophylaxis of thrombotic diseases.

11. A method for controlling thrombotic diseases in humans and animals by administering a pharmaceutically effective amount of at least one compound according to any one of claims 1 to 3 or a drug according to any one of claims 8 to 10.