CA2615888A1

CA2615888A1 - Substituted pyridocarboxamides as inhibitors of plasminogen activator inhibitor 1 (pai-1)

Info

Publication number: CA2615888A1
Application number: CA002615888A
Authority: CA
Inventors: Stephan Siegel; Britta-Nicole Froehlen; Christoph Gerdes; Mark Jean Gnoth; Julia Strassburger; Andreas Wilmen
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 2005-07-22
Filing date: 2006-07-20
Publication date: 2007-03-15
Also published as: EP1910295A1; DE102005034262A1; JP2009502756A; WO2007028456A1

Abstract

The invention relates to substituted pyridocarboxamides, to a process for preparing them and to their use for producing medicaments for the treatment and/or prophylaxis of diseases in humans and animals, particularly of thrombotic disorders.

Description

BHC 05 1 076-Foreign Countries GH/wa/XP

Substituted pyridinecarboxamides II

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

Plasminogen activator inhibitor-I (PAI-1) is the most important regulatory component of the plasminogen-plasmin system. The fibrinolytic system includes the proenzyme plasminogen which is converted by the two plasminogen activators tPA and uPA into the active enzyme plasmin. PAI-I is the main physiological inhibitor of both tissue-type plasminogen activator (tPA) and of urokinase-type plasminogen activator (uPA). One of the main tasks of plasmin in the fibrinolytic system is to degrade fibrin at the site of the vascular injury. The fibrinolytic system is, however, not only responsible for removing fibrin from the circulation, but is also involved in various other processes including ovulation, embryogenesis, proliferation of the intima, angiogenesis, tumorigenesis and atherosclerosis.
Elevated plasma PAI-I levels are associated with a number of disorders and conditions which bring about an impairment of the fibrinolytic system. Thus, for example, elevated plasma PAI-I levels are connected with thrombotic disorders which are characterized for example by the development of a thrombus which locally impairs the vascular blood flow, or which becomes detached and embolizes in order to block the 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 a faster rate of endogenous fibrinolysis and perfusion (Biemond, Circulation, 91, 1 175 (1995); Levi, Circulation, 85, 305 (1992)).

One object of the present invention is therefore to provide novel PAI-1 inhibitors for the treatment of thrombotic disorders 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 pyridinecarboxamides as corticotropin releasing factor (CRF) antagonists for the treatment of disorders of the central nervous system and WO 03/061387 discloses methods for controlling algae by use of substituted pyridinecarboxamides.

The present invention relates to compounds of the formula BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 O

RN XO n rOH (I), H
O
in which X is a group of the formula #

or ),] #
R2 Ra where * is the point of attachment to the carbonyl group, # is the point of attachment to the oxygen atom, and R2 , R3, R4 and R5 are independently of one another hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, Ci-C4-alkyl, CI-C4-alkoxy, Cl-C6-alkylamino, CI -C4-alkoxycarbonyl or Ci-C6-alkylaininocarbonyl, Y is phenyl or pyridyl, where phenyl and pyridyl may be substituted by I to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, CI-C6-alkyl, Cl-C6-alkoxy, Ci-C6-alkylamino, Cl-C6-alkylcarbonyl, Ci-C6-alkoxycarbonyl and CI-alkylaminocarbonyl, n is a number 0, 1, 2 or 3, R' is phenyl BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, CI-C6-alkyl, CI-C6-alkoxy, Cl-C6-alkylamino, Cl-C6-alkylcarbonyl, Cl-C6-alkoxycarbonyl, Ci-C6-alkylaminocarbonyl and Cl-C6-alkylsulphonylamino, and the salts, hydrates, hydrates of the salts and solvates thereof.

Compounds according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds encompassed by the formula (I) of the formulae mentioned below and the salts, solvates and solvates of the salts thereof, as well as the compounds encompassed by the formula (I) and mentioned below as exemplary embodiments, and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned below are not already salts, solvates and solvates of the salts.

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

Where the compounds of the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts preferred for the purposes of the present invention are physiologically acceptable salts of the compounds of the invention. However, salts which are themselves unsuitable for pharmaceutical applications but can be used for example for isolating or purifying the compounds of the invention are also encompassed.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the compounds of the invention also include salts of conventional bases such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates refer for the purposes of the invention to those forms of the compounds of the invention which form a complex in the solid or liquid state through coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination takes place with water.

For the purposes of the present invention, the substituents have, unless specified otherwise, the following meaning:

Alkyl per se and "alk" and "alkyl" in alkoxy, alkylamino, alkylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl and alkylsulphonylamino stand for a linear or branched alkyl radical having usually I to 6, preferably I to 4, particularly preferably I to 3, carbon atoms, by way of example, and preferably for methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy stands by way of example and preferably for methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino stands for an alkylamino radical having one or two alkyl substituents (chosen independently of one another), by way of example and preferably, for methylainino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-inethyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino. Cl-C4-Alkylamino stands for example for a monoalkylarnino radical having I to 4 carbon atoms or for a dialkylamino radical having I to 4 carbon atoms in each alkyl substituent.

Alkylcarbonyl stands by way of example and preferably for methylcarbonyl, ethylcarbonyl, n-propyl-carbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.
Alkylaminocarbonyl stands for an alkylaminocarbonyl radical having one or two alkyl substituents (chosen independently of one another). Cl-C3-Alkylaminocarbonyl stands for example for a monoalkylaminocarbonyl radical having I to 3 carbon atoms or for a dialkylaminocarbonyl radical having I to 3 carbon atoms in each alkyl substituent. Mention may be made, by way of example and BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 -5-preferably, of: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-buty laminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, NN-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl stands by way of example and preferably for methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl,tert-butoxycarbonyl,n-pentoxycarbonyland n-hexoxycarbonyl.
Alkylsulphonylamino stands by way of example and preferably for methylsulphonylamino, ethyl-sulphonylamino, n-propylsulphonylamino, isopropylsulphonylamino, tert-butylsulphonylamino, n-pentylsulphonylamino and n-hexylsulphonylamino.

Heteroaryl stands for an aromatic, monocyclic radical usually having 5 or 6 ring atoms and up to 4, preferably up to 3, heteroatoms from the series S, 0 and N, by way of example and preferably, for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl and pyridazinyl.

Halogen stands for fluorine, chlorine, bromine and iodine. In the formula of the group standing for X, the end point of the line besides which there is respectively a * or # does not stand for a carbon atom or a CH2 group but forms part of the bond to the carbonyl group or to the oxygen atom to which X is bonded.

If radicals in the compounds of the invention are substituted, the radicals may, unless specified otherwise, be substituted one or more times, identically or differently.
Substitution by up to three identical or different substituents is preferred. Substitution by one substituent is very particularly preferred.

Preference is given to compounds of the formula (I) in which X is a group of the formula BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 #

N #
or where * is the point of attachment to the carbonyl group, # is the point of attachment to the oxygen atom, and R2, R3, R4 and R5 are independently of one another hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, CI-C4-alkyl, Cl-C4-alkoxy, Ci-C6-alkylamino, CI -C4-alkoxycarbonyl or Cl-C6-alkylaminocarbonyl, Y is phenyl, where phenyl may be substituted by I to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluorornethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-alkylamino, Ci-C6-alkylcarbonyl, Ci-C6-alkoxycarbonyl and CI-C6-alkylaminocarbonyl, n is a number 0 or 1, R' is phenyl, where phenyl may be substituted by I to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, liydroxycarbonyl, aminocarbonyl, Ci-C6-alkyl, CI-C6-alkoxy, Ci-C6-alkylamino, CI-C6-alkylcarbonyl, Cl-C6-alkoxycarbonyl, CI-C6-alkylaminocarbonyl and Cl-C6-alkylsulphonylamino, and the salts, hydrates, hydrates of the salts and solvates thereof.

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 Preference is also given to compounds of the formula (I) in which X is a group of the formula #

J * ~ #
or R2 Ra N

where * is the point of attacliment to the carbonyl group, # is the point of attachment to the oxygen atom, and R2 , R3, R4 and Rs are hydrogen, Y is phenyl, where phenyl may be substituted by I to 2 substituents, where the substituents are selected independently of one another from the group consisting of halogen and Ci-Ca-alkoxy, n is a number 0 or l, R' is phenyl, where phenyl may be substituted by I to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, methyl, methoxy and methylsulphonylamino, and the salts, hydrates, hydrates of the salts and solvates thereof.
Preference is also given to compounds of the formula (I) in which X is a group of the formula BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 #

* N

where * is the point of attachment to the carbonyl group, # is the point of attachment to the oxygen atom, and R2 and R3 are hydrogen.

Preference is also given to compounds of the formula (I) in which R2 and R3 are hydrogen.
Preference is also given to compounds of the formula (I) in which R4 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 (1) in which R' is phenyl, where phenyl is substituted once by trifluoromethyl.

The present invention further relates to a process for preparing the compounds of the formula (I), characterized in that compounds of the formula RN X--~ F
H

in which X and R' have the meaning indicated above, are reacted with compounds of the formula BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 O OH
N' ~Y " (III), O
in which X and n have the meaning indicated above.

The reaction generally takes place in inert solvents in the presence of a base, preferably in a temperature range from room temperature to reflux of the solvent under atmospheric pressure.
Examples of inert solvents are ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulphoxide or acetonitrile, with preference for dimethyl sulphoxide.

Examples of bases are alcoholates such as sodium or potassium methanolate, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis(trimethylsilyl)amide or lithium diisopropylamide, or organometallic compounds such as butyllithiuin or phenyllithium, or other bases such as sodium hydride or DBU, with preference for sodium hydride.

The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula R~NH (IV), in which R' has the meaning indicated above, with compounds of the formula O
HAX1~1 F (V), in which BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 X has the meaning indicated above.

The reaction generally takes place in inert solvents, in the presence of a dehydrating reagent, where appropriate in the presence of a base, preferably in a temperature range from -30 C to 50 C under atmospheric pressure.

Examples of inert solvents are halohydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to employ mixtures of the solvents. Dichloromethane or dimethylformamide is particularly preferred.

Examples of bases are alkali metal carbonates such as, for example, sodium or potassium carbonate, or bicarbonates, or organic bases such as trialkylamines, e.g. triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Examples of suitable dehydrating reagents in this connection are carbodiimides such as, for example, N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide, N-(3-dimethyl-aminoisopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide -N'-propyloxymethylpolystyrene (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-l-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride or O-(benzotriazol-l-yl)-N,N,NN'-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-(benzotriazol-1-yl)-N,N,N;N'-tetramethyluronium tetrafluoroborate (TBTU) or O-(7-azabenzotriazol-l-yl)-N,N,N;N'-tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), or benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), or N-hydroxysuccinimide, or mixtures thereof, with bases.

The condensation is preferably carried out with TBTU in the presence of dilsopropylethylamine.

The compounds of the formulae (III), (IV) and (V) are known per se to the skilled person or can be prepared by conventional processes known from the literature.

The preparation of the compounds of the invention can be made clear by the following synthesis BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 schemes.

Scheme 1:

O F NHz F F ~ F \
HO ~ \ N + I \ TBTU F O F HO cooH F / O O
DIEZ- CH CI N NaH, DMSO COOH
z z H N N
F- -F / H I ....J
Scheme 2:

O NHz F F
' \ F F
HO F TBTUF O HO F
COOH
I
/ N / DIEA \ N \ F --:- \~ 0 CHzCIz H ~ NaH, DMSO H~
F /N
F F COOH

The compounds of the invention show a valuable range of pharmacological and pharmacokinetic effects which could not have been predicted.

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 of the invention can be explained by their action as PAI-1 inhibitors.

The present invention further relates to the use of the compounds of the invention for the treatment and/or prophylaxis of disorders, preferably of thrombotic disorders.

The compounds of the invention are suitable for the prophylaxis and/or treatment of thrombotic disorders such as, for example, venous and arterial thromboses, pulmonary thromboses, cerebral thromboses, thromboembolism and deep vein thromboses, or coronary heart diseases, cardiac fibrilation, pulmonary fibrosis, cystic fibrosis, thromboembolic complications, or stroke such as, for example, thrombotic stroke and thromboembolic stroke, or transient ischemic attacks, reocclusion and restenosis following coronary procedures (reocclusion and restenosis following percutaneous coronary procedures, reocclusion and restenosis following coronary bypass operations), disseminated intravascular coagulation, or of surgical operations sucli as, for example, pulmonary embolisms, stroke, vascular surgery, vessel replacement, stent patency, organ, tissue and cell implementation and BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 transplantation, or cardiovascular disorders such as, for example, myocardial infarction, atherosclerotic plaque formation, cardiac infarction, stable angina pectoris and unstable angina pectoris, or chronic obstructive lung disease, renal fibrosis, polycystic ovary syndrome, Alzheimer's disease, osteolysis induced by oestrogen deficiency, diabetes, obesity, chronic periodontitis, lymphomas, disorders connected with accumulation of extracellular matrix, inflammatory disorders such as, for example, asthma, septic shock, renal disorders, adiposity, insulin resistance, disorders connected with angiogenesis, or cancer such as, for example, leukaemias, malignant tumours or vascular damage with infections and disorders associated with elevated uPA
levels such as breast cancer and ovarian cancer.

The compounds of the invention can further be employed for supporting thrombolytic therapy, for influencing wound healing, in the prevention and treatment of atherosclerotic vascular disorders such as, for example, restenosis, coronary heart diseases, cerebral ischaemias and peripheral arterial occlusive diseases, of heart failure, of high blood pressure, of inflammatory disorders such as, for example, asthma, inflammatory lung disorders, glomerulonephritis, inflammatory bowel disorders and rheumatic disorders of the locomotor system, of degenerative disorders such as, for example, neurodegenerative disorders and osteoporosis.

The compounds of the present invention can equally be employed for the treatment of blood and blood products which are used for dialysis and storage of blood in liquid phase, in particular for platelet aggregation ex vivo. The present compounds can also be added to human plasma during chemical blood analysis under hospital conditions to determine fibrinolytic capacity.

The compounds of the present invention can also be used in combination with prothrombolytic, fibrinolytic and anticoagulant agents.

The present invention further relates to the use of the compounds of the invention for the prophylaxis and/or treatment of disorders, especially of the aforementioned pathological conditions.

The present invention further relates to the use of the coinpounds of the invention for the manufacture of a medicament for the prophylaxis and/or treatment of disorders, especially of the aforementioned pathological conditions.

The present invention further relates to a method for the prophylaxis and/or treatment of disorders, especially of the aforementioned disorders, by using an amount having cardiovascular activity of the compound of the invention.

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 The present invention further relates to medicaments comprising a compound of the invention in combination with one or more further active ingredients, in particular for the prophylaxis and/or treatment of the aforementioned disorders.

The compounds of the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable way such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route or as implant or stent.

The compounds of the invention can be administered in administration forms suitable for these administration routes.

Suitable for oral administration are administration forms which function according to the prior art and deliver the compounds of the invention rapidly and/or in modified fashion, and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound of the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g.
intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions, sprays;
tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

The compounds of the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 These excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g.
antioxidants such as, for example, ascorbic acid), colours (e.g. inorganic pigments such as, for example, iron oxides) and masking flavours and/or odours.

The present invention further relates to medicaments which comprise at least one compound of the invention, preferably together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use thereof for the aforementioned purposes.

It has generally proved advantageous in both human and veterinary medicine to administer the compound of the invention in total amounts of about 0.01 to about 700, preferably 0.01 to 100, mg/kg of body weight every 24 hours, where appropriate in the form of a plurality of single doses, to achieve the desired results. A single dose comprises the compound of the invention preferably in amounts of about 0.1 to about 80, in particular 0.1 to 30, mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from the stated amounts, in particular as a function of the body weight, route of administration, individual response to the active ingredient, nature of the preparation and time or interval over which administration takes place. Thus, it may be sufficient in some cases to make do with less than the aforementioned minimuin amount, whereas in other cases the stated upper limit must be exceeded. It may in the event of administration of larger amounts be advisable to divide these into a plurality of individual doses over the day.

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

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 A. Examples Abbreviations:
conc. Concentrated DCI Direct chemical ionization (in MS) DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl sulphoxide EA Ethyl acetate (acetic acid ethyl ester) El Electron impact ionization (in MS) ESI Electrospray ionization (in MS) h Hour HATU O-(7-Azabenzotriazol-l-yl)-NN,N;N'-tetramethyluronium hexafluorophosphate TBTU O-(Benzotriazol-l-yl)-N,N,N;N'-tetramethyluronium tetrafluoroborate HOBt 1-Hydroxy- I H-benzotriazole x H20 HPLC High pressure, high performance liquid chromatography LC-MS Coupled liquid chromatography-mass spectroscopy LDA Lithium diisopropylamide min Minutes M.P. Melting point MPLC Medium pressure, medium performance liquid chromatography MS Mass spectroscopy NMR Nuclear magnetic resonance spectroscopy org. Organic quant. Quantitative RF Reflux Rf Retention factor (in TLC) RP-HPLC Reverse phase HPLC
RT Room temperature BHC 05 1 076-Foreign CountriescA 02615888 2008-01-18 Rt Retention time (in HPLC) sat. Saturated TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 Startint! compounds Example lA
2-Fluoro-N-[4-(trifluoromethyl)phenyl]nicotinamide F
F
F F
~
H N

300 mg (2.06 mmol) of 2-fluoronicotinic acid are introduced into 10 ml of dichloromethane in a round-bottom flask, and 993 mg (3.09 mmol) of TBTU are added. Dropwise addition of 0.539 ml (3.09 mmol) of diisopropylethylamine is followed by stirring at RT for 10 min, and then 369 mg (2.27 mmol) of 4-trifluoromethylaniline are added. The mixture is stirred at RT for 16 h, the solvent is completely removed and the residue is purified by preparative HPLC. 428 mg (73% of theory) of product are isolated as solid.

MS (ESIpos): m/z = 285 (M+H)+.

'H-NMR (400MHz, DMSO-d6): 6 = 10.93 (s, 1 H), 8.43 (d, 1 H), 8.29 (t, 1 H), 7.92 (d, 2H), 7.75 (d, 2H), 7.54(t, 1 H).

Example 2A

2-Fluoro-N-(4-fluorophenyl)nicotinamide F /
( O F
\ H N

300 mg (2.06 mmol) of 2-fluoronicotinic acid are reacted with 254.6 mg (2.27 mmol) of 4-fluoroaniline in analogy to the metliod for preparing Example lA to give the corresponding amide.
Purification by preparative HPLC results in 419 mg (87% of theory) of product.

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 MS (TOF): m/z = 234 (M)+.

'H-NMR (400MHz, DMSO-d6): 6 =10.61 (s, IH), 8.41 (d, IH), 8.25 (t, I H), 7.77 (dd, 2H), 7.53 (t, 1 H), 7.22 (t, 2H).

Example 3A

2-Fluoro-N-phenylnicotinamide O F
~ N

300 mg (2.06 mmol) of 2-fluoronicotinic acid are reacted with 213.4 mg (2.27 mmol) of aniline in analogy to the method for preparing Example I A to give the corresponding amide. Purification by preparative HPLC results in 411 mg (92% of theory) of product as solid.

MS (DCI, NH3): m/z = 234 (M+NH4)+

'H-NMR (400MHz, DMSO-d6): b= 10.55 (s, IH), 8.40 (d, IH), 8.25 (t, IH), 7.70 (d, 2H), 7.52 (t, 1 H), 7.37 (t, 2H), 7.13 (t, 1 H).

Example 4A
2-Fluoro-N-(4-fluorophenyl)iso-nicotinamide F \~ ~ O F

H
N

150 mg (1.04 mmol) of 2-fluoro-4-pyridinecarboxylic acid are introduced into 10 ml of dichloromethane in a round-bottom flask, and 502 mg (1.56 mmol) of TBTU are added. Dropwise addition of 0.272 ml (1.56 mmol) of diisopropylethylamine is followed by stirring at RT for 10 min, and then 175.4 mg (1.56 mmol) of 4-fluoroaniline are added. The mixture is stirred at RT for 16 h, the BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 solvent is completely removed and the residue is purified by preparative HPLC.
196 mg (79% of theory) of product are isolated as solid.

MS (DCI, NH3): m/z = 251 (M+NH4)+

1H-NMR (400MHz, DMSO-d6): b= 10.62 (s, 1H), 8.45 (d, 1H), 7.82 (d, 1H), 7.78 (dd, 2H), 7.66 (s, 1H), 7.24 (t, 2H).

Example 5A
2-Fluoro-N-[3-(trifluoromethyl)phenyl]isonicotinamide aH O
F F \ F
F

150 mg (1.04 mmol) of 2-fluoro-4-pyridinecarboxylic acid are reacted with 256.9 mg (1.56 mmol) of 3-trifluoromethylaniline in analogy to the method for preparing Example 6A to give the corresponding amide. Purification by preparative HPLC results in 202 mg (68% of theory) of product.

MS (ESlpos): m/z = 285 (M+H)-'.

'H-NMR (300MHz, DMSO-d6): 8= 10.82 (s, 1 H), 8.47 (d, 1 H), 8.22 (s, 1 H), 8.03 (d, 1 H), 7.83 (m, 1 H), 7.68 (s, 1 H), 7.64 (t, 1 H), 7.53 (d, 1 H).

Example 6A
2-Fluoro-N-phenylisonicotinamide O
H I
N ---' F
i N

1000 mg (7.09 mmol) of 2-fluoro-4-pyridinecarboxylic acid are reacted with 792 mg (8.51 mmol) of aniline in analogy to the method for preparing Example 6A to give the corresponding amide. The BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 crude batch is mixed with saturated citric acid solution and extracted three times with methylene chloride. The combined organic phases are washed once with saturated sodium chloride solution and the solvent is completely removed. This results in 1.36 g(88% of theory) of product.

MS (ESlpos): m/z = 217 (M+H)+.

'H-NMR (300MHz, DMSO-d6): b= 10.53 (s, 1H), 8.44 (d, 1H), 7.83 (dt, 1H), 7.76 (d, 2H), 7.66 (s, 1 H), 7.39 (t, 2H), 7.16 (t, 1 H).

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 Exemplary embodiments Example 1 4-{[3-({[4-(Trifluoromethyl)phenyl]amino}carbonyl)pyridin-2-yl]oxy}benzoic acid O

F e OH
F ~
~ O O ~

N N
H

46.65 mg (0.34 mmol) of 4-hydroxybenzoic acid are introduced into 4 ml of dry DMSO, and 28.15 mg (0.7 mmol) of sodium hydride (60%) are added. After stirring at RT under argon for 10 min, 80 mg (0.28 mmol) of the fluoronicotinamide froin Example lA are added. The mixture is heated at 80 C for I h and at 120 C for a further 16 h. About I ml of water is cautiously added and the crude product is purified by preparative HPLC. 23 mg (19% of theory) of product are isolated as solid.

MS (ESIpos): m/z = 403 (M+H)+.

'H-NMR (300MHz, DMSO-d6): b= 11.7 (s, 1 H), 7.7 (m, 4H), 7.6 (d, 1 H), 7.45 (d, 2H), 7.3 (d, 1 H), 7.1 (d, 2H), 6.1 (t, 1 H).

Example 2 4-[(3-{[(4-Fluorophenyl)amino]carbonyl}pyridin-2-yl)oxy]benzoic acid ~ \ OH
/
O O
N N
H

2.89 g (12.34 mmol) of the 2-fluoronicotinamide from Example 2A are reacted with 2.05 g(14.81 BHC 05 1 076-Forei~n Countries CA 02615888 2008-01-18 mmol) of 4-hydroxybenzoic acid and 1.234 g (30.85 mmol) of sodium hydride (60%) in analogy to the method for preparing Example I to give the corresponding ether derivative in 100 ml of N-methylpyrrolidone. Recrystallization from methylene chloride results in 4.09 g (94% of theory) of product as solid.

MS (ESlpos): m/z = 353 (M+H)+.

'H-NMR (300MHz, DMSO-d6): 8= 12.92 (s, broad, 1 H), 10.66 (s, 1 H), 8.28 (dd, I H), 8.14 (dd, 1 H), 7.98 (d, 2H), 7.73 (dd, 2H), 7.32 (m, 3H), 7.20 (t, 2H).

Example 3 4-{[3-(Anilinocarbonyl)pyridin-2-yl]oxy}benzoic acid j)LOH
o o '', N N
H

80 mg (0.37 mmol) of the 2-fluoronicotinamide from Example 3A are reacted with 61.32 mg (0.44 mmol) of 4-hydroxybenzoic acid and 37 mg (0.93 mmol) of sodium hydride (60%) in analogy to the method for preparing Example I to give the corresponding ether derivative in DMSO (4 ml).
Purification by preparative HPLC results in 23.5 mg (19% of theory) of product.

MS (ESIpos): m/z = 335 (M+H)+.

'H-NMR (300MHz, DMSO-d6): 8= 10.47 (s, 1 H), 8.24 (d, 1 H), 8.10 (d, 1 H), 8.86 (d, 2H), 7.72 (d, 2H), 7.35 (d, 2H), 7.27 (m, 1 H), 7.04-7.13 (m, 3H).

Example 4 4-[(4-{[(4-(Fluorophenyl)amino]carbonyl}pyridin-2-yl)oxy]benzoic acid BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 F
O
O
H
\ N / OH
O

70.77 mg (0.512 mmol) of 4-hydroxybenzoic acid are introduced into 4 ml of dry DMSO, and 42.7 mg (1.07 mmol) of sodium hydride (60%) are added. After stirring at RT under argon for 10 min, 100 mg (0.43 mmol) of the isonicotinamide from Example 4A are added. The mixture is heated at 130 C for 16 h and, after cooling, neutralized with IN hydrochloric acid. The crude product is purified by preparative HPLC. 41 mg (27% of theory) of product are isolated as solid.

MS (ESIpos): m/z = 353 (M+H)+.

'H-NMR (300MHz, DMSO-d6): b= 12.88 (s, broad, I H), 10.55 (d, I H), 8.37 (d, 1 H), 8.0 (d, 2H), 7.79 (dd, 2H), 7.66 (dd, 1 H), 7.59 (s, 1 H), 7.27 (d, 2H), 7.20 (d, 2H).

Example 5 4-{[4-({[3-(Trifluoromethyl)phenyl]amino}carbonyl)pyridin-2-yl]oxy}benzoic acid ~ O
F I
F ~ H I O 'ClyOH
F ~ O

100 mg (0.352 mmol) of the isonicotinamide from Exainple 5A are reacted with 58.3 mg (0.422 mmol) of 4-hydroxybenzoic acid and 35.2 mg (0.88 mmol) of sodiuin hydride (60%) in analogy to the method for preparing Example I to give the corresponding ether derivative in 4 ml DMSO. Purification by preparative HPLC results in 91 mg (62% of theory) of product.

MS (ESIpos): m/z = 403 (M+H)+.

' H-NMR (300MHz, DMSO-d6): b= 12.88 (s, broad, I H), 10.79 (s, 1 H), 8.39 (d, 1 H), 8.24 (s, 1 H), 8.0 (m, 3H), 7.61-7.68 (m, 3H), 7.51 (d, IH), 7.27 (d, 2H).

Example 6 BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 (4-{ [4-(Anilinocarbonyl)pyridin-2-yl]oxy}-3-fluorophenyl)acetic acid H OH

N
37 mg (0.169 mmol) of the isonicotinamide from Example 6A are reacted with 34.5 mg (0.203 mmol) of 3-fluoro-4-hydroxyphenylacetic acid and 16.9 mg (0.42 mmol) of sodium hydride (60%) in analogy to the method for preparing Example I to give the corresponding ether derivative in 4m1 DSMO.
Purification by preparative HPLC results in 6 mg (9% of theory) of product.

MS (ESIneg): m/z = 365 (M-H)+.

'H-NMR (300MHz, DMSO-d6): b= 10.53 (s, I H), 8.28 (d, 1 H), 7.78 (d, 2H), 7.56 (m, 2H), 7.38 (t, 2H), 7.08-7.20 (m, 3H), 7.00 (d, 1 H), 3.17 (s, 2H).

Example 7 4-{[4-(4-Anilinocarbonyl)pyridin-2-yl]oxy}benzoic acid a O H O

if ICDY N OH

O
37 mg (0.169 mmol) of the isonicotinamide from Example 6A are reacted with 28 mg (0.203 mmol) of 4-hydroxybenzoic acid and 16.9 mg (0.42 mmol) of sodium hydride (60%) in analogy to the method for preparing Example 1 to give the corresponding ether derivative in 4 ml DSMO. Purification by preparative HPLC results in 39 mg (69% of theory) of product.

MS (ESIpos): m/z = 335 (M+H)+.

'H-NMR (400MHz, DMSO-d6): 6 = 12.93 (s, broad, 1 H), 10.52 (s, IH), 8.37 (d, 1 H), 8.01 (d, 2H), 7.77 (d, 2H), 7.65 (dd, 1 H), 7.60 (s, 1 H), 7.39 (t, 2H), 7.27 (d, 2H), 7.15 (t, 1 H).

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 B. Assessment of the physiolo$!ical activity Abbreviations:

HEPES 4-(2-Hydroxyethyl)piperazin-l-ethansulphonic acid tPA Tissue plasminogen activator NaCI Sodium chloride PEG 6000 Polyethylene glycol 6000 RT Room temperature The in vitro effect of the compounds of the invention can be shown in the following assays:
1. Plasma fibrinolysis assay Identification of inhibitors of plasminogen activator inhibitor-1 (PAI-1) in the rat, and quantification of the activity of the substances described herein, takes place with the aid of a plasma-based fibrinolysis assay. Inhibition of the fibrinolytic system can take place either at the level of plasmin by a2-antiplasmin or az-macroglobulin or at the level of the plasminogen activators by PAI-1.

Addition of human a-thrombin leads through several intermediate stages to the development of a fibrin network with a three-dimensional structure. This fibrin network is broken down by the serine protease plasmin which is formed previously by the plasminogen activator tPA
from the inactive proenzyme plasminogen. The activity of tPA is controlled by the plasminogen activator inhibitor-l PAI-1. Inhibition of PAI-1 leads to an increased rate of lysis of the fibrin network.

Assay procedure: The recombinant rat plasminogen activator inhibitor 1(PAI-1;
Molecular Innovations Inc., MI, USA) (final concentration: 8.25 nM; 50 mM HEPES, pH 6.2;
50 mM NaCI;
0.1% PEG 6000) is incubated in a volume of 12 l with the substance to be tested in a concentration range from 100 M to 10 nM or the appropriate solvent in a 96-well microtiter plate at room temperature for 3 minutes. Human platelet-poor plasma (Blutspendedienst Deutsches Rotes Kreuz, Hagen, Germany) is diluted in the ratio 1:3 with buffer (150 mM NaCI; 20 mM
HEPES, pH 7.4). 183 l of the plasma/buffer mixture are added per batch to the protein/substance mixture. Then 8 1 of a mixture of calcium chloride (final concentration: 10 mM), human tissue plasminogen activator (tPA;
final concentration: 7.5 nM; Chromogenix, M6lndal, Sweden) and a-thrombin (final concentration:
nM; Kordia, Leiden, Netherlands) are added and thoroughly mixed, and two 80 l portions are BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 transferred into a 384-well microtiter plate. Formation of a fibrin clot and its subsequent lysis are followed by absorption measurement at a wavelength of 405 nm. The kinetics are measured over at least 3 hours at intervals of two minutes at 37 C (Tecan Saphire, Tecan Germany GmbH, Crailsheim, Germany).

Analysis of the data: The clot lysis time (CLT) is the time at which the absorption has reached half the value of the absorption between maximum and minimum absorption. The CLT value found in the absence of PAI-1 is defined as "0% PAI-1 activity" and that in the presence of 8.25 nM is defined as "100% activity". The CLT50 value represents the concentration of test substance with which the clot lysis time has been reduced by one half.

2. Selectivity comparison with other serine proteases 2.1 Plasminogen activators t-PA and urokinase Assay procedure: The substances are characterized in relation to their effect on tPA (tissue plasminogen activator) and urokinase. For this purpose, the PAI-1 inhibitors are incubated 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 NaCI and 0.1% PEG 6000 at RT for 10 min.
The enzymic activities are measured as the increase in fluorescence owing to cleavage of specific peptide substrates (final concentration 10 M; 444XF for tPA and 244XF for urokinase; American Diagnostica) in a SPECTRAFIuor Plus (Tecan, Mannedorf, Switzerland). The highest substance concentration is 10 M.

Analysis: The fluorescence values attained without addition of substance are set equal to 100%, and all other values are then related to this 100%. Dose-activity plots and IC50 values are calculated from the percentages using the GraphPad Prism computer program.

2.2. Coagulation factors FX, FXa, FIXa13 FVIIa FXIa and serine proteases plasmin and trypsin Assay procedure: The coagulation factors factor X (FX), factor Xa (FXa), factor IXa(3 (FIXa(3), factor VIIa (FVIIa), factor XIa (FXIa) and thrombin, and the serine proteases plasmin and trypsin are used for the tests. The generic fluorogenic substrates are the substrates designated I-1100 (Boc-Ile-Glu-Gly-Arg-AMC), 1-1575 (Boc-Glu(OBzl)-Ala-Arg-AMC HCI), 1-1560 (Boc-Asp(OBzl)-Pro-Arg-AMC
HCI), and 1-1275 (MeOSuc-Ala-Phe-Lys-AMC TFA). These substrates can all be obtained from BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 Bachem (Bubendorf, Switzerland). All the experiments are carried out in 50 millimolar (mM) Tris, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% BSA at a pH of 7.4 and at room temperature.
The final volume in all the experiments is 100 microliters ( l).

For the individual mixtures, 10 nM FXa are mixed with 5 M of the substrate I-1100, 0.3 nM FXIa with 5 M I-1575, 0.1 nM trypsin with 5 M I- 1100, 0.002 nM thrombin with 5 gM I-1560, and 0.012 nM plasmin with 50 M 1-1275. For the coupled assay systems, 8.8 nM FIXa(3 or 1 pM FVIIa are mixed in each case with 9.5 nM of FXa and 50 M of the substrate I-1100. The test compounds are made up as 10 millimolar (mM) solutions in dimethyl sulphoxide (DMSO). These 10 mM stock solutions are diluted firstly 1:5 in DMSO and then 1:100 in the assay medium.
Eight serial dilutions are made up from this 20 M solution, with each subsequent concentration corresponding to 1/3 of the initial concentration. 30 l of these individual dilution mixtures are added to the 30 l cells so that the highest substance concentration in this enzyme/substance mixture is 10 M, and the following ones correspond to 3.3 M, 1.1 pM, 0.37 M, 0.12 M, 0.04 M, 0.012 M and 0.004 M. These test substances diluted in this way are added to the individual enzyme assay systems. After incubation for 60 minutes, the amidolytic activity of the enzymes is determined in a SPECTRAFIuor Plus (Tecan, Maennedorf, Switzerland) at the wavelengths of 360 nm (excitation) and 465 nm (emission).

Analysis: The fluorescence values attained without addition of substance are set equal to 100%, and all other values are then related to these 100%. It is thus possible to compare experiments carried out on different days. Dose-activity plots and IC50 values are calculated from the percentages using the GraphPad Prism computer program.

2.3 Inhibition of serine proteases 2.3.1 a2-Antiplasmin The serine protease inhibitor a2-antiplasmin is, besides a2-macroglobulin, able to inhibit the serine protease plasmin.

Assay procedure: Human az-antiplasmin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 50 nM; 50 mM TrisHCl pH 7.3; 200 mM NaCI; 0.2% BSA) is incubated in a volume of 10 microlitres with the substance to be tested in a concentration range from 100 to 10 M or the appropriate solvent in a 96-well inicrotiter plate at room temperature for five minutes. 20 pl of human plasmin (Merck Biosciences, Schwalbach/Taunus, Germany; final concentration: 5 nM) are added per batch to the a2-antiplasmin/substance mixture and incubated at 37 C for 15 minutes. 20 1 of the BHC 05 1 076-Foreign CountriesCA 02615888 2008-01-18 fluorogenic plasmin substrate 11275 (Bachem, Weil am Rhein, Germany; final concentration: 15 M;
50 mM TRIS pH 7.3, 200 mM NaCI; 0.02% BSA) are then added. After incubation at a temperature of 37 C for 40 minutes, the fluorescence signal is measured (Tecan Saphire, Tecan Deutschland GmbH, Crailsheim, Germany; excitation: 360 nm; emission: 465 nm; Gain 50).

Analysis of the data: The fluorescence value found (emission at 465 nm) in the absence of aZ-anti-plasmin is defined as "0% inhibition" and that in the presence of 50 nM is defined as "100%
inhibition". The IC50 value represents the concentration of test substance with which the emitted fluorescence was reduced by one half.

2.3.2 a,-Antitrypsin The serine protease inhibitor ai-antitrypsin is able to inhibit the serine protease trypsin.

Assay procedure: Human ai-antitrypsin (Sigma-Aldrich Chemie GmbH, Tautkirchen, Germany; final concentration: 2 M; 50 mM TrisHCl pH 7.3; 100 mM NaCI; 5 mM calcium chloride;
0.5% BSA) is incubated in a volume of 10 microlitres with the substance to be tested in a concentration range from 100 to 10 M or the appropriate solvent in a 96-well microtiter plate at room temperature for five minutes. 20 l of human trypsin (Sigma-Aldrich, Taufkirchen, Germany; final concentration: 500 nM) are added per batch to the ai-antitrypsin/substance mixture and incubated at 37 C for 15 minutes. 20 l of the fluorogenic trypsin substrate I1100 (Bachem, Weil am Rhein, Germany;
final concentration:
I M; 50 mM TRIS pH 7.3, 200 mM NaCI; 0.02% BSA) are then added. After incubation at a temperature of 37 C for 40 minutes, the fluorescence signal is measured (Tecan Saphire, Tecan Deutschland GmbH, Crailsheim, Germany; excitation: 360 nm; emission: 465 nm;
Gain 50).

Analysis of the data: The fluorescence value found (emission at 465 nm) in the absence of al-anti-trypsin is defined as "0% inhibition" and that in the presence of 2 M is defined as "100% inhibition".
The IC50 value represents the concentration of test substance with which the emitted fluorescence was reduced by one half.

The suitability of the compounds of the invention for treating thrombotic disorders can be shown in the following animal models:

The compounds of the present invention can be investigated in thrombosis models in which fibrinolysis is mediated by a PAI-1-dependent mechanism (compare: Clozel, JCardiovasc Pharmacol 12:520-5 (1998); Levi, Circulation 85:305-12 (1992); Biemond, Circulation 91:1175-81 (1995);

BHC 05 1 076-Foreign CountriescA 02615888 2008-01-18 Friederich, Circulation 96:916-21 (1997)). It is furthermore possible to characterize the compounds of the present invention in relation to their inhibition or reduction in PAI-I
activity in vivo (compare:
Crandall, BBRC 311:904-908 (2003)).

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

To determine the apparent half-life in vivo, the test substances are dissolved in various formulating compositions (e.g. plasma, ethanol, DMSO, PEG400, etc.) or mixtures of these solubilizers and administered intravenously to male Wistar rats. The doses administered are in the range from 0.1 to 1 mg/kg. Blood samples are taken by means of a catheter or as sacrifice plasma at various times over a period of up to 26 h. Quantitative determination of the substances in the test samples takes place in the plasma via calibration samples which are adjusted in plasma. Proteins present in the plasma are removed by precipitation with acetonitrile. The samples are then fractionated by HPLC using reversed phase columns in a 2300 HTLC system (Cohesive Technologies, Franklin, MA, USA). The HPLC
system is coupled via a turbo ion spray interface to an API 3000 Triple Quadropole mass spectrometer (Applied Biosystems, Darmstadt, Germany). The plasma concentration time course is analyzed using a validated kinetic analysis program.

BHC 05 1 076-Foreign CountriescA 02615888 2008-01-18 C. Exemplary embodiments of pharmaceutical compositions The compounds of the invention can be converted into pharmaceutical preparations in the following ways:

Tablet:
Composition:

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

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

10 ml of oral suspension are equivalent to a single dose of 100 mg of the compound of the invention.
Production:

The Rhodigel is suspended in ethanol, and the compound of the invention is added to the suspension.
The water is added while stirring. The mixture is stirred for about 6 hours until the swelling of the Rhodigel is complete.

BHC 05 1 076-Foreign Countries CA 02615888 2008-01-18 Solution which can be administered intravenously:
Composition:

I mg of the compound of th invention, 15 g of polyethylene glycol 400 and 250 g of water for injections.

Production:

The compound of the invention is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterilized by filtration (pore diameter 0.22 m) and dispensed under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimped caps.

Claims

1. Compound of the formula in which X is a group of the formula where * is the the point of attachment to the carbonyl group, # is the point of attachment to the oxygen atom, and R2, R3, R4 and R5 are independently of one another hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C6-alkylamino, C1-C4-alkoxycarbonyl or C1-C6-alkylaminocarbonyl, Y is phenyl or pyridyl, where phenyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-alkylaminocarbonyl, n is a number 0, 1, 2 or 3, R1 is phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylaminocarbonyl and C1-C6-alkylsulphonylamino, or one of the salts, solvates or solvates of the salts thereof.

2. Compound according to Claim 1, characterized in that X ~is a group of the formula where * ~is the point of attachment to the carbonyl group, # ~is the point of attachment to the oxygen atom, and R2, R3 , R4 and R5 are independently of one another hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C6-alkylamino, C1-C4-alkoxycarbonyl or C1-C6-alkylaminocarbonyl, Y is phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-alkylaminocarbonyl, n is a number 0 or 1, R1 is phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylamino, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-alkylaminocarbonyl and C1-C6-alkylsulphonylamino, or one of the salts, solvates or solvates of the salts thereof.

3. Compound according to Claim 1 or 2, characterized in that X ~is a group of the formula where * ~is the point of attachment to the carbonyl group, # ~is the point of attachment to the oxygen atom, and R2, R3, R4 and R5 are hydrogen, Y is phenyl, where phenyl may be substituted by 1 to 2 substituents, where the substituents are selected independently of one another from the group consisting of halogen and alkoxy, n is a number 0 or l, R1 is phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, methyl, methoxy and methylsulphonylamino, or one of the salts, solvates or solvates of the salts thereof.

4. Process for preparing a compound of the formula (I) according to Claim 1 or one of the salts, solvates or solvates of the salts thereof, characterized in that a compound of the formula in which X and R1 have the meaning indicated in Claim 1, is reacted with a compound of the formula in which X and n have the meaning indicated in Claim 1.

5. Compound according to any of Claims 1 to 3 for the treatment and/or prophylaxis of diseases.

6. Use of a compound according to any 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 of Claims 1 to 3 for the manufacture of a medicament for the treatment and/or prophylaxis of thrombotic disorders.

8. Medicament comprising at least one compound according to any of Claims 1 to 3 in combination with a further active ingredient.

9. Medicament comprising at least one compound according to any 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 disorders.

11. Method for controlling thrombotic disorders in humans and animals through administration of a pharmaceutically effective amount of at least one compound according to any of Claims 1 to 3 or of a medicament according to any of Claims 8 to 10.