WO2008043533A2 - Acyl aminoimidazoles and acyl aminothiazoles - Google Patents

Abstract

The invention relates to acyl aminoimidazoles and acyl aminothiazoles, to a method for producing same and to the use thereof for producing medicaments for the treatment and/or prevention of diseases, in particular cardiovascular diseases, preferably thromboembolic diseases.

Description

 Acylaminoimidazoles and acylaminothiazoles

The invention relates to acylaminoimidazoles and acylaminothiazoles and to processes for their preparation and to their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases, preferably of thromboembolic diseases.

Blood clotting is a protective mechanism of the organism that can quickly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and bleeding after vascular injury is essentially through the coagulation system, which involves an enzymatic cascade It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, transforming the soluble fibrinogen into the insoluble fibrin at the end of the cascade Traditionally, a distinction is made in the blood clotting between the intrinsic and the extrinsic system, which result in a final common pathway, where the active enzyme Factor Xa is formed from the ptsoenzyme factor X. The activated serine protease Xa cleaves prothromb The resulting thrombin in turn splits fibrinogen into fibrin. Subsequent cross-linking of the fibrin monomers leads to the formation of blood clots and thus to haemostasis.

In addition, thrombin is a potent trigger of platelet aggregation via the proteolytic activation of platelet receptors, which also makes a significant contribution to hemostasis. Other functions of thrombin that contribute to blood coagulation are the stabilization of the fibrin clot via the activation of factor XIII, the enhancement of the coagulation reaction via the activation of cofactors V and VIII, and the inhibition of fibrinolysis via the activation of procarboxypeptidase B (syn. TAFI ). Finally, by the proteolytic activation of the protein C, thrombin can counteract an excessive activity of the coagulation cascade and thus an excessive hemostasis (thrombosis)

Hemostasis is subject to a complex regulatory mechanism. An uncontrolled activation of the coagulation system or a defective inhibition of the activation processes can cause the formation of local thromboses or embolisms in vessels (arteries, veins, lymphatics) or cardiac cavities. This can lead to serious thromboembolic diseases. In addition, hypercoagulability - systemically - in a consumption coagulopathy can lead to disseminated intravascular coagulation. thromboembolic Complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits, such as hemodialysis, and heart valve prostheses.

Thromboembolic disorders are the most common cause of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th Ed., 1997, W.B. Saunders Company, Philadelphia].

The anticoagulants known in the art, i. Substances for the inhibition or prevention of blood clotting, have various, often serious disadvantages. Efficient treatment or prophylaxis of thromboembolic disorders is therefore found to be very difficult and unsatisfactory in practice (DA Lane, et al, Directing Thrombin, Blood 106, 2605-2612, 2005, D. Gustafsson, et al., Nature Reviews Drug Discovery, 3, 649-659, 2004; L. Wallentin, et al., The Lancet 362, 789-797, 2003).

For the therapy and prophylaxis of thromboembolic diseases, on the one hand heparin is used, which is administered parenterally or subcutaneously. Due to more favorable pharmacokinetic properties, although increasingly low molecular weight heparin is nowadays increasingly preferred; However, this also the known disadvantages described below can not be avoided, which consist in the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life. Since heparin simultaneously inhibits several factors of the blood coagulation cascade, there is an unselective effect. In addition, there is a high risk of bleeding, in particular cerebral hemorrhage and bleeding in the gastrointestinal tract can occur, and it can lead to thrombocytopenia, Alopecia medicomentosa or osteoporosis [Pschyrembel, Clinical Dictionary, 257th edition, 1994, Walter de Gruyter Verlag, page 610, keyword "heparin "Römpp Lexicon Chemistry, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, keyword" heparin "].

A second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indandiones, but especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives, which are unsuitable for the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver. Due to the mechanism of action, the effect is only very slow (latency until the onset 36 to 48 hours). Although the compounds can be administered orally, due to the high risk of bleeding and the narrow therapeutic index, a complex individual adjustment and observation of the patient is necessary [J. Hirsh, J. Dalen, DR Anderson et al., "Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic rank" Chest 2001, 1 19, 8S-21 S, J. Ansell, J. Hirsh, J. Dalen et al., "Managing Oral anticoagulant therapy "Chest 2001, 19, 22S-38S, PS Wells, AM Holbrook, NR Crowther et al.," Interactions of warfarin with drugs and food "Ann. Intern. Med. 1994, 121, 676-683]. In addition, other side effects such as gastrointestinal disturbances, hair loss and skin necrosis are described.

However, in the course of many cardiovascular and metabolic diseases, systemic factors, such as e.g. Hyperlipidemia, diabetes or smoking, due to blood flow changes with stasis, e.g. in atrial fibrillation, or as a result of pathological vascular wall changes, e.g. endothelial dysfunction or atherosclerosis, to an increased tendency of coagulation and platelet activation. This undesirable and excessive hemostasis can lead to thromboembolic diseases and thrombotic complications with life-threatening conditions through the formation of platelet-rich and thrombi.

Recent approaches to oral anticoagulants are at various stages of clinical testing or use, but have also shown disadvantages, such as: highly variable bioavailability, liver damage and bleeding complications.

An object of the present invention is therefore to provide novel compounds as thrombin inhibitors for the treatment of cardiovascular diseases, in particular of thromboembolic diseases, in humans and animals, which have a large therapeutic range.

WO 2005/092864 describes structurally similar imidazole derivatives and their use for the treatment of neurodegenerative and neurological diseases, such. Alzheimer's. WO 02/053161 describes the use of imidazole and thiazole derivatives for the treatment of fibrotic diseases.

The invention relates to compounds of the formula

in which

X is NH or S, - A -

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

where phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, -C ₄ alkylamino, C _r C ₄ -alkylthio and C _r C ₄ alkylcarbonyl,

R ^{2 is} phenyl or 5- or 6-membered heteroaryl,

where phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, C _r C ₄ alkylamino, C _r C ₄ -alkylthio and C _r C ₄ alkylcarbonyl,

R ^{3 is} hydrogen or methyl,

R ⁴ is C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₃ -C ₆ -cycloalkyl,

wherein alkyl and alkenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, amino carbonyl, CpC ₄ alkoxy, Ci-C ₄ -Alkylamino and C ₃ -C ₆ -cycloalkyl,

or

R ³ and R ⁴ are joined together and, with the atoms to which they are attached, form a pyrrolidine ring or a 1,3-thiazolidine ring,

wherein the pyrrolidine ring and the 1,3-thiazolidine ring may be substituted with 1 to

2 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, amino, CpC ₄ alkyl, C ₂ -C ₄ alkenyl, Ci-C ₄ - alkoxy and C _r C ₄ alkylamino,

R ⁵ is hydrogen, halogen, hydroxy, amino, C, -C ₆ alkyl, C _r C ₆ alkoxy, C _r C ₆ - alkylamino, CpC _ö alkylcarbonyloxy, Ci-Q-alkylcarbonylamino or 5- to 7-membered

Heterocyclyl is

wherein alkyl and alkylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, amino, Hydroxycarbonyl, Ci-C _ö alkylamino, C] -C ₄ -alkoxycarbonyl and 5- to 7-membered heterocyclyl,

in which heterocyclyl may in turn be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, oxo,

Trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ₄ alkyl, C, -C ₄ alkoxy, C _r C ₄ alkylamino, C _r C ₄ alkylthio, C _r C ₄ alkylcarbonyl, C _r C ₄ - alkoxycarbonyl , C _r C ₄ alkylcarbonylamino, _{Ci-C4-alkylaminocarbonyl,} Ci-C ₄ - alkoxycarbonyl-amino, and _{Ci-C4-alkylcarbonyloxy,}

and

where heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C 1 -C ₄ -alkyl, QC ₄ -alkoxy, C] -C ₄ alkylamino, Ci-C ₄ - alkylthio, _{Ci-C4-alkylcarbonyl,} Ci-C ₄ alkoxycarbonyl, _{Ci-C4-alkylcarbonylamino,} Cp

C ₄ alkylaminocarbonyl, C 1 -C ₄ alkoxycarbonylamino and Q 1 alkylcarbonyloxy,

or

R ⁴ and R ⁵ are joined together and form a pyrrolidinone ring with the atoms to which they are attached

wherein the pyrrolidinone ring may be substituted with 1 to 2 substituents, wherein the

Substituents independently of one another are selected from the group consisting of hydroxy, amino, QQ-alkyl, Cj-C ₄ -alkoxy and C] -C ₄ -alkylamino,

R ^{6 is} phenyl, 5- or 6-membered heteroaryl or 5-7-membered heterocyclyl,

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, nitro, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ₄ alkyl, C _r C ₄ alkoxy, C] -C ₄ alkylamino, C _r C ₄ alkyl thio, Q Gi-alkylcarbonyl, Ci-C ₄ alkoxycarbonyl, C _r C ₄ alkylcarbonylamino, CpC ₄ -Al- kylaminocarbonyl, C _r C ₄ alkoxycarbonylamino, C _r C ₄ alkylcarbonyloxy, C _r C ₄ alkyl sulfonyl and C _{r is} C ₄ alkylsulfinyl, and

where heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, C 1 -C ₄ -alkylamino, CpC ₄ -

Alkylthio, _{Ci-C4-alkylcarbonyl,} C _r C ₄ alkoxycarbonyl, CRQ-alkylcarbonylamino, Ci- C ₄ alkylaminocarbonyl, Ci-C ₄ -alkoxycarbonylamino and CPQ-alkylcarbonyloxy,

or

R ⁵ and R ⁶ are joined together and together with the carbon atom to which they are attached form a group of the formula

where * denotes the carbon atom to which R ⁵ and R are bonded,

and

R ⁷ and R ⁸ are joined together and together with the carbon atom to which they are attached form a cyclopentane ring or cyclohexane ring,

wherein the cyclopentane ring and the cyclohexane ring may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, C ₁ - C ₄ alkyl, C _r C ₄ - Alkoxy and C] -C ₄ alkylamino,

and

where R ³ and R ^{5 are} not both simultaneously attached to R ⁴ and

where R ⁴ and R ^{6 are} not both simultaneously attached to R ⁵ ,

and their salts, their solvates, and the solvates of their salts. Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as those of formula (I), hereinafter referred to as embodiment (e) and their salts, solvates and solvates of the salts, as far as the compounds of formula (I) 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 of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, 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 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 from 1 to 16 carbon atoms. Atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

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

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).

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, alkylthio, alkylcarbonyl. Alkylcarbonylamino. Alkylcarbonyloxy, alkylaminocarbonyl, alkylsulfonyh, alkylsulfinyl, alkoxycarbonyl and alkoxycarbonylamino are a linear or branched alkyl radical having 1 to 6, preferably 1 to 4, carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl , tert-butyl, n-pentyl and n-hexyl.

Alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4, particularly preferably 2 to 3, carbon atoms. Examples which may be mentioned are: vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.

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

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-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn Hexyl-N-methyl-amino. C ₁ -C ₃ -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.

Alkylthio is exemplified and preferably methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Alkylcarbonyl is exemplified and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-burylcarbonyl and tert-butylcarbonyl. Alkylcarbonylamino is, by way of example and by way of preference, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino and tert-butylcarbonylamino.

Alkylcarbonyloxy is by way of example and preferably methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, iso-propylcarbonyloxy, n-butylcarbonyloxy and tert-butylcarbonyloxy.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and by preference for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, NN- Diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-N-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl. C ₁ -C ₃ -alkylaminocarbonyl is, for example, a monoalkylamino-carbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.

Alkylsulfonyl is exemplified and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.

Alkylsulfinyl is exemplified and preferably methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfinyl and tert-butylsulfinyl.

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

Alkoxycarbonylamino is by way of example and preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.

Cycloalkyl represents a monocyclic cycloalkyl group having usually 3 to 6, preferably 3, 5 or 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Heterocyclyl is a monocyclic, heterocyclic radical having usually 5 to 7, preferably 5 or 6 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series Ν, O, S, SO, SO ₂ , wherein a nitrogen atom can also form a Ν-oxide. The heterocyclyl radicals may be saturated or partially unsaturated. Preferred are 5- or 6-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S, by way of example and preferably pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidin-1-yl , Piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, perhydroazepinyl, piperazin-1-yl and piperazine-2 yl.

Heteroaryl is an aromatic, monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 2 heteroatoms from the series S, O and N, where a nitrogen atom can also form an N-oxide, by way of example and preferably for thienyl, furyl , Pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.

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

When radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted, the radicals may, unless otherwise specified, be monosubstituted 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 is NH or S,

R ^{1 is} phenyl, pyridyl or pyrimidyl,

wherein phenyl, pyridyl and pyrimidyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci-Q-alkyl, C _r C ₄ alkoxy, C, -C ₄ alkylamino, C _r C ₄ -alkylthio and C _r C ₄ alkylcarbonyl,

R ^{2 is} phenyl, thienyl, furyl, thiazolyl, oxazolyl or imidazolyl,

wherein phenyl, thienyl, furyl, thiazolyl, oxazolyl and imidazolyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, Ci-C ₄ alkyl and Ci-C ₄ alkoxy,

R ^{3 is} hydrogen,

R ^{4 is} C _r C ₆ -alkyl or C ₃ -C ₆ -cycloalkyl, wherein alkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, Ci-C ₄ alkoxy, Ci-C ₄ alkylamino and C ₃ -C ₆ cycloalkyl .

or

R ³ and R ⁴ are joined together and form a pyrrolidine ring with the atoms to which they are attached

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

R ⁵ is hydrogen, halogen, hydroxy, amino, C _r C ₆ alkyl, C, -C ₆ alkoxy, C ₁ -C ₆ - alkylamino, Q-COE-alkylcarbonyloxy, Cj-Cό alkylcarbonylamino, morpholinyl, thiomorpholinyl or 4- (C 1 -C ₄ -alkyl) piperazinyl,

where alkyl and alkylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, C ₁ -C ₆ -alkylamino, CpC ₄ -alkoxycarbonyl, pyrrolidinyl, piperidinyl,

Morpholinyl, thiomorpholinyl and piperazinyl,

wherein pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl may in turn be substituted with 1 to 2 substituents where the substituents are independently selected from the group consisting of C _r C ₄ alkyl and C, -C ₄ alkoxy,

or

R ⁴ and R ⁵ are joined together and form a pyrrolidinone ring with the atoms to which they are attached

wherein the pyrrolidinone ring may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of

C, -C ₄ alkyl,

R ^{6 is} phenyl, tetrahydrofuranyl, pyranyl, piperidinyl or thiopyranyl,

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, nitro, trifluoromethyl, trifluoromethoxy, Ci-C ₄ alkyl, C _r C ₄ - alkoxy, _{Ci-C4-alkylcarbonylamino,} C) -C ₄ -alkylaminocarbonyl and Ci-C ₄ - alkoxycarbonylamino,

and

where tetrahydrofuranyl, pyranyl, piperidinyl and thiopyranyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, oxo, hydroxycarbonyl, aminocarbonyl, C 1 -C ₄ -alkyl, C] -C ₄ alkoxy, Ci-C ₄ alkyl carbonylamino, _{Ci-C4-alkylaminocarbonyl} and _{Ci-C4-alkoxycarbonylamino,}

or

R ⁵ and R ⁶ are joined together and together with the carbon atom to which they are attached form a group of the formula

where * denotes the carbon atom to which R ⁵ and R ^{6 are} bonded,

and

R ⁷ and R ⁸ are joined together and together with the carbon atom to which they are attached form a cyclohexane ring,

and

where R ³ and R ^{5 are} not both simultaneously attached to R ⁴ and

where R ⁴ and R ^{6 are} not both simultaneously attached to R ⁵ ,

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

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

X is NH or S, R ^{1 is} phenyl or pyridyl,

wherein phenyl and pyridyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen and methoxy,

R ^{2 is} phenyl or thienyl,

wherein phenyl and thienyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of fluorine, chlorine and bromine,

R ^{3 is} hydrogen,

R ^{4 is} iso-propyl,

or

R ³ and R ⁴ are joined together and form a pyrrolidine ring with the atoms to which they are attached

wherein the pyrrolidine ring may be substituted with 1 to 2 substituents methyl,

R ^{5 is} hydrogen, dQ-alkyl or C, -C ₄ -alkoxy,

wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, hydroxycarbonyl and QC ₄ - alkoxycarbonyl,

or

R ⁴ and R ⁵ are joined together and form a pyrrolidinone ring with the atoms to which they are attached

wherein the pyrrolidinone ring may be substituted with 1 to 2 substituents methyl,

R ^{6 is} phenyl or 4-pyranyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen,

Hydroxy and C 1 -C ₄ -alkoxy, or

R ⁵ and R ⁶ are joined together and together with the carbon atom to which they are attached form a group of the formula

where * denotes the carbon atom to which R ⁵ and R ^{6 are} bonded,

and

R ⁷ and R ⁸ are joined together and together with the carbon atom to which they are attached form a cyclohexane ring,

and

where R ³ and R ^{5 are} not both simultaneously attached to R ⁴ and

where R ⁴ and R ^{6 are} not both simultaneously attached to R ⁵ ,

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

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

Preference is also given to compounds of the formula (I) in which R ^{1 is} phenyl, where phenyl may be substituted by a substituent fluorine.

Preference is also given to compounds of the formula (I) in which R ^{2 is} phenyl or thienyl, where phenyl and thienyl may be substituted by a substituent fluorine or chlorine.

Particular preference is also given to compounds of the formula (I) in which R ^{2 is} thienyl, where thienyl may be substituted by a fluorine substituent.

Very particular preference is also given to compounds of the formula (I) in which R ^{2 is} 5-fluoro-2-thienyl or 5-chloro-2-thienyl.

Very particular preference is also given to compounds of the formula (I) in which R ^{2 is} 5-fluoro-2-thienyl. Preference is also given to compounds of the formula (I) in which R ^{3 is} hydrogen.

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

Preference is also given to compounds of the formula (I) in which R ^{5 is} hydrogen or C 1 -C ₄ -alkyl, where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy and hydroxycarbonyl.

Preference is also given to compounds of the formula (I) in which R is phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy and C 1 -C ₄ -alkoxy ,

Particular preference is also given to compounds of the formula (I) in which R ^{6 is} phenyl, where phenyl may be substituted by 2 substituents methoxy or by a substituent methoxy and by a substituent chlorine.

Very particular preference is also given to compounds of the formula (I) in which R ^{6 is} 3,4-dimethoxyphenyl or 3-chloro-4-methoxyphenyl.

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

[A] Compounds of the formula

in which

X, R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning,

with compounds of the formula

(IH),

in which

R ⁵ and R ^{6 have} the abovementioned meaning, and

Y ^{1 is} halogen, preferably chlorine, bromine or iodine, or hydroxy,

to be implemented

or

[B] Compounds of the formula

in which

X, R ¹ and R ^{2 have} the abovementioned meaning,

with compounds of the formula

in which

R ³ , R ⁴ , R ⁵ and R ^{6 have} the abovementioned meaning, and

Y ^{2 is} halogen, preferably chlorine, bromine or iodine, or hydroxy,

be implemented.

The reaction according to process [A] and process [B] is carried out, if Y ¹ or Y ² is halogen, generally in inert solvents, in the presence of a base, preferably in a temperature range from ^{0 0} C to 40 ⁰ C at atmospheric pressure. Inert solvents are, for example, halohydrocarbons, such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran or methylene chloride.

Examples of bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsiryl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is diisopropylethylamine.

The reaction according to process [A] and process [B] is carried out, if Y ¹ or Y ² is hydroxy, generally in inert solvents, in the presence of dehydrating reagents, optionally in the presence of a base, preferably in a temperature range from 0 ⁰ C to Room temperature at normal pressure.

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) (optionally in the presence of pentafluorophenol ( PFP)), 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-sulfate or 2 tert-butyl 5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl ) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, NN ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1H) - (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or 0- (7-azabenzotriazol-1-yl) -NNN ', N-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole ( HOBt), o benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures thereof, with bases. Preferably, the condensation is carried out with HOBt and EDC.

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. Preferably, the condensation is carried out with diisopropylethylamine.

Inert solvents are, for example, halohydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide, acetone and the like. nitrile or hexamethylphosphoric triamide. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.

The compounds of the formula (III) are known or can be synthesized by known methods from the corresponding starting compounds.

The compounds of formula (FV) are known or can be synthesized by known methods from the corresponding starting compounds. The preparation of the aminoimidazoles is described, for example, by Cook, et al. J. Chem. Soc., 1949, 1074-1076 and Bador, et al. J. Chem. Soc., 1950, 2775-2780.

The compounds of formula (V) are known or can be synthesized by known methods from the corresponding starting compounds. Among others, peptide couplings and alkylations are used.

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

in which

X, R ¹ , R ² and R ^{3 have} the abovementioned meaning, and

Y ^{3 is} halogen, preferably iodine, bromine or chlorine,

with compounds of the formula

H ₂ NR ⁴ (VII),

in which

R ^{4 has} the meaning given above,

be implemented. The reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from 0 ⁰ C to 40 ⁰ C at atmospheric pressure.

Inert solvents are, for example, halohydrocarbons, such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran or methylene chloride.

Examples of bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is diisopropylethylamine

The compounds of formula (VII) are known or can be synthesized by known methods from the corresponding starting compounds.

The compounds of the formula (VI) are known or can be prepared by combining compounds of the formula (IV) with compounds of the formula

in which

R ^{3 has} the meaning given above,

Y ^{3 is} halogen, preferably iodine, bromine or chlorine, and

Y ^{4 is} halogen, preferably iodine or bromine, or hydroxy,

be implemented.

The reaction takes place according to method [A].

The compounds of formula (VIII) are known or can be synthesized by known methods from the corresponding starting compounds. As an alternative to the previously described process, the amines (II) can also be prepared by reductive amination of the primary amines with a suitable ketone or aldehyde. The primary amines are thereby obtained by acylation of the aminoimidazoles (FV), the primary amine function being protected during the acylation with a suitable protecting group, such as a Boc group, which is cleaved after reaction according to the reaction conditions known to those skilled in the art. Preferred acylating agents are the N-protected amino acids, which are activated using a coupling reagent.

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

scheme:

The compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum. These are compounds which influence the proteolytic activity of the serine protease thrombin. The compounds of the invention inhibit the enzymatic cleavage of substrates that play an essential role in the activation of blood coagulation and aggregation of platelets. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

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

For the purposes of the present invention, "thromboembolic disorders" include in particular diseases such as acute coronary syndrome (ACS), heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable Angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty, stent or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, venous thrombosis, especially in deep leg veins and renal veins, transient ischemic attacks, and thrombotic and thromboembolic stroke.

The compounds according to the invention are therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as, for example, brain ischemia, stroke and systemic thromboembolisms and ischaemias, in patients with acute, intermittent or persistent cardiac arrhythmias, such as, for example, atrial fibrillation, and those who become one

Cardioversion, further in patients with valvular heart disease or with artificial heart valves. In addition, the compounds of the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).

Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.

In addition, the compounds according to the invention also have an influence on wound healing, for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases such as asthma, inflammatory lung diseases, Glomerulonephritis and inflammatory bowel diseases into consideration, moreover, also for the prophylaxis and / or treatment of Alzheimer's disease. In addition, the compounds of the present invention can inhibit tumor growth and metastasis, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and in the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumor patients, especially those undergoing major surgery or chemo- or radiotherapy.

In addition, the compounds of the invention may also be used to prevent coagulation ex vivo, e.g. for the preservation of blood and plasma products, for the cleaning / pre-treatment of catheters and other medical aids and devices, for the coating of artificial surfaces of in vivo or ex vivo used medical aids and devices or for biological samples containing platelets.

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

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

Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

• lipid-lowering drugs, in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) - reductase inhibitors;

Coronary / vasodilators, especially angiotensin converting enzyme (ACE) inhibitors; AII (angiotensin II) receptor antagonists; beta-adrenoceptor antagonists; alpha-1-adrenoceptor antagonists; diuretics; Calcium channel blockers; Substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulators;

Plasminogen activators (thrombolytics / fibrinolytics) and thrombolysis / fibrinolysis enhancing compounds, such as plasminogen activator inhibitor (PAI inhibitor) inhibitors or thrombin-activated fibrinolysis inhibitor inhibitors (TAFI inhibitors); • anticoagulant substances (anticoagulants);

antiplatelet agents (platelet aggregation inhibitors, platelet aggregation inhibitors);

Fibrinogen receptor antagonists (glycoprotein IIb / IIIa antagonists);

• antiarrhythmic drugs

• Chemotherapeutic agents of malignant tumors such as anti-metabolites, alkylating cytostatic drugs, topoisomerase inhibitors, mitosis inhibitors and cytostatic antibiotics, hormones, hormone antagonists, other cytotoxic drugs (antibodies, kinase inhibitors, cytokines).

Another object of the present invention is a method for preventing blood coagulation in vitro, especially in blood or biological samples containing platelets, which is characterized in that an anticoagulatory effective amount of the compound of the invention is added.

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, conjunctivae 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 functioning rapidly and / or modified compounds of the invention donating application forms, the compounds of the invention in crystalline and / or amorphised and / or dissolved

Contain form such. Tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings containing the

Control release of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or

Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For the Parenteral administration are suitable as application forms, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

The oral application is preferred.

For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, Pastes, foams, scattering 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 dodecylsulfate, 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, as well as their use for the purposes mentioned above.

In general, it has been found to be beneficial to administer amounts of about 5 to 250 mg per 24 hours when administered parenterally to achieve effective results. When administered orally, the amount is about 5 to 100 mg per 24 hours.

Nevertheless, it may be necessary to deviate from the 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.

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. The term "w / v" means "weight / volume". Thus, for example, "10% w / v" means: 100 ml of solution or suspension contains 10 g of substance.

A) Examples

Abbreviations:

Section. absolutely

Boc tert-butoxycarbonyl

CDCl ₃ deuterochloroform

CO ₂ carbon dioxide d day

DIEA N, N-diisopropylethylamine

DMAP 4-N, N-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory

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

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

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 min. minutes

MS mass spectrometry

MW molecular weight [g / mol]

NMR nuclear magnetic resonance spectroscopy

PyBOP 1-Benzotriazolyloxy-tripyrrolidinophosphonium hexafluorophosphate

Rf Retention Index (at DC)

RP-HPLC reverse phase HPLC

RT room temperature

R, retention time (by HPLC)

TFA trifluoroacetic acid

THF tetrahydrofuran HPLC methods:

Method 1: Instrument: HP 1100 with DAD Detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml perchloric acid / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B, 6.7 min 2% B, 7.5 min 2% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.

Method 2: Instrument: HP 1100 with DAD Detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml perchloric acid / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B, 9.2 min 2% B, 10 min 2% B; Flow: 0.75 ml / min; Oven: 3O ⁰ C; UV detection: 210 nm.

LC-MS methods:

Method 1: Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ^■ »2.5 min 30% A -> 3.0 min 5% A -» 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O ⁰ C; UV detection: 210 nm.

Method 2: Instrument: Micromass Platform LCZ with HPLC Agilent Series 1 100; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 100% A - »2.9 min 30% A -> 3.1 min 10% A -» 5.5 min 10% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 208-400 nm.

Method 3: Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A - »3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.

GC-MS methods:

Method 1: Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; constant flow with helium: 0.88 ml / min; Oven: 7O ⁰ C; Inlet: 25O ⁰ C; Gradient: 70 ⁰ C, 30 ° C / min → 310 ⁰ C (3 min hold). starting compounds

Example IA

Benzyl-benz-carbimidothioate hydrobromide

A solution of 10 g (72.8 mmol) of thiobenzamide and 12.5 g (72.8 mmol) of benzyl bromide in 300 ml of dioxane for 48 h at 100 ⁰ C heated. The solvent is evaporated to one fifth of the amount in vacuo. Allow to cool and filtered from the precipitated solid. The solid is washed with a little dioxane and diethyl ether and dried in vacuo. This gives 13.1 g (58% of theory) of crystals.

HPLC (Method 1): R ₄ = 3.89 min

MS (DCIpos): m / z = 228 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 11.5 (b, 2H), 7.9 (d, 2H), 7.8 (t, IH), 7.65 (t, 2H), 7.55 (d, 2H), 7.4 (m, 3H), 4.7 (s, 2H).

Example 2A

2,5-diphenyl-lH-imidazol-4-amine

300 mg (0.97 mmol) of benzyl-benz-carbimidothioate hydrobromide and 128 mg (0.97 mmol) of amino (phenyl) -acetonitrile are dissolved in 20 ml of chloroform and heated to 70 ° C. for 16 h. It is allowed to cool, diluted with water and saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified by preparative HPLC with a Gradients of acetonitrile and water purified. The product-containing fractions are concentrated to dryness in vacuo. This gives 116 mg (51% of theory) of product.

HPLC (Method 1): R ₁ = 3.56 min

MS (DCIpos): m / z = 236 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 11.8 (s, IH), 7.1-8.0 (m, 10H), 4.7 (s, 2H).

Example 3A

2-chloro-N- (2,5-diphenyl-lH-imidazol-4-yl) acetamide

375 mg (1.59 mmol) of 2,5-diphenyl-1H-imidazol-4-amine are dissolved in 5 ml of 1,2-dichloroethane and admixed with 333 μl (2.39 mmol) of triethylamine and 234 mg (2.1 mmol) of chloroacetyl chloride. It is stirred for 15 min at room temperature and a further 16 h at 45 ⁰ C, before using dichloromethane and

Water is diluted. It is saturated with sodium bicarbonate solution until basic

Reaction added and the phases separated. The organic phase is dried with sodium sulfate, filtered and concentrated to dryness in vacuo. The residue is chromatographed by HPLC and a gradient of acetonitrile and water and the product-containing

Fractions are combined and concentrated to dryness in vacuo. 372 mg (75% of theory) are obtained.

Th.) Product.

HPLC (Method 1): R _t = 3.56 min

MS (DCIpos): m / z = 312 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.6 (s, IH), 10.0 (s, IH), 7.2-8.1 (m, 10 H), 4.25 (s, 2H).

Example 4A

N- (2,5-diphenyl-1H-imidazol-4-yl) -N ² -isopropylgrycinamide

365 mg (1.17 mmol) of 2-chloro-N- (2,5-diphenyl-1H-imidazol-4-yl) acetamide are dissolved in 5 ml of acetonitrile and treated with 559 mg (9.37 mmol) of isopropylamine. After completion of the addition, stirring is continued for 16 h at room temperature, before the reaction solution is diluted with dichloromethane, extracted twice with water and dried over sodium sulfate. The organic phase is concentrated to dryness in vacuo and the residue is chromatographed by HPLC and a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness in vacuo. This gives 326 mg (83% of theory) of product.

HPLC (Method 1): R, = 3.29 min

MS (DCIpos): m / z = 335 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.5 (s, IH), 9.6 (b, IH), 7.2-8.1 (m, 10 H), 3.3 (m, 2H), 2.8 (m , IH), 1.0 (d, 6H).

Example 5A

Benzyl 4-fluorobenz carbimidothioate hydrochloride

2 g (16.5 mmol) of 4-fluorobenzonitrile and 3.5 g (28.1 mmol) of benzylmercaptan are dissolved in 10 ml of anhydrous dioxane and cooled to ⁰ ° C. It is introduced over 40 min hydrogen chloride gas and stirred for a further 16 h at room temperature. The solution is mixed with 50 ml of diethyl ether and the crystals which precipitate are filtered off and dried in vacuo. 1.3 g (28% of theory) of crystals are obtained. HPLC (Method 1): R, = 3.94 min

MS (DCIpos): m / z = 246 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.0 (b, IH), 8.0 (m, 2H), 7.3-7.6 (m, 7H), 4.6 (s, 2H).

Example 6A

Benzyl-5-fluorothiophene-2-carbimidothioate hydrochloride

8 g (59.5 mmol) of 5-fluorothiophene-2-carbonitrile and 12.5 g (101.2 mmol) of benzylmercaptan are dissolved in 80 ml of anhydrous dioxane and cooled to ⁰ ° C. It is introduced over 40 min hydrogen chloride gas and left for a further 3 days at room temperature. The solution is mixed with 300 ml of diethyl ether and the crystals which precipitate are filtered off and dried in vacuo. 16 g (95% of theory) of crystals are obtained.

HPLC (Method 1): R, = 3.91 min

MS (DCIpos): m / z = 252 (M + H) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.5 (b, IH), 7.9 (b, IH), 7.5 (d, 2H), 7.3-7.45 (m, 3H), 7.1 (s, IH), 4.6 (s, 2H).

Example 7A

Amino (phenyl) acetonitrile

4 g (23.7 mmol) of alpha-cyano-benzylamine are dissolved in 100 ml of dichloromethane and extracted twice with 15 ml of saturated sodium bicarbonate solution. It gets more saturated Washed sodium chloride solution, the organic phase dried over sodium sulfate, filtered and evaporated to dryness in vacuo. 2.75 g (98% of theory) of crystals are obtained.

LC-MS (Method 2): R, = 1.53 min

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.2-7.6 (m, 5H), 5.0 (s, IH), 2.8 (s, 2H).

Example 8A

Amino (6-chloropyridin-3-yl) acetonitrile

2.9 g (44.2 mmol) of potassium cyanide are mixed in 60 ml of aqueous ammonia and 3.8 g (70.6 mmol) of ammonium chloride. To this suspension, a solution of 5 g (35.3 mmol) of 6-chloronicotinaldehyde in 30 ml of methanol is added dropwise over one hour. It is stirred for 16 h before being diluted with dichloromethane. The phases are separated and the aqueous phase is extracted twice more with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness in vacuo. The residue is chromatographed on silica gel with a gradient of dichloromethane and methanol, the product-containing fractions are combined and concentrated to dryness in vacuo. This gives 1.3 g (19% of theory) of product.

LC-MS (Method 1): R, = 0.66 min

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.85 (s, IH), 8.2 (m, 2H), 7.6-7.8 (m, 2H).

Example 9A

Bromo (4-methoxyphenyl) acetonitrile

2.9 g (16.3 mmol) of N-bromo-succinimide and 0.223 mg (1.36 mmol) of α, α-azo-isobutyronitrile in 10 ml of carbon tetrachloride and 2.0 g (13.59 mmol) of 4-methoxybenzyl cyanide are added. After refluxing for 3 hours, the solvent is removed in vacuo under reduced pressure and the residue is purified by flash chromatography. The product fractions are combined and the solvent removed. 2.53 g (82% of theory) of the desired product are obtained.

HPLC (Method 1): R _t = 3.47 min

MS (DCI (NH ₃ )): m / z = 243.1 (M + NH,) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.53 (d, J = 7.53 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.57 (s, IH), 3.80 (s, 3H ).

Example IQA

2-bromo-5-phenyl-l, 3-thiazol-4-carbonsäuremethylester

5.0 g (21.3 mmol) of methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate are dissolved in 50 ml of dry acetonitrile and 7.15 g (32.0 mmol) of copper (II) bromide are added. At room temperature, 3.8 ml (3.30 g, 32.0 mmol) of tert-butylnitrite are added dropwise. After addition, the batch is stirred until no gas evolution is observed. Then add water and dichloromethane, acidify the solution with aqueous 12N hydrochloric acid, add more dichloromethane, the organic phase is separated and dried over magnesium sulfate. After filtration, the solvent is removed and the residue is dried in vacuo. This gives 5.95 g (83% of theory) of the desired product.

HPLC (method 1): R ₁ = 4.50 min

MS (DCI (NH ₃ )): m / z = 314.9 (M + NH ») ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.57-7.42 (m, 5H), 3.71 (s, 3H). Example IIA

2-bromo-5-phenyl-l, 3-thiazole-4-carboxylic acid

5.99 g (20.1 mmol) of 2-bromo-5-phenyl-l, 3-thiazole-4-carboxylic acid methyl ester are dissolved in 36 ml of tetrahydrofuran and mixed with 30 ml of an aqueous IM lithium hydroxide solution. The

Reaction solution is stirred for 2 h at room temperature and then acidified with aqueous hydrochloric acid and diluted with aqueous, saturated ammonium chloride solution. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are over

Dried sodium sulfate, filtered and concentrated on a rotary evaporator to dryness. Without further purification, 5.5 g (96% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 3.40 min

MS (DCI (NH ₃ )): m / z = 300.9 (M + NH,) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.2 (br s, IH), 7.56-7.41 (m, 5H).

Example 12A

tert -Butyl (2-bromo-5-phenyl-1,3-thiazol-4-yl) carbamate

To a solution of 5.5 g (19.36 mmol) of 2-bromo-5-phenyl-1,3-thiazole-4-carboxylic acid and 2.97 ml (2.16 g, 21.29 mmol) of triethylamine in 48 ml of dry 1,2-dimethoxyethane and 19.1 ml (14.81 g, 199.77 mmol) of tert-butanol under argon at room temperature 4.59 ml (5.86 g, 21.29 mmol) of diphenylphosphoric acid are added dropwise. After the addition, the reaction mixture is stirred overnight at an oil bath temperature of 90 ⁰ C. After cooling, aqueous saturated sodium bicarbonate solution is added and the aqueous solution extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness. The residue is purified by flash chromatography, the product fractions combined and evaporated to dryness. After drying under high vacuum, 3.58 g (52% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 4.82 min

MS (ES +): m / z = 355 and 357 (M + H) ⁺

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 9.24 (s, IH), 7.59-7.22 (m, 5H), 1.31 (s, 9H).

Example 13A

tert-butyl (2,5-diphenyl-l, 3-thiazol-4-yl) carbamate

800 mg (2.25 mmol) of tert-butyl (2-bromo-5-phenyl-l, 3-thiazol-4-yl) carbamate and 660 mg (5.41 mmol) of phenylboronic acid are dissolved in 20.3 ml of dry N, N-dimethylformamide and added 2.48 ml of aqueous 2M sodium carbonate solution. The solution is degassed by passing an argon stream through for 15 minutes. Then 164.77 mg (0.23 mmol) of 1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride (1: 1 complex with dichloromethane) are added and the reaction is allowed to proceed under an argon atmosphere at an oil bath temperature of 95 ^{Stir 0} C overnight. The reaction solution is filtered through Celite ^® and washed with ethyl acetate. The solvent is removed in vacuo with gentle heating and the residue is purified by preparative HPLC. The product fractions are combined, the solvent is removed and the residue is dried in vacuo. 296 mg (27% of theory) of the desired product are obtained. HPLC (Method 2): R, = 5.24 min

MS (DCI (NH ₃ )): m / z = 353.1 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.20 (s, IH), 7.97-7.87 (m, 2H), 7.64-7.32 (m, 8H), 1.31 (s, 9H).

Example 14A

2,5-diphenyl-l, 3-thiazol-4-amine

296 mg (0.84 mmol) of tert-butyl (2,5-diphenyl-l, 3-thiazol-4-yl) carbamate is dissolved in 20 ml of a 4N solution of hydrogen chloride in dioxane and stirred for 2 h at room temperature. With aqueous potassium hydroxide solution, the reaction mixture is made basic and washed with aqueous, saturated sodium carbonate solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo with gentle warming to dryness. Without further purification, 189 mg (89% of theory) of the desired product are obtained.

HPLC (Method 2): R, = 4.87 min

MS (DCI (NH ₃ )): m / z = 253 (M + H) ⁺

Example 15A

5- (4-methoxyphenyl) -2-phenyl-l, 3-thiazol-4-amine

500 mg (2.21 mmol) of bromo- (4-methoxyphenyl) -acetonitrile are dissolved in 10 ml of dichloromethane and 303.44 mg (2.21 mmol) of thiobenzamide are added. The approach will be added overnight Reflux stirred. After cooling, the precipitated solid is filtered off with suction and dried under high vacuum. 548 mg (76% of theory) of product are obtained.

HPLC (Method 1): R, = 4.64 min

MS (DCI (NH ₃ )): m / z = 283.3 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.86 (d, J = 6.6 Hz, 2H), 7.54-7.41 (m, 5H), 7.02 (d, J = 7.02 Hz, 2H), 4.74 (br s, 2H), 3.79 (s, 3H).

The aminoimidazoles of the following table are prepared analogously to Example 2A.

The chloroacetyl-aminoimidazoles of the following table are prepared analogously to Example 3A.

The chloroacetyl-aminoimidazoles of the following table are prepared analogously to Example 4A.

Example structure characterization

MS (ESIpos): m / z = 371 (M + H) ⁺ HPLC (Method 1): R, = 3.42 min.

22A ¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.5 (s, IH), 9.5 (b, IH), 8.05 (t, 2H), 7.6-7.8 (m,

2H), 7.1-7.4 (m, 4H), 6.0 (b, IH), 3.2-3.4 (b, 2H), 2.7 (m, IH), 1.0 (d, 6H).

MS (ESIpos): m / z = 359 (M + H) ⁺ HPLC (Method 1): R, = 3.34 min.

23A ¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.7 (s, IH), 9.6 (s, IH), 7.2-7.8 (m, 6H), 6.8 (s, IH),

3.8 (b, 2H), 2.8 (m, IH), 1.0 (d, 6H).

MS (ESIpos): m / z = 394 (M + H) HPLC (method 1): R, = 3.49 min.

24A ¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 13.0 (b, IH), 8.6 (b, IH), 8.0 (d, IH), 7.55 (d, IH),

7.3 (s, IH), 6.8 (m, IH), 3.2-3.4 (b, 2H), 2.7 (m, IH), 1.0 (d, 6H).

Example 25A

tert -Butyl (2R) -2 - {[2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] carbamoyl} pyrrolidine-1-carboxylate

250 mg (0.96 mmol) of 2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-amine and 208 mg (0.96 mmol) of 1- (tert-butoxycarbonyl) -D-proline are dissolved in 5 ml N, N-dimethylformamide and with 441 ul diisopropylethylamine and 550 mg (1.45 mmol) of N - [(dimethylamino) (3H- [l, 2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene ] -N-methylmethanaminium hexafluorophosphate. It is stirred for 4 days at room temperature before the reaction mixture is chromatographed by preparative HPLC and a gradient of acetonitrile and water. The product-containing fractions are combined and concentrated to dryness in vacuo. This gives 284 mg (65% of theory) of product.

MS (ESIpos): m / z = 457 (M + H) ⁺

HPLC (Method 1): R, = 4.20 min.

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 12.6 (s, IH), 9.7 (d, IH), 7.2-7.8 (m, 6H), 6.8 (b, IH), 4.2 (m, IH) , 3.3 (m, 2H), 2.2 (m, 2H), 1.8 (m, 2H) 1.3-1.5 (m, 9H).

Example 26A

tert -Butyl (4S) -4 - {[2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] carbamoyl} -1,3-thiazolidine-3-carboxylate

50 mg (0.19 mmol) 2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazole-4-amine and 45 mg (0.19 mmol) (7?) - N- (t-butylcarbonyl) -thiazolidine 4-carboxylic acid are dissolved in 5 ml of dichloromethane and treated with 101 .mu.l of diisopropylethylamine and 50 mg (0.29 mmol) of benzotriazole-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphat. The mixture is stirred under reflux for 16 h before the reaction mixture is concentrated and chromatographed by preparative HPLC and a gradient of acetonitrile and water. The product-containing fractions are combined and concentrated to dryness in vacuo. This gives 61 mg (67% of theory) of product.

MS (ESIpos): m / z = 458 (M + H) ⁺

LC-MS (Method 1): R, = 2.20 min.

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 12.7 (s, IH), 9.8 (b, IH), 7.2-7.8 (m, 6H), 6.8 (b, IH), 4.2 (m, IH) , 3.3 (m, 2H), 2.2 (m, 2H), 1.8 (m, 2H) 1.3-1.5 (m, 9H).

Example 27A

tert -Butyl N- [2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] -D-prolineamide

270 mg of tert-butyl 1-2- {[2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] carbamoyl} pyrrolidine-1-carboxylate are dissolved in 15 ml of dichloromethane and washed with 680 μl (8.8 mmol) triflouretic acid added. After 16 h, the reaction solution is diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated to dryness in vacuo. The residue is purified by chromatography using HPLC and a gradient of acetonitrile and water, the product fractions are combined and concentrated to dryness in vacuo. 154 mg (73% of theory) of product are obtained.

MS (ESIpos): m / z = 357 (M + H) ⁺

HPLC (Method 1): R, = 3.35 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.7 (s, IH), 9.6 (s, IH), 7.0-7.8 (m, 7H), 6.8 (s, IH), 3.7 (m, IH), 1.6-3.0 (m, 6H).

Example 28A

2-chloro-N- (2,5-diphenyl-l, 3-thiazol-4-yl) acetamide

268.1 mg (1.06 mmol) of 2,5-diphenyl-l, 3-thiazol-4-amine is dissolved in dry dichloromethane and cooled to 0 ⁰ C. 1 19 ul (156 mg, 1.38 mmol) of chloroacetyl chloride is added dropwise and the mixture is allowed to stir overnight at room temperature. The mixture is mixed with saturated aqueous ammonium chloride solution, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried over sodium sulfate. After filtration, the solvent is removed in vacuo. Without further purification, 242 mg (47% of theory) of the desired product are obtained.

HPLC (Method 1): R ₁ = 4.65 min

MS (DCI (NH ₃ )): m / z = 329 (M + H) ⁺ Example 29A

N- (2,5-diphenyl-1,3-thiazol-4-yl) -N ² -isopropylglycine amide

242 mg (0.74 mmol) of 2-chloro-N- (2,5-diphenyl-l, 3-thiazol-4-yl) acetamide are dissolved in dry dichloromethane and treated with 314 .mu.l (218.1 mg, 3.69 mmol) of isopropylamine. The reaction solution is stirred overnight at 45 ⁰ C and then treated with aqueous, saturated sodium carbonate solution. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with aqueous, saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness in vacuo with gentle heating. The residue is purified by preparative HPLC. The isolated product fractions are combined and evaporated to dryness. 89 mg (34% of theory) of the desired product are obtained.

LC-MS (Method 3): R, = 1.44 min; MS (ES +): m / z = 352.1 (M + H) ⁺

Example 3OA

Ethyl 2- (3,4-dimethoxyphenyl) pent-4-enoate

Under an argon atmosphere, 5.00 g (22.30 mmol) of ethyl (3,4-dimethoxyphenyl) acetate are dissolved in dry tetrahydrofuran and cooled down to -78 ° C. 28.98 ml (5.32 g, 28.98 mmol) an IM solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran are added dropwise over 30 min. With occasional addition of dry tetrahydrofuran, the suspension is maintained in a stirrable state. The suspension is stirred for 1 h at -78 ⁰ C and then 2.89 ml (4:05 g, 33.44 mmol) are added dropwise 3-bromoprop-l-ene. The reaction solution is stirred for 2 h at -20 ⁰ C and then treated with aqueous saturated ammonium chloride solution, water and a hexane / diethyl ether mixture. The aqueous phase is extracted twice with a hexane / diethyl ether mixture. The combined organic phases are washed with water and aqueous, saturated sodium chloride solution. After drying, the solvent is removed on a rotary evaporator. Without further purification, 6.33 g (64% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 4.61 min

MS (DCI (NH ₃ )): m / z = 282 (M + NH,) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 6.94-6.68 (m, 3H), 5.78-5.43 (m, IH), 5.11-4.92 (m, 2H), 4.14-3.95 (m, 2H), 3.78-3.67 (m, 6H), 3.67-3.58 (m, IH), 2.75-2.32 (m, 2H), 1.17-1.05 (m, 3H).

Example 31A

Ethyl 2- (3,4-dimethoxyphenyl) -4-oxobutanoate

6.33 g (23.95 mmol) of ethyl 2- (3,4-dimethoxyphenyl) pent-4-enoate are dissolved in 67 ml of dry dichloromethane and cooled to -78 ° C. It passes ozone through the solution until the starting material is consumed. Subsequently, oxygen is passed through the solution and 7.03 ml of dimethyl sulfide are added. The reaction mixture is allowed to warm to room temperature overnight and rotated in vacuo under reduced pressure to dryness. The residue is purified by flash chromatography. The product fractions are combined and concentrated to dryness. This gives 1.48 g (23% of theory) of the desired product.

GC-MS (Method 1): R ₁ = 6.83 min; MS (EI): m / z = 266 (M) ⁺ Example 32A

Methyl- [3- (3,4-dimethoxyphenyl) -2-oxopyrrolidin-l-yl] acetate

To a cooled to 0 ⁰ C solution of 1.16 g (4.36 mmol) of ethyl 2- (3,4-dimethoxyphenyl) -4-oxobutanoat and 601.6 mg (4.79 mmol) of methyl glycinate hydrochloride in 32.5 ml of glacial acetic acid portionwise 2.85 g ( 43.56 mmol) of zinc. The mixture is boiled for 4 h under reflux and then allowed to cool the solution. Chloroform is added, filtered and the filter cake is washed with ethanol / chloroform (1: 1). The filtrate is under gentle

Heating in vacuo. The residue is dissolved in ethyl acetate and the insoluble constituents are filtered off. The filtrate is heated with gentle heating in vacuo until

Dry in a rotary evaporator and purify the residue by flash chromatography. 900 mg (26% of theory) of the desired product are obtained.

HPLC (method 1): R ₁ = 3.49 min

MS (ES +): m / z = 294 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 6.93-6.72 (m, 3H), 4.12 (dd, J = 23.0, 17.6 Hz, 2H), 3.76-3.70 (m, 6H), 3.68 (s, 3H), 3.63-3.40 (m, 3H), 2.50-1.93 (m, 2H, partially under DMSO signal).

Example 33A

[3- (3,4-dimethoxyphenyl) -2-oxopyrrolidin-l-yl] acetic acid

912.1 mg (3.11 mmol) of methyl [3- (3,4-dimethoxyphenyl) -2-oxopyrrolidin-1-yl] acetate are dissolved in 15 ml of tetrahydrofuran and admixed with 15 ml of an aqueous 1N lithium hydroxide solution. The reaction mixture is stirred for 3 h at room temperature, acidified with aqueous 6N hydrochloric acid, treated with aqueous saturated ammonium chloride solution and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to dryness under reduced pressure and gentle heating. Without further purification, 637 mg (73% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 3.23 min

MS (DCI (NH ₃ )): m / z = 297.1 (M + NH,) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.87 (brs, IH), 6.92-6.72 (m, 3H), 4.00 (dd, J = 29.1, 17.6 Hz, 2H), 3.77-3.68 (m , 6H), 3.62-3.38 (m, 3H), 2.49-1.89 (partially under DMSO signal, m, 2H).

Example 34A

Ethyl-N - [(3,4-dimethoxyphenyl) acetyl] -N-isopropylglycinat

5.00 g (27.52 mmol) of ethyl N-isopropylglycinate hydrochloride are dissolved in 100 ml of dry dichloromethane and 8.44 ml (6.13 g, 60.55 mmol) of triethylamine and catalytic amounts of DMAP are added. At ⁰ ° C, 5.91 g (27.52 mmol) of 3,4-dimethoxyphenylacetyl chloride are added and the reaction mixture is allowed to come to room temperature. The mixture is stirred for a further 1 h at room temperature. Additional dichloromethane is added and the reaction is stopped by the addition of 20 ml of 1N aqueous sodium bicarbonate solution. The organic phase is separated and washed with 1N aqueous sodium hydroxide solution, aqueous 1N hydrochloric acid solution and water. After drying over magnesium sulfate, the solvent is removed and the residue is purified by flash chromatography. The product fractions are combined and concentrated to dryness. 5.18 g (58% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 4.00 min

MS (DCI (NH ₃ )): m / z = 324.3 (M + H) ^{+ 1} H-NMR (400 MHz, DMSOd ₆ ): δ = 6.95-6.61 (m, 3H), 4.24-3.96 (m, 3H), 3.87 (s, 2H), 3.78-3.61 (m, 8H), 1.26- 1.09 (m, 3H), 0.99 (d, J = 6.9 Hz, 6H).

Example 35A

N - [(3,4-dimethoxyphenyl) acetyl] -N-isopropylglycine

5.18 g (16.02 mmol) of ethyl N - [(3,4-dimethoxyphenyl) acetyl] -N-isopropylglycinate are dissolved in 72 ml of tetrahydrofuran, and 72 ml of an aqueous 1N lithium hydroxide solution are added. The mixture is allowed to stir overnight at room temperature and then acidified with concentrated, aqueous hydrochloric acid solution. The aqueous phase is extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness. Without further purification, 4.23 g (89% of theory) of the desired product are obtained.

HPLC (Method 1): R _t = 3.46 min

MS (ES +): m / z = 296 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.36 (brs, IH), 6.95-6.62 (m, 3H), 4.72-3.95 (m, 2H), 3.85-3.33 (m, 9H), 1.04 -0.94 (m, 6H).

Example 36A

1-iodoacetone

Dissolve 4.34 ml (5.00 g, 54.04 mmol) of chloroacetone in 10 ml of acetone and add 9.87 g (59.44 mmol) of potassium iodide. After stirring for 1.5 h at room temperature, the solid is filtered off and washed with Washed acetone. The mother liquor is evaporated with gentle warming and gentle vacuum to dryness. The residue is reacted further without further purification.

GC-MS (Method 1): R, = 2.07 min; MS (EI +): m / z = 184.0 (M) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 4.03 (s, 2H), 2.30 (s, 3H).

Example 37A

2- (E / Z) -1-iodoacetone-O-benzyl loxime

8.375 g (45.52 mmol) of 1-iodoacetone and 5.61 g (45.52 mmol) of O-benzylhydroxylamine are dissolved in methanol / water (45 ml / 14 ml) and stirred at room temperature for 1 h. The solvent is reduced in volume under reduced pressure to a volume of 15 ml and dichloromethane and water are added. The aqueous phase is extracted three times with dichloromethane and the organic phases are combined. After drying over sodium sulfate, the solvent is removed and the residue is purified by flash chromatography. 8.88 g (65% of theory) of the desired product are obtained.

HPLC (method 1): R, = 4.85 and 4.95 min

MS (ES +): m / z = 290 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ , isomer mixture): δ = 7.42-7.42 (m, 10H), 5.10 (s, 2H), 5.06 (s, 2H), 4.00 (s, 2H), 3.90 ( s, 2H), 1.95 (s, 3H), 1.93 (s, 3H).

Example 38A

Ethyl 4- (E / Z) -4 - [(benzyloxy) imino] -2- (3,4-dimethoxyphenyl) pentanoate

To a cooled to -78 ⁰ C solution of 1:55 mg (6.92 mmol) of ethyl 3,4-dimethoxyphenylacetate in 40 ml dry tetrahydrofuran is added dropwise under an argon atmosphere 4:50 ml (0.96 g, 8.99 mmol) of a 2M solution of lithium diisopropylamide in tetrahydrofuran. The solution is allowed to warm to room temperature and then cooled again to -78 ⁰ C from. A solution of 2.00 g (6.92 mmol) of 2- (E / Z) -l-iodoacetone-O-benzyloxime in 9 ml of dry tetrahydrofuran is added dropwise, and the mixture is again brought to room temperature and stirred for 1 h under reflux. The solvent is then removed and the residue is purified by flash chromatography. The product fractions are combined and dried in vacuo. This gives 2.10 g (65% of theory) of the desired product.

HPLC (Method 1): R _t = 4.87 and 4.97 min

MS (DCI (NH ₃ )): m / z = 386 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ , mixture of isomers): δ = 7.39-7.22 (m, 5H), 6.92-6.65 (m, 3H), 5.01-4.91 (m, 2H), 4.12-3.82 (m, 3H ), 3.74-3.63 (m, 6H), 2.99-2.76 (m, IH), 2.56-2.44 (m, IH, under DMSO signal), 1.83-1.59 (m, 3H), 1.16-1.04 (m, 3H ).

Example 39A

3- (3,4-dimethoxyphenyl) -5-methylpyrrolidin-2-one

500 mg (1.30 mmol) of ethyl 4- (E / Z) -4 - [(benzyloxy) imino] -2- (3,4-dimethoxyphenyl) pentanoate are dissolved in 300 ml of methanol and 1.52 g of a 50% Raney Nickel suspension in water are added. The reaction suspension is hydrogenated overnight at 2.5 bar and room temperature. The catalyst is removed by filtration through Celite ^® and the solution evaporated to dryness. The residue is separated by preparative HPLC and the product fractions are combined. After drying under high vacuum, 204 mg (67% of theory) of the desired product are obtained.

HPLC (Method 1): R _t = 3.37 min

MS (DCI (NH ₃ )): m / z = 236 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.83 (s, IH), 6.91-6.69 (m, 3H), 3.75-3.69 (m, 6H), 3.67-3.46 (m, 2H), 2.60-2.45 (m, IH under DMSO signal), 2.28-1.98 (m, 1H), 1.17 (t, J = 5.9 Hz, 3H).

Example 4OA

tert-butyl [3- (3,4-dimethoxyphenyl) -5-methyl-2-oxopyrrolidin-l-yl] acetate

3

Under an argon atmosphere, 289.0 mg (1.23 mmol) of 3- (3,4-dimethoxyphenyl) -5-methylpyrrolidin-2-one are dissolved in dry 1-methyl-2-pyrrolidinone and 58.95 mg (1.47 mmol) of a 60 % sodium hydride suspension added. After stirring at room temperature for 10 min, 362.75 μl (479.19 mg, 2.46 mmol) of tert-butyl bromoacetate are added. There is a strong exothermic reaction. After a further 20 minutes at room temperature, the reaction is stopped with water and the reaction mixture is separated by preparative HPLC without further work-up. The product fractions are combined and the solvent is removed in vacuo with gentle heating. 147 mg (34% of theory) of the desired product are obtained.

HPLC (Method 1): R ₁ = 4.27 min

MS (ES +): m / z = 350.0 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 6.92-6.71 (m, 3H), 4.15-3.99 (m, IH), 3.89-3.54 (m, 9H), 2.68-1.51 (m, 2H), 1.42 (s, 9H), 1.25-1.15 (m, 3H).

Example 41A

3- (3,4-Dimethoxyphenyl) -5-methyl-2-oxopyrrolidin-l-yl] acetic acid

270 mg (0.77 mmol) of tert-butyl [3- (3,4-dimethoxyphenyl) -5-methyl-2-oxopyrrolidin-1-yl] acetate are dissolved in 7.5 ml of a 4M solution of hydrogen chloride in dioxane / water and 1.5 h stirred at room temperature. The solution is concentrated in vacuo with gentle warming to dryness and the residue is dissolved in 2 ml of water and 10 ml of ethyl acetate. The solution is stirred vigorously for 5 min. The solution is dried over an EXtrelut ^® NT3 column and washed several times with ethyl acetate. The solution is concentrated in vacuo under reduced pressure and gentle heating. Without further purification, 205 mg (78% of theory) of product are obtained.

HPLC (Method 1): R, = 3.41 min

MS (ES): m / z = 292.1 (MH) ^"

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.71 (br s, IH), 6.94-6.68 (m, 3H), 4.24-3.43 (m, 10H), 2.70- 1.49 (m, 2H), 1.30 -1.12 (m, 3H).

Example 42A

succinate 4-tert-Butyl-l-ethyl-2- (3,4-dimethoxyphenyl)

To a cooled to -78 ° C solution of 10.0 g (44.59 mmol) of ethyl (3,4-dimethoxyphenyl) acetate in 50 ml of dry tetrahydrofuran under an argon atmosphere 28.98 ml (10.63 g, 57.97 mmol) of a 2M solution of Sodium hexamethylenedisilazane added dropwise in tetrahydrofuran. In order to avoid solidification of the reaction solution, an additional 30 ml of dry tetrahydrofuran are added. The reaction mixture is stirred for 1 h at -78 ⁰ C and then is added 9.88 ml (13.05 g, 66.89 mmol) of bromoacetic acid tert-butyl ester added. The solution is stirred for 2 h at -2O ⁰ C and then warmed to room temperature overnight. Add saturated aqueous ammonium chloride solution, water and a 1: 1 mixture of hexane: diethyl ether. The aqueous phase is extracted twice with 1: 1 hexane / diethyl ether. The combined organic phases are washed successively with water and aqueous, saturated sodium chloride solution, dried, filtered and finally evaporated in vacuo to dryness. The residue is separated by flash chromatography. The product fractions are combined, the solvent removed and dried under high vacuum. 13.7 g (73% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 4.72 min

MS (DCI (NH ₃ )): m / z = 356 (M + NFL /

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 6.92-6.73 (m, 3H), 4.11-3.97 (m, 2H), 3.92-3.84 (m, IH), 3.73 (s, 3H), 3.72 (s, 3H), 2.98-2.87 (m, IH), 2.59-2.51 (m, IH, under DMSO signal), 1.37 (s, 9H), 1.13 (t, J = 7.1 Hz, 3H).

Example 43A

4-tert-butoxy-2- (3,4-dimethoxyphenyl) -4-oxobutanoic acid

4.0 g (11.82 mmol) of 4-tert-butyl-1-ethyl-2- (3,4-dimethoxyphenyl) succinate are dissolved in 2.1 ml

Dissolved methanol and it adds a solution of 82.92 mg (1.48 mmol) of potassium hydroxide in 2.1 ml of water. The reaction mixture is stirred overnight at room temperature and then carefully neutralized with an IN aqueous hydrochloric acid solution and diluted with an aqueous, saturated ammonium chloride solution. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness. Without further purification, 376 mg (quantitative yield) of the desired product are obtained.

MS (DCI (NH ₃ )): m / z = 328 (M + NH,) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.31 (brs, IH), 6.95-6.73 (m, 3H), 3.86-3.76 (m, IH), 3.73 (s, 3H), 3.72 (s, 3H), 3.00-3.82 (m, IH), 2.57-2.45 (m, IH, under DMSO signal), 1.36 (s, 9H).

Example 44A

Ethyl 2- (3,4-dimethoxyphenyl) -3-hydroxypropanoate

4.0 g (13.4 mmol) of ethyl (3,4-dimethoxyphenyl) acetate are dissolved with 422 mg (13.4 mmol) of aqueous formaldehyde in 13 ml of dimethylsulfonamide. 262 mg (0.77 mmol) of sodium ethoxide are added as a 20% strength by weight solution in ethanol. After 30 minutes, the mixture is treated with acetic acid until acidic and purified by preparative HPLC using a gradient of acetonitrile and water. The product fractions are combined and evaporated to dryness in vacuo. This gives 1.9 g (56% of theory) of product.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 6.9 (m, 2H), 6.8 (m, IH), 5.0 (t, IH), 4.1 (m, 2H), 3.9 (m, IH), 3.7 (d, 6H), 3.6 (m, IH), 3.55 (m, IH), 1.2 (t, 3H).

Example 45A

2- (3,4-Dimethoxyphenyl) -3-hydroxypropanoic acid

300 mg (1.18 mmol) of ethyl 2- (3,4-dimethoxyphenyl) -3-hydroxypropanoate are dissolved in 2 ml of a mixture of acetone and water, and 34 mg (1.42 mmol) of lithium hydroxide are added. It is stirred for 1 h at 50 ⁰ C before again 8 mg (0.33 mmol) of lithium hydroxide are added. After a further hour at 50 ° C, the reaction mixture is diluted with ethyl acetate and acidified with dilute hydrochloric acid until acidic reaction. The organic phase is washed twice with dilute hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue is purified by preparative HPLC using a gradient of acetonitrile and water. The product fractions are combined and concentrated to dryness in vacuo. This gives 131 mg (49% of theory) of product.

MS (ESIpos): m / z = 244 (M + NH,) ⁺

HPLC (Method 1): R, = 2.83 min.

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 12.3 (b, IH), 6.9 (m, 2H), 6.8 (m, IH), 4.6 (b, IH), 3.9 (t IH), 3.7 ( d, 6H), 3.5 (m, 2H).

Example 46A

4 - {[tert-butyl (dimethyl) silyl] oxy} -2- (3,4-dimethoxyphenyl) butanoic acid

500 mg (2.55 mmol) (3,4-Dimethoxyphenyl) acetic acid are dissolved in 25 ml of anhydrous tetrahydrofuran and 78 ⁰ C up cooled. At this temperature, 1.17 g (6.37 mmol) of sodium hexamethylenedisilazane are added as IM solution in tetrahydrofuran within 10 min. When the addition is complete, 670 mg (2.8 mmol) of 2- (bromoethoxy) tert-butyldimethylsilane are added and the mixture is stirred at this temperature for a further 30 minutes before the cooling is removed. After a further 16 h, the reaction mixture is diluted with ethyl acetate and acidified with five percent potassium bisulfate solution until acidic. The organic phase is washed twice more with this and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue is purified by preparative HPLC using a gradient of acetonitrile and water purified. The product fractions are combined and evaporated to dryness in vacuo to give 361 mg (40% of theory) of product.

MS (ESIpos): m / z = 355 (M + H) ⁺

HPLC (Method 1): R, = 4.95 min.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.2 (b, IH), 6.9 (d, IH), 6.8 (m, 2H), 3.7 (s, 6H), 3.5 (m, 3H), 2.6 (s, 6H), 2.2 (m, IH), 1.8 (m, IH), 0.9 (s, 9H).

Example 47A

2- (3,4-dimethoxyphenyl) pent-4-enoic acid

5.0 g (25.5 mmol) (3,4-Dimethoxyphenyl) acetic acid are dissolved in 250 ml of anhydrous tetrahydrofuran and 78 ⁰ C up cooled. At this temperature 1 1.7 g (63.7 mmol) of sodium hexamethylenedisilazane as IM solution in tetrahydrofuran was added within 10 min. After completion of the addition, 3.4 g (28.0 mmol) of allyl bromide are added and stirred for a further 30 min at this temperature, before the cooling is removed. After a further 16 h, the reaction mixture is diluted with ethyl acetate and acidified with five percent potassium bisulfate solution until acidic. The organic phase is washed twice more with this and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue is purified by preparative HPLC using a gradient of acetonitrile and water. The product fractions are combined and concentrated to dryness in vacuo. This gives 4.7 g (78% of theory) of product.

MS (ESIpos): m / z = 254 (M + NH ₄₎ ⁺

HPLC (Method 1): R, = 3.85 min.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.2 (b, IH), 6.9 (m, 2H), 6.8 (m, IH), 5.7 (m, IH), 5.0 (m, 2H), 3.7 (d, 6H), 3.5 (t, IH), 2.7 (m, IH), 2.4 (m, IH). Example 48A

S- (2,4-dimethoxybenzyl) -5-chlorothiophene-2-carbothioate

20 g (123.0 mmol) of 5-chlorothiophene-2-carboxylic acid, 20.6 g (123.0 mmol) of 2,4-dimethoxybenzylamine, 25.9 g (135.3 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.75 g

(6.15 mmol) of DMAP and 20.7 g (135.3 mmol) of HOBt are dissolved in 250 ml of anhydrous THF and the mixture is stirred at RT overnight. After removal of the solvents in vacuo, the residue is taken up in methylene chloride and extracted twice against water and once against saturated sodium chloride solution. The organic phases are dried over sodium sulfate, filtered and the solvent removed in vacuo. After flash column chromatographic purification on silica gel (methylene chloride), 33.7 g (87% of theory) of

Product.

LC-MS (Method 3): m / z = 312.2 (M + H) ⁺

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 8.9 (t, IH), 7.7 (d, IH), 7.2 (d, IH), 7.1 (d, IH), 6.6 (d, IH), 6.5 (dd, IH), 4.3 (d, 2H), 3.8 (s, 3H), 3.7 (s, 3H).

Example 49A

5-chloro-N- (2,4-dimethoxybenzyl) thiophen-2-carbothioamide

28.7 g (92.0 mmol) of Example 48A is dissolved in 450 ml of toluene. Then 20.5 g (50.6 mmol) of Lawesson's reagent are added and the solution is stirred at 90 ^° C. for 3 h. After two flashes column-chromatic purification on silica gel (cyclohexane / toluene 1: 1) to obtain 21.1 g (70% of theory) of the product.

HPLC (Method 1): R, = 4.95 min

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.5 (t, IH), 7.7 (d, IH), 7.2 (d, IH), 7.1 (d, IH), 6.6 (d, IH) , 6.5 (dd, IH), 4.8 (d, 2H), 3.8 (s, 3H), 3.8 (s, 3H).

Example 5OA

5-Chloro-thiophen-2-carbothioamide

21.1 g (64.3 mmol) of Example 49A and 34.7 g (321.3 mmol) of methoxybenzene are dissolved in a mixture of trifluoroacetic acid / methylene chloride (1: 5) and the mixture is stirred at RT overnight. The solvents are removed in vacuo and the residue treated with diethyl ether and pentane. The precipitated solid is filtered off, recrystallized from ethyl acetate and, after removal of the solvent, the crude product is purified by flash column chromatography on silica gel (cyclohexane / ethyl acetate 2: 1). 9.7 g (85% of theory) of the product are obtained.

HPLC (Method 1): R, = 3.88 min

MS (DCIpos): m / z = 178 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 9.8 (s, IH), 9.5 (s, IH), 7.6 (d, IH), 7.2 (d, IH).

Example 51A

S-Benzyl-S-chlorothiophene - ^ - carbimidothioate hydrobromide

4.0 g (22.5 mmol) of Example 5OA and 4.0 g (23.6 mmol) of benzyl bromide are dissolved in 100 ml of dioxane and the mixture is stirred at 100 ^° C. for 4 h. The reaction mixture is then washed with diluted some acetonitrile, cooled to ⁰ ° C. and the solid filtered off with suction. After removal of the residual solvent under reduced pressure, 2.7 g (29% of theory, 85% purity) of the product are obtained. The mother liquor is likewise stirred with acetonitrile, and the solid is filtered off with suction and dried in vacuo. 2.8 g (25% of theory, 69% purity) of the product are obtained.

HPLC (Method 1): R ₄ = 4.03 min

MS (DCIpos): m / z = 270 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.5 (d, IH), 7.1-7.6 (m, 7H), 4.3 (d, IH).

The aminoimidazole of the following table is prepared analogously to Example 2A.

Example 53A

(2i?) -? -? - / -butyl-2-methyl-5-methoxypyrrolidine-1,2-dicarboxylate

8.20 g (35.8 mmol) of Boc-D-proline methyl ester are dissolved in 70 ml of methanol, treated with 1.00 g (3.3 mmol) of tetraethylammonium pαra-toluenesulfonate and in an electrochemical cell with double jacket under argon as inert gas with a circulating cryostat to 5 ⁰ C cooled. The cell is equipped with two graphite electrodes of approx. 1.0 x 1.0 x 0.25 cm graphite electrodes, spaced at a distance of approx. 2 cm. to stand by each other. Through this, a constant current of about 250 mA for 20 h is passed (about 5F / mol). The reaction solution is taken up in 500 ml of diethyl ether registered, wherein the conductive salt precipitates as oil and can be separated. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This gives 9.00 g (97% of theory) of crude product, which is used without further purification in the next stage.

GC-MS (Method 1): R, = 5.05 min; m / z = 158 (M-Boc + H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 4.15-4.02 (m, 3H), 3.87-3.76 (m, IH), 2.30-2.20 (m, IH), 2.06-1.90 (m, IH ), 1.90-1.76 (m, IH), 1.42-1.30 (m, 9H), 1.21-0.95 (m, 6H).

Example 54A

(2R, 5S) -l-terNButyl-2-methyl-5-methylpyrrolidine-l, 2-dicarboxylate

In a flame dried apparatus 12.62 g (61.4 mmol) of copper bromide-Dimethylsulfϊd complex presented in 225 ml of absolute diethyl ether and cooled to -5o ⁰ C under an argon atmosphere. Then 38.0 ml of methyl lithium (60.8 mmol, 1.6 molar solution in diethyl ether) are added dropwise. The mixture is stirred for 30 min at -45 ° C to -35 ⁰ C and then 9.75 ml (92.1 mmol) of boron trifluoride diethyl etherate are added dropwise. It is stirred for a further 15 minutes at -45 ° C and then 9.00 g (34.7 mmol) of (2R) -l-tert-butyl-2-methyl-5-methoxypyrrolidin-l, dicarboxylate 2 - added dropwise. The reaction solution is slowly thawed overnight. It gives 60 ml of conc. Ammonia solution to the reaction mixture and stirred for a further 30 min. The reaction mixture is filtered through diatomaceous earth, washed with dichloromethane and the combined filtrates are phase separated. The organic phase is dried over sodium sulfate and concentrated. The product is separated on silica gel with cyclohexane / ethyl acetate 6/1. 5.3 g (62% of theory) of clearly diastereomerically enriched (ώr ~ 9: 1) product are obtained.

LC-MS (Method 2): R _t = 3.51 min; m / z = 144 (M-Boc + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 4.22-4.15 (m, 1H), 4.02-3.87 (m, 1H), 3.67-3.58 (m, 3H), 2.36-2.19 ( m, 1H), 2.05-1.88 (m, 1H), 1.87-1.75 (m, 1H), 1.57-1.45 (m, 1H), 1.44-1.29 (m, 9H), 1.13-1.06 (m, 3H)

Example 55A

(2R, 5S) - 1 - (terf -butoxycarbonyl) -5-methylproline

In 40 ml of water / dioxane (1/1), 5.25 g (21.6 mmol) of (2R, 5S) -l-tert-butyl-2-methyl-5-methylpyrrolidine-1,2-dicarboxylate with 2.72 g (64.7 mmol) Lithium hydroxide monohydrate and stirred overnight. The reaction mixture is concentrated in vacuo and mixed with 50 ml of saturated ammonium chloride solution. It is carefully adjusted to pH 2-3 with dilute hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. After concentration, 4.50 g (89% of theory) of (2i, 5 ₁ S) -l- (ferr-butoxycarbonyl) -5-methylproline are obtained in a diastereomeric ratio of dr = 9: 1.

LC-MS (Method 2): R ₁ = 3.06 min; m / z = 228.0 (MH) ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 4.23-4.14 (m, 1H), 4.03-3.86 (m, 1H), 3.35-3.31 (s, 1H), 2.37-2.18 (m, 1H), 2.04-1.90 (m, 1H), 1.87-1.74 (m, 1H), 1.58-1.46 (m, 1H), 1.43-1.28 (m, 9H), 1.13-1.07 (m, 3 H).

Example 56A

tert -Butyl (2R, 5S) -2 - {[2- (5-chloro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] carbamoyl} -5-methylpyrrolidine-1-carboxylate

A solution of 464 mg (1.68 mmol) of Example 52A in 8 ml of DMF is treated with 424 mg (1.85 mmol) of Example 55A, 704 mg (1.85 mmol) of HATU and 1.2 ml (6.73 mmol) of N, N-diisopropylethylamine. The mixture is then stirred overnight at room temperature. For workup, the reaction mixture is separated directly by preparative HPLC with a gradient of acetonitrile and water. The product-containing fractions are combined and after removal of the solvents in vacuo, they are further purified by preparative HPLC. After the solvents have been spun off from the product-containing fractions, 612 mg (75% of theory) of the product are obtained.

MS (ESIpos): m / z = 487 (M + H) ⁺

HPLC (Method 1): R, = 4.49 min.

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 12.8-12.6 (m, IH), 9.6-10.0 (dd, IH), 7.1-7.8 (m, 7H), 4.2-4.4 (m, IH), 3.8-4.0 (m, IH), 1.4-2.4 (m, 3H), 1.1-1.4 (m, 13H).

embodiments

example 1

N ² - [(3,4-dimethoxyphenyl) acetyl] -N- (2,5-diphenyl-1H-imidazol-4-yl) -N ² -isopropylglycine amide

A solution of 60 mg (0.18 mmol) N- (2,5-diphenyl-1H-imidazol-4-yl) -N2-isopropyl-glycinamide in 2.5 ml of DMF is treated with 40 mg (0.19 mmol) of 3,4-dimethoxyphenylacetic acid, 2.42 mg (0.018 mmol) of 1H-benzotriazol-1-ol and 38 mg (0.19 mmol) of N- [2- (dimethylamino) ethyl] -N'-isopropylcarbodiimide as coupling reagent. The mixture is then stirred overnight at room temperature. For workup, the reaction mixture is separated directly by preparative HPLC with a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness in vacuo. 84 mg (88% of theory) of the product are obtained.

MS (ESIpos): m / z = 513 (M + H) ⁺

HPLC (Method 1): R, = 4.06 min.

¹ H-NMR (400 MHz, DMSO-d6): δ = 12.4-12.6 (d, IH), 9.6-9.8 (d, IH), 6.6-8.1 (m, 13H), 4.7 (m, IH), 3.5 -4.3 (m, 10H), 1.1 (m, 6H).

The examples in the following table are prepared analogously to Example 1 using the appropriate amine and the appropriate carboxylic acid. Also used as coupling reagents are N - [(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylmethane-ammonium hexafluorophosphate (HATU) or (1H-benzotriazole -l-yloxy) (tripyrrolidin-1-yOphosphonium hexafluorophosphate (PyBOP) is used.

Example 22

N- {2 - [(2,5-Diphenyl-l, 3-thiazol-4-yl) amino] -2-oxoethyl} -N-isopropyl-2-oxo-1-oxaspiro [4.5] decane-4-carboxamide

50 mg (0.14 mmol) of N- (2,5-diphenyl-1,3-thiazol-4-yl) -N ² -isopropylglycine amide, 39.5 mg (0.20 mmol) of 2-oxo-1-oxaspiro [4.5] decane-4 Carboxylic acid and 79.3 .mu.l (58.84 mg, 0.46 mmol) of diisopropylethylamine are dissolved in dry N, N-dimethylformamide. Add 75.73 mg (0.20 mmol) of HATU and allow to stir overnight at room temperature. The reaction mixture is diluted with water and acetonitrile and purified by preparative HPLC. The product fractions are combined and evaporated to dryness. This gives 26 mg (34% of theory) of the desired product.

HPLC (Method 2): R, = 4.93 min

MS (ES +): m / z = 532 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 10.48-10.11 (m, IH), 8.00-7.26 (m, 10H), 4.69-3.53 (m, 3H), 3.00-2.55 (m, 2H), 2.35-0.81 (m, 17H).

Example 23

N ² - [(3,4-dimethoxyphenyl) acetyl] -N- (2,5-diphenyl-1,3-thiazol-4-yl) -N ² -isopropylglycine amide

40 mg (0.11 mmol) of N- (2,5-diphenyl-1,3-thiazol-4-yl) -N ² -isopropylglycine amide, 31.3 mg (0.16 mmol) of (3,4-dimethoxyphenyl) -acetic acid and 63.4 μl ( 47.07 mg, 0.36 mmol) of diisopropylethylamine are dissolved in dry N, N-dimethylformamide. Add 60.58 mg (0.16 mmol) of HATU and allow to stir overnight at room temperature. The reaction mixture is diluted with water and acetonitrile and purified by preparative HPLC. The product fractions are combined and evaporated to dryness. 41 mg (69% of theory) of the desired product are obtained.

HPLC (Method 2): R, = 4.78 min

MS (ES +): m / z = 530 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.44-10.06 (m, IH), 8.00-6.55 (m, 13H), 4.70-3.85 (m, 3H), 3.78- 3.52 (m, 8H ), 1.11-0.86 (m, 6H).

Example 24

2- [3- (3,4-Dimethoxyphenyl) -2-oxopyrrolidin-1-yl] - N - [2- (5-fluoro-2-thienyl) -4-phenyl-1H-imidazol-5-yl] -acetamide

100 mg (0.36 mmol) of [3- (3,4-dimethoxyphenyl) -2-oxopyrrolidin-1-yl] acetic acid, 111.4 mg (0.43 mmol) of 2- (5-fluoro-2-thienyl) -4-phenyl-1H -imidazole-5-amine and 187.0 μl (138.83 mg, 1.07 mmol) of diisopropylethylamine are dissolved in dry dichloromethane. 279.49 mg (0.54 mmol) of PyBOP are added and the mixture is stirred overnight at 65.degree. C. bath temperature. After cooling, the reaction mixture is concentrated by rotary evaporation, dissolved with water and acetonitrile and purified by preparative HPLC. The product fractions are combined and evaporated to dryness. For further purification, the product is purified a second time by preparative HPLC. 62 mg (33% of theory) of the desired product are obtained.

HPLC (method 2): R ₄ = 3.91 min

MS (ES +): m / z = 521 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.94-12.62 (m, IH), 10.19-9.75 (m, IH), 7.78-6.66 (m, 10H), 4.28-4.00 (m, 2H), 3.80-3.41 (m, 9H), 2.48 - 1.91 (m, 2H partially under the DMSO signal).

Example 25

(4S) -3 - [(3,4-Dimethoxyphenyl) acetyl] -N- [2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] -1,3-thiazolidine -4-carboxamide

To a solution of 61 mg (0.13 mmol) of tert -butyl- (4S) -4 - {[2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] carbarnoyl} -l , 3-thiazolidine-3-carboxylate in 1 ml of dichloromethane are added at 0 ⁰ C 1 ml of trifluoroacetic acid. It is stirred for 18 hours at RT and concentrated to dryness. Then 2.5 ml of DMF are added and it is mixed with 28 mg (0.14 mmol) of 3,4-dimethoxyphenylacetic acid, with 112 ul of diisopropylethylamine and 54 mg (0.14 mmol) of N- [(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylmethanaminium- hexafluorophosphate added. It is stirred for 18 hours at room temperature before the reaction mixture is chromatographed by preparative HPLC and a gradient of acetonitrile and water. The product-containing fractions are combined and concentrated to dryness in vacuo. 56 mg (78% of theory) of product are obtained.

MS (ESIpos): m / z = 553 (M + H) ⁺

HPLC (Method 1): R, = 1.96 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.6-12.8 (m, IH), 9.8-10.1 (m, IH), 6.7-7.8 (m, 10H), 4.3-5.2 (m, 3H ), 3.5-3.9 (m, 8H), 3.0-3.5 (m, 2H).

Example 26

N ² - [(3,4-Dimethoxyphenyl) acetyl] -N ² -isopropyl-N- [5- (4-methoxyphenyl) -2-phenyl-1,3-thiazol-4-yl] glycinamide

A solution of 75 mg (0.27 mmol) of 5- (4-methoxyphenyl) -2-phenyl-1,3-thiazol-4-amine, 94.13 mg (0.32 mmol) of N - [(3,4-dimethoxyphenyl) acetyl] - N-isopropylglycine, 207.34 mg (0.40 mmol) of PyBOP and 138.8 ul (103.0 mg, 0.80 mmol) of diisopropylethylamine in 3 ml of dry dichloromethane are stirred overnight at an oil bath temperature of 65 ⁰ C. After cooling, the residue is dissolved in acetonitrile / water and separated by preparative HPLC. The product fractions are combined and concentrated in vacuo with gentle warming to dryness. 39 mg (25% of theory) of the desired product are obtained.

HPLC (Method 1): R _t = 4.62 min

MS (ES +): m / z = 560 (M + H) ^{+ 1} H-NMR (400 MHz, DMSOd ₆ ): δ = 10.35-9.93 (m, IH), 7.99-6.55 (m, 12H), 4.70-3.58 (m, 14H), 1.11-0.88 (m, 6H).

Example 27

2- [3- (3,4-Dimethoxyphenyl) -5-methyl-2-oxopyrrolidin-1-yl] - N - [2- (5-fluoro-2-thienyl) -4-phenyl-1H-imidazole-5 yl] acetamide

100 mg (0.34 mmol) of 3- (3,4-dimethoxyphenyl) -5-methyl-2-oxopyrrolidin-1-yl] acetic acid and 106.08 mg (0.41 mmol) of 2- (5-fluoro-2-thienyl) -4- phenyl-1H-imidazole-5-amine are dissolved in dry dichloromethane and 178.15 μl (132.19 mg, 1.02 mmol) of N, N-diisopropylethylamine and 266.12 mg (0.51 mmol) of PyBOP are added. The mixture is stirred at an oil bath temperature of 65 ⁰ C overnight and then evaporated to dryness. The residue is coevaporated with toluene and then purified by preparative HPLC. The product fractions are combined and concentrated to dryness. After drying under high vacuum, 43 mg (24% of theory) of the desired product are obtained.

HPLC (Method 1): R ₄ = 3.94 min

MS (ES +): m / z = 535 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.96-12.60 (m, IH), 10.23-9.68 (m, IH), 7.90-6.59 (m, 10H), 4.48-3.48 (m, 10H), 2.41-2.73 (m, IH), 2.27-1.98 (m, IH), 1.68-1.07 (m, 3H).

Example 28

tert -butyl-3- (3,4-dimethoxyphenyl) -4 - [(2 - {[2- (5-fluoro-2-thienyl) -4-phenyl-1H-imidazol-5-yl] amino} -2 -oxoethyl) (isopropyl) amino] -4-oxobutanoate

250.0 mg (0.70 mmol) of N- [2- (5-fluoro-2-thienyl) -5-phenyl-1H-imidazol-4-yl] -N ² -isopropyl-glycinamide is dissolved in dry N, N-dimethylbrominamide and Add 238.1 mg (0.77 mmol) of 4-tert-butoxy-2- (3,4-dimethoxyphenyl) -4-oxobutanoic acid, 371.28 mg (0.98 mmol) of HATU and 388.8 μl (288.46 mg, 2.23 mmol) of N, N-diisopropylethylamine added. The reaction mixture is stirred at room temperature overnight. The solution is diluted with acetonitrile and water and purified by preparative HPLC. The product fractions are combined and the solvent removed. The residue is dried under high vacuum. 367 mg (79% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 4.48 min

MS (ES +): m / z = 651 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.85-12.53 (m, IH), 9.83-9.45 (m, IH), 7.88-6.67 (m, 10 H), 4.63-3.57 (m, 8H), 3.52 (s, 2H), 2.92-2.68 (m, IH), 2.58-2.39 (m, IH), 1.41-0.58 (m, 15H).

Example 29

3- (3,4-Dimethoxyphenyl) -4 - [(2 - {[2- (5-fluoro-2-thienyl) -4-phenyl-1H-imidazol-5-yl] amino} -2-oxoethyl) ( isopropyl) amino] -4-oxobutanoic

Tert-Butyl 3- (3,4-dimethoxyphenyl) -4- [(2 - {[2- (5-fluoro-2-thienyl) -4-phenyl-1H-imidazole-5-yl] 314 mg (0.48 mmol) yl] amino} -2-oxoethyl) (isopropyl) amino] -4-oxobutanoate are dissolved in 20 ml of a 4N solution of hydrogen chloride in dioxane and stirred overnight at room temperature. The solvent is removed in vacuo with gentle heating and the residue is separated by preparative HPLC. The product fractions are combined and evaporated to dryness. 121.2 mg (42% of theory) of the desired product are obtained.

HPLC (Method 1): R, = 3.91 min

MS (ES +): m / z = 595 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.90-12.52 (m, IH), 12.21-11.93 (brs, IH), 9.86-9.45 (m, IH), 7.90-6.68 (m, 10H) , 4.67-4.26 (IH), 4.26-3.53 (m, 7H), 3.52-3.38 (s, 2H), 3.02-2.75 (m, IH), 2.60-2.35 (m, IH), 1.26-0.58 (m, 6H).

Example 30

2- (3,4-Dimethoxyphenyl) -N- (2- {[2- (5-fluoro-2-thienyl) -4-phenyl-1H-imidazol-5-yl] amino} -2-oxoethyl) - 4-hydroxy-N-isopropylbutanamide

To a solution of 50 mg (0.14 mmol) of N- (2,5-diphenyl-1H-imidazol-4-yl) -N ² -isopropyl-glycinamide in 2 ml of DMF is added 54 mg (0.15 mmol) of 4 - {[ tert-butyl (dimethyl) silyl] oxy} -2- (3,4-dimethoxyphenyl) butanoic acid, it is mixed with 30 .mu.l (0.17 mmol) of diisopropylethylamine and 80 mg of PyBOP stirred overnight at room temperature. The solution is diluted with dichloromethane and washed twice with five percent potassium bisulfate solution, dried over sodium sulfate, filtered and concentrated in vacuo to 2 ml. The residue is treated with 0.3 ml of trifluoroacetic acid and diluted after a further 5 min with dichloromethane. The organic phase is washed with 1N sodium hydroxide solution and saturated sodium chloride solution, dried and evaporated to dryness in vacuo. For workup, the reaction mixture is separated directly by preparative HPLC with a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness in vacuo. This gives 12 mg (15% of theory) of the product.

MS (ESIpos): m / z = 581 (M + H) ⁺

HPLC (Method 1): R, = 3.90 min.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 12.6-12.9 (m, IH), 9.6-9.8 (m, IH), 6.7-7.9 (m, HH), 0.8-4.6 (m, 20H ).

Example 31

2- (3,4-dimethoxyphenyl) -N- (2- {[2- (5-fluoro-2-thienyl) -4-phenyl-1H-imidazol-5-yl] amino} -2 - oxoethyl) -3-hydroxy-N-isopropylpropanamide

To a solution of 80 mg (0.25 mmol) N- (2,5-diphenyl-1H-imidazol-4-yl) -N ² -isopropyl-glycinamide in 2 ml of DMF is added 56 mg (0.25 mmol) of 2- (3 , 4-dimethoxyphenyl) -3-hydroxypropanoic acid, it is mixed with 50 .mu.l (0.28 mmol) of diisopropylethylamine and 128 mg (0.25 mmol) of PyBOP and stirred overnight at room temperature. For workup, the reaction mixture is separated directly by preparative HPLC with a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness in vacuo. This gives 19 mg (13% of theory) of the product.

MS (ESIpos): m / z = 567 (M + H) ⁺

HPLC (Method 1): R, = 3.88 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.6-12.9 (m, IH), 9.6-9.8 (m, IH), 6.7-7.9 (m, HH), 0.8-4.6 (m, 18H ).

Example 32

N- (2,5-diphenyl-1H-imidazol-4-yl) -N ² -isopropyl-N ² - (tetrahydro-2H-pyran-4-yl-acetyl) glycinamide

To a solution of 60 mg (0.18 mmol) of N- (2,5-diphenyl-1H-imidazol-4-yl) -N2-isopropyl-glycinamide in 2.5 ml of DMF is added 28 mg (0.2 mmol) of tetrahydro-2H-pyran -4-yl-acetic acid. It is mixed with 2.4 mg (0.02 mmol) of hydroxybenzotriazole and 38 mg (0.2 mmol) EDC and stirred overnight at room temperature. For workup, the reaction mixture is separated directly by preparative HPLC with a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness in vacuo. This gives 64 mg (75% of theory) of the product.

MS (ESIpos): m / z = 461 (M + H) ⁺

HPLC (Method 1): R, = 3.81 min.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.4-12.8 (m, IH), 9.6-9.8 (m, IH), 7.2-8.2 (m, 10H), 3.7-4.7 (m, 5H), 3.3 (s, 2H), 0.9-2.4 (m, 13H).

The examples in the following table are prepared analogously to Example 25 using the appropriate BOC-protected amine 56A and the appropriate carboxylic acid.

=

1.5-

δ =

1.4-

B) Assessment of physiological efficacy

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

In vitro enzyme Assav

Measurement of thrombin inhibition

To determine the thrombin inhibition of the substances listed above, a biochemical test system is used in which the reaction of a thrombin substrate is used to determine the enzymatic activity of human thrombin. Thrombin separates from the peptic substrate aminomethylcoumarin, which is measured fluorescently. The determinations are carried out in microtiter plates.

Substances to be tested are dissolved in various concentrations in dimethylsulfoxide and incubated for 15 min with human thrombin (0.06 nmol / l dissolved in 50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) aminomethane], 100 mmol / l NaCl , 0.1% BSA [bovine serum albumin], pH 7.4) at 22 ° C. Subsequently, the substrate (5 .mu.mol / 1 Boc-Asp (OBzl) -Pro-Arg-AMC from Bachern) is added. After incubation for 30 min, the sample is excited at a wavelength of 360 nm and the emission is measured at 460 nm. The measured emissions of the test mixtures with test substance are compared with the test batches without test substance (excluding dimethylsulfoxide instead of test substance in dimethyl sulfoxide) and IC ₅₀ values are calculated from the concentration-effect relationships. Representative activity data from this test are listed in Table A below:

Table A

Determination of selectivity

To demonstrate the selectivity of the substances with respect to thrombin inhibition, the test substances are tested for their inhibition of other human serine proteases, such as factor Xa, factor XIa, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol / l of Kordia), factor XIa (0.4 nmol / l of Kordia), trypsin (83 mU / ml of Sigma) and plasmin (0.1 μg / ml of Kordia) these enzymes become dissolved (50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) aminomethane], 100 mmol / l NaCl, 0.1% BSA [bovine serum albumin], 5 mmol / l calcium chloride, pH 7.4) and for 15 min with test substance in various concentrations in dimethyl sulfoxide and with dimethyl sulfoxide without test substance incubated. The enzymatic reaction is then started by adding the appropriate substrates (5 μmol / 1 Boc-Ile-Glu-Gly-Arg-AMC from Bachern for factor Xa and trypsin, 5 μmol / 1 Boc-Glu (OBzl) -Ala-Arg). Bachmann's AMC for factor XIa, 50 μmol / 1 MeOSuc-Ala-Phe-Lys-AMC from Bachern for plasmin). After an incubation period of 30 min at 22 ^° C., the fluorescence is measured (excitation: 360 nm, emission: 460 nm). The measured emissions of the test mixtures with test substance are compared with the test batches without test substance (excluding dimethylsulfoxide instead of test substance in dimethyl sulfoxide) and IC ₅₀ values are calculated from the concentration-effect relationships.

Thrombin plasma assay

In a 96-well flat-bottomed plate, 20 μl of substance dilution (in water) with 20 μl of ecarin (Ecarin reagent, Sigma E-0504, final concentration 20 mU / ml, 20 mU final concentration in the well)

Ca buffer (200 mM Hepes + 560 mM NaCl + 10 mM CaCl ₂ + 0.4% PEG). In the first upper 3 WeIPs Al - A3 only Ca buffer is added, these samples serve as unstimulated ones

Controls. Furthermore, 20 μl of fluorogenic thrombin substrate (Bachern

1-1120, 50 μM final conc. in the well) and 20 ul citrated plasma (Octapharma) added and well homogenized. The plate is measured in the Spectra fluor plus reader with an excitation filter 360 nm and emission filter 465 nm for 20 min. Every minute. The IC _5O value determination takes place after approx. 12 minutes, when 70% of the maximum value is reached.

Thrombin generation assay (thrombogram)

The effect of the test substances on the Thrombogram (thrombin generation assay according to Hemker) is determined in vitro in human plasma (Octaplas® from Octapharma).

In Hemker's thrombin generation assay, the activity of thrombin in clotting plasma is determined by measuring the fluorescent cleavage products of substrate 1-1140 (Z-Gly-Gly-Arg). AMC, Bachern). The reactions are carried out in the presence of varying concentrations of test substance or the corresponding solvent. Reagents from the company Thrombinoscope are used to start the reaction (PPP reagent: 30 pM recombinant tissue factor, 24 μM phospholipids in HEPES). In addition, a Thrombin Calibrator from the company Thrombinoscope is used, whose amidolytic activity is required for calculating the thrombin activity in a sample with an unknown amount of thrombin. The test is carried out according to the manufacturer (Thrombionsocpe BV): 4 .mu.l of the test substance or the solvent, 76 .mu.l of plasma and 20 .mu.l of PPP reagent or thrombin calibrator are incubated at 37 ⁰ C for 5 min. After addition of 20 μl of 2.5 mM thrombin substrate in 20 mM Hepes, 60 mg / ml BSA, 102 mM CaCl ₂ , the thrombin generation is measured for 120 min every 20 s. The measurement is carried out with a fluorometer (Fluoroskan Ascent) from Thermo Electron, which is equipped with a 390/460 nM filter pair and a dispenser.

By using the "thrombinoscope software", the thrombogram is calculated and graphically displayed and the following parameters are calculated: lag time, time to peak, peak, ETP (endogenous thrombin potential) and start tail.

Determination of the anticoagulant effect

The anticoagulant activity of the test substances is determined in vitro in human, rabbit and rat plasma. For this purpose, blood is removed using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9. The blood is mixed well immediately after collection and centrifuged for 15 minutes at approximately 4000 g. The supernatant is pipetted off.

The prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated for 3 minutes at 37 ^° C. with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time.

The thrombin time (TT) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Thrombin Reagent from Roche). The test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by adding the thrombin reagent and determines the time of coagulation. The concentration of test substance is determined which causes a doubling of the thrombin time.

The activated partial thromboplastin time (APTT) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (PTT Reagent from Roche). The test compounds are incubated for 3 minutes at 37 ° C with the plasma and the PTT reagent (cephalin, kaolin). Subsequently, coagulation is triggered by addition of 25 mM CaCl ₂ and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the APTT.

Thromboelastography (thromboelastogram)

The thromboelastography is performed with the help of the thromboelastograph ROTEM from Pentapharm and the associated accessories cup and pin. The measurement is in whole blood, which is previously taken in sodium citrate monovettes Sarstedt. The blood is kept in the monovettes using a shaker in motion and at 37 ⁰ C for 30 min. pre-incubated. For the measurement, 20 μl of CaCl ₂ solution from a 200 mM stock solution (diluted in 0.9% NaCl) are introduced into the cups (final concentration 12.5 mM). Add 3.2 μl of substance or solvent. The measurement is started by adding 300 μl of whole blood. After the addition, pipette up and down briefly with the pipette tip without creating any air bubbles. The measurement takes place over 2.5 hours or is stopped at the beginning of fibrinolysis. The following parameters are determined for the evaluation: CT (clotting time / [sec.]), CFT (clotting formation time / [sec.]), MCF (maximum clot firmness / [mm]) and the alpha angle [ ⁰ J. Die Measurement points are collected every 3 seconds and displayed graphically over the y-axis as MCF [mm] and on the x-axis as time [sec].

Arteriovenous Shunt and Bleeding Model (Combination Model Rat)

Fasting male rats (strain: HSD CPB: WU) weighing 300-350 g are anesthetized with inactin (150-180 mg / kg). Thrombus formation is induced in an arteriovenous shunt by the method of Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214. For this purpose, the left jugular vein and the right carotid artery are dissected free. An extracorporeal shunt is placed between the two vessels by means of a 10 cm long polyethylene tube (PE 60). This polyethylene tube is centered in another 3 cm polyethylene tube (PE 160), which includes a roughened and looped nylon thread to create a thrombogenic surface. The extracorporeal circuit is maintained for 15 minutes. Then the Shunt removed and the nylon thread with the thrombus weighed immediately. The net weight of the nylon thread was determined before the start of the test.

To determine the bleeding time immediately after opening the shunt circuit, the tail tip of the rats is catered for by 3 mm with a razor blade. The tail is placed in 37 ⁰ C tempered physiological saline and the bleeding from the incision wound observed over 15 minutes. The time to stop the bleeding for at least 30 seconds (initial bleeding time), the total bleeding time within 15 minutes (cumulative bleeding time) and the amount of blood loss via the photometric determination of the collected hemoglobin are determined.

The test substances are administered either intravenously via the contralateral jugular vein as a single bolus or as a bolus followed by continuous infusion or orally by means of a gavage, prior to application of the extracorporeal circuit and tail tip incision.

C) Exemplary embodiments of pharmaceutical compositions

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

Tablet:

Composition:

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

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

production:

The mixture of the compound of Example 1, lactose and starch is 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).

Oral suspension:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of rhodigel (xanthan gum) (FMC, 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 of Example 1 is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels is complete, it 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 Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile filtered (pore diameter 0.22 microns) and filled under aseptic conditions in heat sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

Claims

claims

1. Compound of the formula

in which

X is NH or S,

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

wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C _r C ₄ alkyl, QC-alkoxy, C _r C ₄ alkylamino, Ci-C ₄ alkylthio and _{Ci-C4-alkylcarbonyl,}

R ^{2 is} phenyl or 5- or 6-membered heteroaryl,

where phenyl and heteroaryl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl,

Trifluoromethoxy, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, C _r C ₄ alkylamino, C] -C ₄ alkylthio and _{Ci-C4-alkylcarbonyl,}

R ^{3 is} hydrogen or methyl,

R ^{4 is} C _r C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₃ -C ₆ -cycloalkyl,

wherein alkyl and alkenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, CpQ-alkoxy, Ci-C ₄ alkylamino and C ₃ -C ₆ -cycloalkyl, or

R ³ and R ⁴ are joined together and, with the atoms to which they are attached, form a pyrrolidine ring or a 1,3-thiazolidine ring,

wherein the pyrrolidine ring and the 1,3-thiazolidine ring may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, Q-G _t -alkyl, C ₂ -C ₄ alkenyl, C _r C ₄ alkoxy and C _r C ₄ alkylamino,

R ⁵ is hydrogen, halogen, hydroxy, amino, C _r C ₆ alkyl, C _r C ₆ alkoxy, C ₁ -C ₆ - alkylamino, Ci-Cβ-alkylcarbonyloxy, Ci-Cβ-alkylcarbonylamino or 5- to 7- is a membered heterocyclyl,

wherein alkyl and alkylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, Q-Cβ-alkylamino, Ci-C ₄ -alkoxycarbonyl and 5- to 7-membered heterocyclyl,

wherein heterocyclyl may in turn be substituted with 1 to 3

Substituents wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ₄ alkyl, CpQ-alkoxy, CpC ₄ - alkylamino, C, -C ₄ alkylthio, C, -C ₄ alkylcarbonyl, Ci-C ₄ -

Alkoxycarbonyl, Ci-C ₄ alkylcarbonylamino, C _r C ₄ alkylaminocarbonyl, Ci-C ₄ alkoxycarbonyl-amino, and Ci-Q-alkylcarbonyloxy,

and

where heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl,

Trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy,

Ci-C ₄ alkylamino, C] _-C4 alkylthio, _{Ci-C4-alkylcarbonyl,} Ci-C ₄ alkoxycarbonyl,

_{Ci-C4-alkylcarbonylamino,} Ci-C ₄ alkylaminocarbonyl, C _r C ₄ - alkoxycarbonylamino and C] -C ₄ alkylcarbonyloxy,

or R ⁴ and R ⁵ are joined together and form a pyrrolidinone ring with the atoms to which they are attached

wherein the pyrrolidinone ring may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, ^' amino, Ci-C ₄ alkyl, C _r C ₄ alkoxy and C] -C ₄ -

alkylamino,

R ^{6 is} phenyl, 5- or 6-membered heteroaryl or 5-7-membered heterocyclyl,

wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from

Group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,

Trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, Ci-C ₄ alkyl, C _r C ₄ alkoxy,

Ci-C ₄ alkylamino, Ci-C ₄ alkylthio, _{Ci-C4-alkylcarbonyl,} C] -C ₄ alkoxycarbonyl,

Ci-Q-alkylcarbonylamino, CRQ-alkylaminocarbonyl, Ci-C ₄ - alkoxycarbonylamino, Ci-C ₄ alkylcarbonyloxy, _{Ci-C4-alkylsulfonyl} and CpC ₄ -

Alkylsulfϊnyl,

and

where heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl,

Trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C] _-C4 alkyl, Ci-C ₄ alkoxy, Ci-C ₄ alkylamino, C _t -C ₄ alkylthio, QQ-alkylcarbonyl, C _r C ₄ alkoxycarbonyl, Ci-G _t -alkylcarbonylamino, C 1 -C ₄ -alkylaminocarbonyl, C 1 -C ₄ -

Alkoxycarbonylamino and Ci-Q-alkylcarbonyloxy,

or

R ⁵ and R ⁶ are joined together and together with the carbon atom to which they are attached form a group of the formula

where * denotes the carbon atom to which R ⁵ and R ^{6 are} bonded,

and

R ⁷ and R ⁸ are joined together and together with the carbon atom to which they are attached form a cyclopentane ring or cyclohexane ring,

wherein the cyclopentane ring and the cyclohexane ring may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, hydroxy, amino, Ci-C ₄ alkyl, C] -C ₄ - Alkoxy and C 1 -C ₄ -alkylamino,

and

where R ³ and R ^{5 are} not both simultaneously attached to R ⁴ and

where R ⁴ and R ^{6 are} not both simultaneously attached to R ⁵ ,

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

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

X is NH or S,

R ^{1 is} phenyl, pyridyl or pyrimidyl,

where phenyl, pyridyl and pyrimidyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C ₄ -alkyl, ci C ₄ alkoxy, C! -C ₄ alkylamino,

C _r C ₄ -alkylthio and C _r C ₄ alkylcarbonyl,

R ^{2 is} phenyl, thienyl, furyl, thiazolyl, oxazolyl or imidazolyl,

where phenyl, thienyl, furyl, thiazolyl, oxazolyl and imidazolyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano,

Trifluoromethyl, C _r C ₄ alkyl and C _r C ₄ alkoxy,

R ^{3 is} hydrogen, R ^{4 is} C _r C ₆ -alkyl or C ₃ -C ₆ -cycloalkyl,

wherein alkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _r C ₄ alkoxy, Cj-C ₄ - alkylamino and C ₃ -C ₆ cycloalkyl .

or

R ³ and R ⁴ are joined together and form a pyrrolidine ring with the atoms to which they are attached

wherein the pyrrolidine ring may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of C 1 -C ₄ -alkyl and C 1 -C ₄ -alkoxy,

R ⁵ is hydrogen, halogen, hydroxy, amino, C _r C ₆ alkyl, C _r C ₆ alkoxy, C ₁ -C ₆ - alkylamino, Ci-Cβ-alkylcarbonyloxy, CrC ₆ alkylcarbonylamino, morpholinyl, thiomorpholinyl or 4- (C ₁ -C ₄ -alkyl) piperazinyl,

wherein alkyl and alkylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, Ci-C ₆ alkylamino, Ci-C ₄ alkoxycarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl .

in which pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl may in turn be substituted by 1 to 2 substituents, the substituents being selected independently of one another from the group consisting of C 1 -C ₄ -alkyl and C 1 -C ₄ -alkoxy,

or

R ⁴ and R ⁵ are joined together and form a pyrrolidinone ring with the atoms to which they are attached

wherein the pyrrolidinone ring may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of Ci-C ₄ alkyl,

R ^{6 is} phenyl, tetrahydrofuranyl, pyranyl, piperidinyl or thiopyranyl, 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, nitro, trifluoromethyl, trifluoromethoxy, Ci-C ₄ alkyl, Ci-C ₄ alkoxy , C ₁ -C ₄ alkylcarbonylamino, C] -C ₄ - alkylaminocarbonyl and _{Ci-C4-alkoxycarbonylamino,}

and

where tetrahydrofuranyl, pyranyl, piperidinyl and thiopyranyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, oxo, hydroxycarbonyl, aminocarbonyl, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, C _r

C ₄ alkylcarbonylamino, _{Ci-C4-alkylaminocarbonyl} and C] -C ₄ -

alkoxycarbonylamino,

or

R ⁵ and R ⁶ are joined together and together with the carbon atom to which they are attached form a group of the formula

where * denotes the carbon atom to which R ⁵ and R ^{6 are} bonded,

and

R ⁷ and R ⁸ are joined together and together with the carbon atom to which they are attached form a cyclohexane ring,

and

where R ³ and R ^{5 are} not both simultaneously attached to R ⁴ and

where R ⁴ and R ^{6 are} not both simultaneously attached to R ⁵ ,

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

3. A compound according to any one of claims 1 or 2, characterized in that

X is NH or S,

R ^{1 is} phenyl or pyridyl,

wherein phenyl and pyridyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen and methoxy,

R ^{2 is} phenyl or thienyl,

wherein phenyl and thienyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of fluorine, chlorine and bromine,

R ^{3 is} hydrogen,

R ^{4 is} iso-propyl,

or

R ³ and R ⁴ are joined together and form a pyrrolidine ring with the atoms to which they are attached

wherein the pyrrolidine ring may be substituted with 1 to 2 substituents methyl,

R ⁵ is hydrogen, C _r C ₄ alkyl or C ₁ -C ₄ -alkoxy group,

wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, hydroxycarbonyl and C _r C ₄ alkoxycarbonyl,

or

R ⁴ and R ⁵ are joined together and form a pyrrolidinone ring with the atoms to which they are attached

wherein the pyrrolidinone ring may be substituted with 1 to 2 substituents methyl,

R ^{6 is} phenyl or 4-pyranyl, wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy and C] -C ₄ alkoxy,

or

R ⁵ and R ⁶ are joined together and together with the carbon atom to which they are attached form a group of the formula

where * denotes the carbon atom to which R and R are bonded,

and

R ⁷ and R ⁸ are joined together and together with the carbon atom to which they are attached form a cyclohexane ring,

and

where R ³ and R ^{5 are} not both simultaneously attached to R ⁴ and

where R ⁴ and R ^{6 are} not both simultaneously attached to R ⁵ ,

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, characterized in that by methods

[A] a compound of the formula

in which X, R ¹ , R ² , R ³ and R ^{4 have} the meaning given in claim 1, with a compound of the formula

in which

R ⁵ and R ^{6 have} the meaning given in claim 1, and

Y ^{1 is} halogen, preferably chlorine, bromine or iodine, or hydroxy, is reacted, or

[B] a compound of the formula

in which

X, R ¹ and R ^{2 have} the meaning given in claim 1, with a compound of the formula

in which

R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given in claim 1, and Y ^{2 is} halogen, preferably chlorine, bromine or iodine, or hydroxy,

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 thromboembolic diseases.

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

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

10. A method for combating cardiovascular diseases in humans and animals by administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 3, a drug according to claim 8 or a medicament obtained according to claim 6 or 7.