WO2020165031A1 - Substituted isoquinoline-piperidinylmethanone derivatives - Google Patents

Abstract

The invention relates to novel substituted isoquinoline piperidinylmethanone derivatives, to processes for preparing same, to the use thereof in a method for treating and/or preventing diseases, and to the use thereof for producing pharmaceuticals for the treatment and/or prevention of diseases.

Description

Substituted isoquinoline piperidinyl methanone derivatives

The invention relates to new substituted isoquinoline-piperidinyl methanone derivatives, processes for their production, their use in a process for the treatment and / or prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases.

The compound of the formula (I) acts as a selective adrenoreceptor a ₂ c receptor antagonist and can be used for the treatment and / or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities, in particular to promote the wound healing of diabetic foot ulcers , diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular diseases, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders and disorders of the circulatory system, Raynaud's phenomena, CRESTio-intermittent syndrome, microcirculatory disorders, neurological disorders can be used.

The compound of the formula (I) and its production process are described in WO 2015/091414 A1, a detailed discussion of the research synthesis being disclosed in these publications.

As part of the clinical development of [4- (3,4-dihydroisoquinolin-2 (lH) -yl) piperidin-l-yl] [2- (2-oxa-6-azaspiro [3.3] hept-6-yl) pyrimidin-5-yl] methanone was the need for a process for the preparation of the main metabolites of the compound of the formula (I) in order to a) test their effectiveness and b) quantify their presence in the blood serum of the test person.

One object of the present invention is therefore to develop new metabolites of the compound of general formula (I) as selective adrenoreceptor a ₂ c receptor antagonists for the treatment and / or prophylaxis of diseases such as, for. B. cardiovascular diseases or peripheral circulatory disorders (Microangiopathies) such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers).

Very high quality standards had to be produced for pharmaco-kinetic measurements in order to be able to carry out reliable quantification. From the structure elucidation of the after administration of [4- (3, 4-dihydroisoquinolin-2 (lH) -yl) piperidin-1-yl] [2- (2-oxa-6-azaspiro [3.3] hept-6-yl) pyrimidin-5 - yl] methanone of the formula (I) obtained metabolites (via MS from the serum of various animal species, as well as humans), it turned out that there are 9 main metabolites, which are structurally in the formulas ( IA), (IB) and (IC) can be combined.

The invention therefore relates to substituted isoquinoline-piperidinyl-methanone derivatives of the general formula (I-A), (I-B) or the general formula (I-C)

in which

R ^{1 is} a group of the formula

stands, and

R ^{2 represents} hydrogen or hydroxyl, and their A oxides. Salts, solvates, salts of the A-oxides and solvates of the A-oxides and salts. The invention also relates to substituted isoquinoline-piperidinyl-methanone derivatives of the general formula (IA), (IB) or the general formula (IC)

in which

R ^{1 is} a group of the formula

stands, and

R ^{2 represents} hydrogen or hydroxyl, and their A'-oxides. Salts, solvates, salts of the A'-oxides and solvates of the A'-oxides and salts.

Compounds according to the invention are the compounds of the formula (IA), (IA '), (IB) and (IC) and their salts, solvates and solvates of the salts represented by the formula (IA), (IA'), (IB) and ( IC) encompassed compounds of the formulas mentioned below and their salts, solvates and solvates of the salts as well as the compounds encompassed by formula (I), mentioned below as exemplary embodiments and their salts, solvates and solvates of the salts, insofar as the formula (I ) included, the compounds mentioned below are not already salts, solvates and solvates of the salts.

Compounds according to the invention are also A'-oxides of the compounds of the formula (IA), (IA '), (IB) and (IC) and their salts, solvates and solvates of the salts. Physiologically acceptable salts of the compounds according to the invention are preferred as salts in the context of the present invention. Also included are salts which are not themselves suitable for pharmaceutical applications, but can be used, for example, for the isolation, purification or storage of the compounds according to the invention.

A suitable pharmaceutically acceptable salt of the compounds of the present invention can be, for example, an acid addition salt of a compound of the present invention having a sufficiently basic nitrogen atom in a chain or ring, such as an acid addition salt with an inorganic acid or "mineral acid", for example hydrochloric acid , Hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, disulphuric acid, phosphoric acid or nitric acid, or with an organic acid such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, hydrochloric acid, undecanoic acid, lauric acid - (4-

Hydroxybenzoylbenzocic acid c. Camphoric acid, cinnamic acid, cyclopentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulphonic acid, itaconic acid, trifluoromethanesulphonic acid, benzenesulphonic acid, benzene-sulphonic acid, toluosulphonic acid, 2-sulfonsulphonic acid, toluenesulphonic acid, dodecylsulphonic acid, benzenesulphonic acid - Naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanic acid,

Glycerophosphoric acid, aspartic acid, sulfosalicylic acid or thiocyanic acid.

Another suitable pharmaceutically acceptable salt of a sufficiently acidic compound of the present invention is also an alkali salt, for example a sodium or potassium salt, an alkaline earth salt, for example a calcium, magnesium or strontium salt, or an aluminum or zinc salt or an ammonium salt, which is derived is from ammonia or an organic primary, secondary or tertiary amine with 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, lime benzine, tris (hydroxethymethyl) amine '-Methylmorpholine. Arginine, lysine, 1,2-ethylenediamine, L'-methylpipcridine. N- methylglucamine, N. N- D i m e th y lg 1 ucam i n. A'-ethyl glucamine. 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quaternary Ammonium ion with 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra («- p ro py 1) am monium. Tetra ("- butyl) ammonium, A-benzyl-A.A.A-trimethylammonium, choline or benzalkonium.

The person skilled in the art is also aware that acid addition salts of the claimed compounds can be produced by reacting the compounds with the corresponding inorganic or organic acid after a A number of known methods can be produced. Alternatively, alkali and alkaline earth salts of the acidic compounds according to the invention are prepared by reacting the compounds according to the invention with the appropriate base according to various known methods.

The present invention includes all possible salts of the compounds of the present invention as individual salts or as a mixture of these salts in any proportion.

If in the present text, in particular in the experimental part, a compound is mentioned as a salt form with the corresponding base or acid for the synthesis of intermediates and examples of the present invention, the exact stoichiometric composition of the salt form, as determined by the respective production and / or purification method obtained, in most cases not known. Unless otherwise stated, additions to chemical names or structural formulas that refer to salts, such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF3COOH”, “x Na ⁺ ” mean a salt form , the stoichiometry of this salt is not given. This applies accordingly to cases in which synthesis intermediates or example compounds or salts thereof were obtained as solvates, for example as hydrates, according to the production and / or purification process described.

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

The compounds according to the invention can exist in different stereoisomeric forms depending on their structure, i.e. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropic isomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers. For this purpose, chromatographic methods are preferably used, in particular HPLC chromatography on achiral or chiral separation phases. In the case of carboxylic acids as intermediate or end products, separation via diastereomeric salts with the aid of chiral amine bases can alternatively also take place.

In the context of the present invention, the term “enantiomerically pure” is understood to mean that the compound in question is present in an enantiomeric excess of more than 95%, preferably more than 98%, with regard to the absolute configuration of the chiral centers. The enantiomeric excess (ee value) is calculated by evaluating the chromatogram of an HPLC analysis on a chiral phase using the following formula: Enantiomer 1 (area percent) - Enantiomer 2 (area percent)

Enantiomer 1 (area percent) + enantiomer 2 (area percent)

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

The present invention also includes all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention is against another atom of the same atomic number, but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature (“unnatural component”) ) is exchanged. The expression “unnatural part” is to be understood as a part of such an isotope that is higher than its natural abundance. The natural frequencies of isotopes to be used in this context can be found in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70 (1), 217-235, 1998. Examples of isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine , like ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ C1, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound according to the invention, such as in particular those in which one or more radioactive isotopes are incorporated, can be useful, for example, for investigating the mechanism of action or the distribution of active substances in the body; Due to their comparatively easy production and detection, compounds labeled with ³ H or ¹⁴ C isotopes are particularly suitable for this purpose. In addition, the incorporation of isotopes, such as deuterium, can lead to certain therapeutic advantages as a result of greater metabolic stability of the compound, such as, for example, an extension of the half-life in the body or a reduction in the required effective dose; Such modifications of the compounds according to the invention can therefore optionally also represent a preferred embodiment of the present invention. With regard to the treatment and / or prophylaxis of the disorders indicated here, the isotopic variant (s) of the compounds of the general formula (I) preferably contain deuterium (“deuterium-containing compounds of the general formula (I)”). Isotopic variants of the compounds of the general formula (I) into which one or more radioactive isotopes, such as ³ H or ¹⁴ C, are incorporated, are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred because they are easy to install and detect. Positron-emitting isotopes such as ¹⁸ F or ^U C can be incorporated into a compound of the general formula (I). These isotopic variants of the compounds of general formula (I) are suitable for use in in vivo imaging applications. Deuterium-containing and ¹³ C-containing compounds of the general formula (I) can be used in preclinical or clinical studies Mass spectrometry analyzes can be used (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131). Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the instructions given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

Isotopic variants of the compounds of the general formula (IA) and (IB) can generally be prepared by methods known to the person skilled in the art, such as those described in the schemes and / or examples described here, by replacing a reagent with an isotopic variant of the reagent, preferably a deuterium-containing reagent, replaced. Depending on the desired deuteration sites, in some cases deuterium from D2O can either be incorporated directly into the compounds or into reagents that can be used for the synthesis of such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al ., Chem. Eur. J, 2007, 13, 4052). A photochemical deuteration and tritiation method has also been described (YY Loh et al., Science 10.1126 / science. Aap9674 (2017). A useful reagent for incorporating deuterium into molecules is also deuterium gas. A quick route to incorporating deuterium is catalytic deuteration of olefinic bonds (HJ Leis et al., Curr. Org. Chem., 1998, 2, 131; JR Morandi et al., J. Org. Chem., 1969, 34 (6), 1889) and acetylenic bonds (NH Khan, J. Am. Chem. Soc., 1952, 74 (12), 3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865). For the direct exchange of hydrogen for deuterium in hydrocarbons containing functional groups Metal catalysts (ie, Pd, Pt, and Rh) in the presence of deuterium gas can be used (JG Atkinson et al., U.S. Patent 3,966,781) Various deuterated reagents and building blocks are commercially available from companies such as C / D / N Isotopes, Quebec, Canada ; Cambridge Isotopes Laboratory atories Ine., Andover, MA, USA; and CombiPhos Catalysts, Ine., Princeton, NJ, USA. Further information on the state of the art with regard to deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem., 1990, 55, 3992-3997; Hanzlik, R. P. et al., Biochem. Biophys. Res. Commun., 1989, 160, 844; Reider, P.J. et al., J. Org. Chem., 1987, 52, 3326-3334; M. Jarman et al., Carcinogenesis, 1993, 16 (4), 683-688; J. Atzrodt et al. , Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., 2000, J. Chem. Soc, Chem. Commun. , 1519-1520; K. Kassahun et al., WO 2012/112363.

In addition, the present invention also comprises prodrugs of the compounds according to the invention. The term “prodrugs” encompasses compounds which can themselves be biologically active or inactive, but are converted into compounds according to the invention during their residence time in the body (for example metabolically or hydrolytically). For the purposes of the present invention, the term “treatment” or “treat” includes inhibiting, delaying, stopping, relieving, weakening, restricting, reducing, suppressing, suppressing or curing a disease, ailment, a disease, an injury or a health Disruption, development, course or progression of such conditions and / or the symptoms of such conditions. The term “therapy” is understood here to be synonymous with the term “treatment”.

The terms "prevention", "prophylaxis" or "prevention" are used synonymously in the context of the present invention and denote the avoidance or reduction of the risk, an illness, a disease, an illness, an injury or a health disorder, an unfolding or getting, experiencing, suffering or having a progression of such conditions and / or the symptoms of such conditions.

The treatment or prevention of an illness, ailment, a disease, an injury or a health disorder can be partial or total.

In one embodiment of the present invention, the compound (I-A) is in the form of the N-oxide (I-Al):

in which the radicals RI and R2 have the meanings given above.

In a further embodiment of the present invention, the compound (I-A) is in the form of the N-oxide (I-A ‘1):

in which the radicals RI and R2 have the meanings given above. Compounds from the group of the formula are preferred

Compounds of the formula are also preferred

The compounds (I-C-1), (I-A‘-2) and (I-A‘-3) are particularly preferred. The compounds (I-C-1) and (I-A‘-2) are very particularly preferred.

Compounds of the general formula (I) and their preparation are disclosed in WO 2015/091414 A1. The compounds of the formula (IA), (IB) and (IC) according to the invention can be prepared by the known organic synthesis techniques.

The production of the metabolite (I-A‘-2)

takes place, for example, starting from the compound of the general formula (I) by reaction with a protic solvent, such as, for example, a carboxylic acid or mineral acid. For example, formic acid, acetic acid, citric acid or hydrochloric acid, nitric acid, sulfuric acid or sulfonic acids are suitable. Sulfuric acid is preferred.

For the synthesis of the metabolite (IA'-2) the compound benzyl- (l - {[2- (2-oxa-6- azaspiro [3.3] heptan-6-yl) pyrimidin-5-yl] carbonyl} piperidine- 4-yl) carbamate

with 2- (2,4-dinitrophenyl) isoquinolinium chloride according to Barbier et al, J. Org. Chem, 1996, Vol. 61, 9596-9598 to (M-2)

implemented.

The metabolites (IBl) and (IA'-3) are prepared starting from compound (I), for example enzymatically in the presence of oxygen by cytochrome P450 monooxygenases in a temperature range of approx. 20 to 40 ° C. Suitable for this are, for example, human CYP3A4 as a microsome preparation from overexpressing insect cells or water-soluble CYP102A1 variants that have been overexpressed in a suitable microorganism such as bacillus megaterium (BM3) (e.g. Arnold et al, Chem. Eur. J. 2009, Vol . 15, 11723-11729). CYP 102A1 _BM3 variants and a temperature of 37 ° C are preferred.

The process for the preparation of the metabolite (IA'-1) comprises steps 1) to 5), wherein in the first step (1) 2- (2-oxa-6-azaspiro [3.3] hept-6-yl) pyrimidin-5 -carboxylic acid (compound from Example 18A) between 40 ° C and 80 ° C, preferably at 60 ° C with a protic solvent to give compound (II)

is implemented. Suitable protic solvents are, for example, carboxylic acids or mineral acids such as formic acid, acetic acid, citric acid or hydrochloric acid, nitric acid, sulfuric acid or sulfonic acids. Sulfuric acid and a temperature of 60 ° C. are preferred.

The compound (II) is for example base-catalyzed in the presence of an oxidizing agent to compound (III) by known processes in the second step (2)

implemented. Suitable oxidizing agents are, for example, strong oxidizing agents such as chromium trioxide, hypervalent Iodreagenzien (for example, 2-iodoxybenzoic acid, IBX), 2,2,6,6-tetramethyl-piperidin-l-oxyl (TEMPO), potassium peroxomonosulfate (Oxone ^®) and potassium permanganate. Potassium permanganate is preferred.

Bases are, for example, alkali hydroxides, e.g. Lithium, potassium or sodium hydroxide, each of which can be used in the form of an aqueous solution. An aqueous solution of sodium hydroxide is preferred.

In a third step (3), compound (III) is converted to compound (IV) by known processes in the presence of an acid chloride former and an alcohol

esterified.

Suitable alcohols are, for example, methanol, ethanol, n-propanol or isopropanol. Methanol or ethanol are preferred. Examples of suitable acid chloride formers are phosphorus trichloride (PC13) or phosphorus pentachloride (PC15) or thionyl chloride. Thionyl chloride is preferably used for such an esterification. The reaction takes place at room temperature and normal pressure.

The compound (IV) is converted to compound (V) in a further reaction step (4) in the presence of a dehydrating reagent and a base

implemented.

Suitable dehydration reagents are, for example, carbodiimides such as A, A'-dicthyl-, N, N, '-dipropyl-, A, A'-diisopropyl-, A, A'-dicyclohexylcarbodiimide, A- (3-dimethylaminoisopropyl) -A '- ethylcarbodiimide hydrochloride (EDC), A-cyclohexylcarbodiimide-A'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbony ldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-fert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride (T3P), or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 0- (benzotriazol-1-yl) - N, N, N, N ', / V'-tetra-methyluronium-hexafluorophosphate (HBTU), 2- (2-oxo- 1 - (2H) -pyridyl) -1, 1, 3,3-tetra-methyluronium tetrafluoroborate (TPTU) or G- (7-Azabcnzotriazol- 1 -yl) -A, AA 'A'-tctramcthyl uroniumhxafluorophosphat (HATU), or 1-Hydroxybenzotriazol (HOBt), or Benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (BOP) phosphonium Hydroxysuccinimide. or mixtures of these, with bases.

Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as dietyl ether, dioxane or tetrahydrofuran, or dimethylformamide, or acetic acid or glacial acetic acid, or dichloromethane, trichloromethane or 1,2-dichloroethane. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.

Bases are for example organic bases such as trialkylamines e.g. Triethylamine, A-methylmorpholine. A-methylpiperidine. 4-dimethylaminopyridine or diisopropylethylamine, diisopropylethylamine is preferred.

In a last reaction step (5) the compound (M-3) is obtained from compound (V) by ester hydrolysis. The saponification is generally carried out in inert solvents in the presence of at least one base, preferably in a temperature range from 0 ° C. to 60 ° C. at atmospheric pressure.

Bases are, for example, alkali hydroxides, e.g. Lithium, potassium or sodium hydroxide, each of which can be used in the form of an aqueous solution. Aqueous solutions of lithium hydroxide and sodium hydroxide are preferred.

Inert solvents are, for example, polar solvents such as alcohols, for example methanol, ethanol, n-propanol or isopropanol, or ethers such as dioxane, tetrahydrofuran, or dimethylformamide. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.

The compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological effects, including valuable pharmacokinetic properties. These are selective adrenoreceptor ot2c receptor antagonists which lead to vascular relaxation and / or to an inhibition of platelet aggregation and / or to a lowering of blood pressure and / or to an increase in the coronary or peripheral blood flow. They are therefore suitable for the treatment and / or prophylaxis of diseases, preferably of cardiovascular diseases, diabetic microangiopathies, diabetic ulcers on the extremities, in particular for promoting the Wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart diseases, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemias, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication in humans and animals, and peripheral neuropathies.

In particular, the compounds according to the invention show a disease-selective improvement in the peripheral blood flow (micro and macro circulation) under pathophysiologically changed conditions such as e.g. as a result of diabetes or atherosclerosis.

The compound of the formula (I) and its metabolites are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

The compound of the formula (I) and its metabolites are therefore suitable for the treatment of cardiovascular diseases such as, for example, for the treatment of high blood pressure, primary and / or secondary prevention and treatment of heart failure, for the treatment of stable and unstable angina pectoris, pulmonary hypertension, peripheral and cardiac vascular diseases (e.g. peripheral occlusive disease), arrhythmias, for the treatment of thromboembolic diseases and ischemias such as myocardial infarction, stroke, transient and ischemic attacks, peripheral circulatory disorders, to prevent restenoses such as after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal angioplasties (PTA), percutaneous transluminal angioplasties ) and bypass as well as for the treatment of ischemia syndrome, atherosclerosis, asthmatic diseases, diseases of the urogenital system such as prostate hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence z can be used.

In addition, the compound of the formula (I) and its metabolites can be used for the treatment of primary and secondary Raynaud's phenomenon, of microcirculatory disorders, intermittent claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic nephropathy, diabetic retinopathy, diabetic ulcers on the extremities, diabetic erectile ulcers Dysfunction, CREST syndrome, erythematosis, onychomycosis, tinnitus, dizziness, sudden hearing loss, Meniere's disease and rheumatic diseases.

The compounds of the formula (I) and its compounds are also suitable for the treatment of respiratory distress syndromes and chronic obstructive airways diseases (COPD), of acute and chronic renal insufficiency and for promoting wound healing and, in particular, diabetic wound healing.

In addition, the compound of the formula (I) and its metabolites are suitable for the treatment and / or prophylaxis of accompanying and / or secondary diseases of diabetes mellitus. Examples of accompanying and / or secondary diseases of diabetes mellitus are diabetic heart diseases, such as diabetic coronary heart diseases, diabetic coronary microvascular disease (MVD), diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, high blood pressure, diabetic microangiopathy, diabetic neuropathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers on the extremities, and diabetic foot syndrome. The compound of the formula (I) and its metabolites are also suitable for promoting diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers. The promotion of the wound healing of diabetic foot ulcers is defined, for example, as an improvement in wound closure.

Furthermore, the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraines. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (apoplexia cerebri) such as stroke, cerebral ischemia and head and brain trauma . The compound of the formula (I) and its metabolites can also be used to combat painful conditions.

In addition, the compound of the formula (I) and its metabolites can also be used for the treatment and / or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thrombosis, edema, cancer (skin cancer, liposarcomas, carcinoma of the gastric Intestinal tract, liver, pancreas, lungs, kidneys, ureters, prostate and genital tract), diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis , Schizophrenia), from inflammatory diseases, autoimmune diseases (Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis, asthma), kidney diseases (glomerulonephritis), thyroid diseases (hyperthyroidism), hyperhidrosis, liver disease (psoriasis), skin diseases (pancreatic disease) , Eczema, neurodermatitis, dermatitis, keratitis s, scarring, wart formation, chilblains), skin transplants, viral diseases (HPV, HCMV, HIV), cachexia, osteoporosis, avascular bone necrosis, gout, incontinence, for wound healing, for wound healing in patients with sickle cell anemia, and for angiogenesis.

The present invention further relates to the use of the compound of the formula (I) and its metabolites for the treatment and / or prophylaxis of diseases, preferably of thromboembolic diseases and / or thromboembolic complications.

The “thromboembolic diseases” in the sense of the present invention include in particular diseases such as myocardial infarction with an increase in the ST segment (STEMI) and without an increase in the ST segment (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolisms, deep venous thrombosis and renal venous thrombosis and thrombotic and transembolic attacks, ischromic and pulmonary ischromic and pulmonary vein ischromic and transembolic attacks Hypertension.

The substances are therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as, for example, brain ischemia, stroke and systemic thromboembolism and ischemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those who are undergoing cardioversion , also in patients with heart valve diseases or with intravascular bodies such. B. artificial heart valves, catheters, intra-aortic bailon counter-pulsation and pacemaker probes. In addition, the compounds according to the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).

Thromboembolic complications also occur with microangiopathic hemolytic anemias, extracorporeal blood circulation, such as e.g. Hemodialysis, hemofiltration, cardiac support system and artificial heart, as well as heart valve prostheses.

The compound of the formula (I) and its metabolites are particularly suitable for the primary and / or secondary prevention and treatment of heart failure.

In the context of the present invention, the term heart failure also encompasses more specific or related forms of disease such as right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, heart failure with heart valve defects, mitral valve stenosis, tridal stenosis, aortic valve insufficiency, mitral insufficiency, aortic valve insufficiency. Pulmonary valve insufficiency, combined heart valve defects, heart muscle inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcohol-toxic cardiomyopathy, cardiac storage diseases, diastolic heart failure and systolic heart failure.

The compound of the formula (I) and its metabolites are very particularly suitable for the treatment and / or prophylaxis of cardiovascular diseases, in particular heart failure, and / or circulatory disorders and microangiopathies in diabetes.

The compound of the formula (I) and its metabolites are also suitable for the primary and / or secondary prevention and treatment of the abovementioned diseases in children. The present invention further relates to the compound of the formula (I) and its metabolites for use in a method for the treatment and / or prophylaxis of diseases, in particular the diseases mentioned above.

The present invention also relates to the use of the compound of the formula (I) and its metabolites for the treatment and / or prophylaxis of diseases, in particular the diseases mentioned above.

The present invention further relates to the use of the compound of the formula (I) and its metabolites for the production of a medicament for the treatment and / or prophylaxis of illnesses, in particular the diseases mentioned above.

The present invention further relates to a method for the treatment and / or prophylaxis of diseases, in particular the diseases mentioned above, using a therapeutically effective amount of a compound of the formula (I) and its metabolites.

The compound of the formula (I) and its metabolites can be used alone or, if necessary, in combination with other active ingredients. The present invention also relates to medicaments containing a compound of the formula (I) and its metabolites and one or more further active ingredients, in particular for the treatment and / or prophylaxis of the diseases mentioned above. Suitable combination active ingredients are exemplified and preferred: active ingredients that change lipid metabolism, antidiabetic agents, blood pressure reducers, sympathetic tone lowering agents, blood circulation-promoting and / or antithrombotic agents, and antioxidants, aldosterone and mineralocorticoid receptor antagonists, organic vasopressin receptor antagonists Nitrates and NO donors, IP receptor agonists, positive inotropic compounds, calcium sensitizers, ACE inhibitors, cGMP and cAMP modulating compounds, natriuretic peptides, NO-independent stimulators of guanylate cyclase, NO-independent activators of guanylate cyclase, inhibitors of human neutrophils Elastase, compounds that inhibit the signal transduction cascade, compounds that modulate the heart's energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB i-receptor antagonists, LTBzi-synthesis inhibitors), analgesics (aspirin), antidepressants and other psychotropic drugs.

The present invention relates in particular to combinations with at least one of the compounds of the formula (I) and its metabolites with at least one active ingredient that changes lipid metabolism, an antidiabetic, an antihypertensive agent and / or an antithrombotic agent. The compound of the formula (I) and its metabolites can preferably be combined with one or more of the active ingredients mentioned below:

• Active ingredients that change lipid metabolism, for example and preferably from the group of

HMG-CoA reductase inhibitors from the class of statins, such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors such as, for example and preferably BMS-188494 or TAK-475, ACAT inhibitors such as, for example and preferably, melinamide, pactimibe, eflucimibe or SMP-797, LDL receptor inducers, cholesterol absorption inhibitors such as, for example and preferably, ezetimibe, tiqueside or pamaqueside, polymeric bile acid adsorbers such as and for example preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide, bile acid reabsorption inhibitors such as, for example and preferably, ASBT (= IBAT) inhibitors such as Elobixibat (AZD-7806), S-8921, AK-105, Canosimibe (BARI-1741, AVE-5530), SC-435 or SC-635, MTP inhibitors such as, for example and preferably, Implitapide or JTT-130, lipase inhibitors such as, for example and preferably, orlistat, LpL activators, fibrates, niacin, CETP inhibitors, such as, for example and preferably, torcetrapib, dalcetrapib (JTT-705) or CETP vaccine (Avant), PPAR-g and / or PPAR-5 agonists, such as, for example and preferably, pioglitazone or rosiglitazone and / or Enduroboi (GW-501516), RXR modulators, FXR modulators, LXR modulators,

Thyroid hormones and / or thyroid mimetics such as, for example and preferably, D-thyroxine or 3,5,3'-triiodothyronine (T3), ATP citrate lyase inhibitors, Lp (a) antagonists, cannabinoid receptor 1 antagonists, such as for example and preferably rimonabant or surinabant (SR- 147778), leptin receptor agonists, bombesin receptor agonists, histamine receptor

Agonists, agonists of the niacin receptor, such as, for example and preferably, niacin, acipimox, acifran or Radecol, and antioxidants / radical scavengers such as, for example and preferably, probucol, succinobucol (AGI-1067), BO-653 or AEOL-10150;

• Antidiabetic drugs that are mentioned in the Red List 2014, Chapter 12. Antidiabetic agents are preferably understood to mean insulin and insulin derivatives and orally active hypoglycemic active ingredients. Insulin and insulin derivatives here include both insulins of animal, human or biotechnological origin and mixtures thereof. The orally active hypoglycemic active ingredients preferably include sulphonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors and PPAR-gamma agonists. Tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide are exemplified and preferred as sulphonylureas, metformin is exemplified and preferred as biguanide, repaglinide or nateglinide are exemplified and preferably mentioned as meglitinide derivatives, glucosidase inhibitors are exemplified and preferred Acarbose, oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK 1- Receptor agonists, leptin receptor agonists, inhibitors of liver enzymes which are involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake and potassium channel openers, such as those disclosed in WO 97/26265 and WO 99/03861 are;

• Active substances that lower blood pressure, for example and preferably from the group of calcium antagonists such as, for example and preferably, nifedipine, amlodipine, verapamil or diltiazem, angiotensin AII antagonists, such as, for example and preferably, losartan, valsartan, candesartan, embusartan or telmisartan, ACE inhibitors , such as, for example and preferably, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril, beta-receptor blockers, such as, for example and preferably, propranolol, atenolol, timolol, pindolol, metolol, penupranolol, nadupranolol, branololol , Mepindolol, Carazalol, Sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindolol, alpha-receptor blockers, such as, for example and preferably, prokinasein inhibitors Inhibitors and vasopeptidase inhibitors, as well as diuretics, as exemplified and preferably a loop diuretic such as furosemide, bumetanide or torsemide, or a thiazide or thiazide-like diuretic such as chlorothiazide or hydrochlorothiazide or Al antagonists such as Rolofylbne, Tonopofylline and SLV-320;

• agents which lower the sympathetic tone, such as, for example and preferably, reserpine, clonidine or alpha-methyl-dopa, or in combination with a potassium channel agonist, such as, for example and preferably, minoxidil, diazoxide, dihydralazine or hydralazine;

• Antithrombotic agents, for example and preferably from the group of platelet aggregation inhibitors, such as, for example and preferably, aspirin, clopidogrel, ticlopidine, cilostazol or dipyridamole, or anticoagulants such as thrombin inhibitors, such as, for example and preferably, Ximelagatran, Melagudinran, Bivlexane II / IIIa antagonists, such as, for example and preferably, tirofiban or abciximab, a factor Xa inhibitor, such as, for example and preferably, rivaroxaban, edoxaban (DU- 176b), apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM- 150, KFA- 1982, EMD-503982, MCM-17, MEN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428, with heparin or a low molecular weight (FMW) heparin derivative or with a vitamin K antagonist such as, for example and preferably, coumarin;

Aldosterone and mineralocorticoid receptor antagonists, such as, for example and preferably, spironolactone, eplerenone or finerenone;

Vasopressin receptor antagonists such as, by way of example and by way of preference, conivaptan, tolvaptan, fixivaptan or satavaptan (SR-121463); • organic nitrates and NO donors such as, for example and preferably, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, or in combination with inhaled NO;

• IP receptor agonists such as, for example and preferably, iloprost, treprostinil, beraprost and selexipag (NS -304);

• positive-inotropically active compounds, such as, for example and preferably, cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, adrenaline, noradrenaline, dopamine or dobutamine;

• Calcium sensitizers, such as, for example and preferably, levosimendan;

• Compounds that inhibit the breakdown of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil and Tadalafil and PDE 3 inhibitors such as milrinone;

• natriuretic peptides, e.g. “atrial natriuretic peptide” (ANP, Anaritide), “B-type natriuretic peptide” or “brain natriuretic peptide” (BNP, Nesiritide), “C-type natriuretic peptide” (CNP) and urodilatin;

• NO-independent, but heme-dependent stimulators of guanylate cyclase, such as in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

• NO- and heme-independent activators of guanylate cyclase, such as in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

• Inhibitors of human neutrophil elastase (HNE), such as Sivelestat and DX-890 (Reltran);

• compounds which inhibit the signal transduction cascade, such as, for example, tyrosine kinase inhibitors and multikinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and or

• Compounds that influence the heart's energy metabolism, such as Etomoxir, dichloroacetate, ranolazine and trimetazidine.

Particularly preferred in the context of the present invention are combinations containing at least one of the compound of the formula (I) and its metabolites and one or more other active ingredients selected from the group consisting of HMG-CoA reductase inhibitors (statins), diuretics, beta

Receptor blockers, organic nitrates and NO donors, ACE inhibitors, angiotensin all- Antagonists, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors and anticoagulants, and their use for the treatment and / or prevention of the aforementioned diseases.

Particularly preferred within the scope of the present invention are combinations containing at least one of the compound of formula (I) and its metabolites and one or more other active ingredients selected from the group consisting of heparin, antidiabetic agents, ACE inhibitors, diuretics and antibiotics, and their use in a method for promoting diabetic wound healing and for treating and / or preventing diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers.

Particularly preferred within the scope of the present invention is the use of at least one of the compounds of the formula (I) and its metabolites in a method for promoting diabetic wound healing and for treating and / or preventing diabetic ulcers on the extremities, in particular for promoting diabetic wound healing Foot ulcers, where the compound of the formula (I) is used in addition to one or more of the following physical and / or topical therapies: wound management such as bandages, wound excision, weight loss with adapted footwear, PDGF (Regranex), hyperbaric oxygen therapy, wound therapy with negative pressure.

The compound of the formula (I) and its metabolites can act systemically and / or locally. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

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

For oral administration, according to the prior art, fast and / or modified application forms which release the compound of the formula (I) and its metabolites and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form are suitable, e.g. Tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings that control the release of the compound according to the invention), tablets or films / wafers that disintegrate quickly in the oral cavity, films / fyophylisates, capsules (for example hard or Soft gelatine capsules), coated tablets, granulates, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorption step (eg intravenous, intraarterial, intracardial, intraspinal or intralumbar) or with inclusion of an absorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable forms of administration for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Oral application is preferred.

In the exemplary use of the compound of formula (I) and its metabolites for promoting diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers, application in the form of a topical formulation is preferred in addition to oral application.

For the other application routes, e.g. Inhalation medicaments (e.g. powder inhalers, nebulizers), nasal drops, solutions, sprays; Lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as plasters), milk, Pastes, foams, powder, implants or stents.

The compound of the formula (I) and its metabolites can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These auxiliary materials include Carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers ( eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and taste and / or odor correctors.

The present invention also relates to medicaments which contain at least one compound of the formula (I) and its metabolites, preferably together with one or more inert, non-toxic, pharmaceutically suitable auxiliary substances, and their use for the purposes mentioned above.

In general, it has proven to be advantageous for oral administration to administer amounts of about 0.1 to 250 mg per 24 hours, preferably from 0.1 to 50 mg per 24 hours, in order to achieve effective results. The dose can be divided into several applications per day. Examples are application two or three times a day. Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application takes place.

The present invention also provides a compound of the formula (I) and its metabolites, as described above, for use in a method for the treatment and / or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities , in particular to promote wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart diseases, peripheral and cardiac vascular diseases, thromboembolic diseases, and ischemia, peripheral microcirculatory disorders, Raynaud circulatory disorders , Intermittent claudication, and peripheral and autonomic neuropathies.

Another object of the present invention is a compound of formula (I) and its metabolites, as described above, for use in a method for the treatment and / or prophylaxis of primary and secondary forms of heart failure, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemias , peripheral circulatory disorders, Raynaud's phenomenon, microcirculation disorders, intermittent claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic nephropathy, diabetic retinopathy, diabetic ulcers on the extremities and CREST syndrome, as well as for diabetic wound healing of diabetic foot ulcers, in particular to promote wound healing in diabetic foot ulcers .

Another object of the present invention is a compound of formula (I) and its metabolites, as described above, for the production of a medicament for the treatment and / or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities, in particular to promote the wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart diseases, peripheral and cardiac vascular diseases, thromboembolic diseases and ischaemia, peripheral microcirculatory disorders, CR-ray disorders, Intermittent claudication, and peripheral and autonomic neuropathies.

Another object of the present invention is the use of a compound of the formula (I) and its metabolites, as described above, for the production of a medicament for the treatment and / or prophylaxis of primary and secondary forms of cardiac insufficiency, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, microcirculatory disorders, intermittent claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic nephropathy, diabetic retinopathy, diabetic syndromes, and especially for EST on the extremities and CR to promote wound healing of diabetic foot ulcers.

The present invention also relates to a medicament containing a compound of the formula (I) and its metabolites, as described above, in combination with one or more inert, non-toxic, pharmaceutically suitable auxiliary substances.

Another object of the present invention is a medicament containing a compound of the formula (I) and its metabolites, as described above, in combination with one or more other active ingredients selected from the group consisting of active ingredients that change lipid metabolism, antidiabetic agents, blood pressure reducers, Agents that lower the sympathetic tone, agents that promote blood circulation and / or have an antithrombotic effect, as well as antioxidants, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, positive inotropic compounds, calcium sensitizers ACE inhibitors, cGMP and cAMP modulating compounds, natriuretic peptides, NO-independent stimulators of guanylate cyclase, NO-independent activators of guanylate cyclase, inhibitors of human neutrophil elastase, compounds that inhibit the signal transduction cascade, the energy metabolism of H. ore modulating compounds, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory drugs, analgesics, antidepressants and other psychotropic drugs.

Another object of the present invention is a method for the treatment and / or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities, in particular for promoting the wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile Dysfunction, diabetic heart failure, diabetic coronary microvascular diseases, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemias, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and effective autonomic neuropathies in humans and animals at least one compound of the formula (I) and its metabolites, as described above, or a medicament, as described above. Another object of the present invention is a method for the treatment and / or prevention of prophylaxis of primary and secondary forms of heart failure, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemias, peripheral circulatory disorders, Raynaud's phenomenon, microcirculatory disorders, intermittent claudication, peripheral and autonomic Neuropathies, diabetic microangiopathies, diabetic nephropathy, diabetic retinopathy, diabetic ulcers on the extremities and CREST syndrome, as well as for diabetic wound healing, in particular to promote the wound healing of diabetic foot ulcers, in humans and animals by administering an effective amount of at least one compound of the formula ( I) and its metabolites, as described above, or a drug, as described above.

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

If in the synthesis intermediates and exemplary embodiments of the invention described below, a compound is listed in the form of a salt of the corresponding base or acid, the exact stoichiometric composition of such a salt is as it is according to the respective preparation and / or Purification method obtained was usually not known. Unless specified more precisely, name and structural formula additions such as "hydrochloride", "trifluoroacetate", "oxalate salt", "sodium salt" or "x HCl", "x CF3COOH", "xC" are therefore ₂ 0 ₄ ² "," x Na ⁺ "are not to be understood stoichiometrically in the case of such salts, but are purely descriptive with regard to the salt-forming components they contain.

The same applies analogously to the case that synthesis intermediates or exemplary embodiments or salts thereof were obtained in the form of solvates, such as hydrates, whose stoichiometric composition (if defined type) is not known, according to the production and / or purification processes described. A) Examples

Abbreviations:

ACN acetonitrile

approx

d day (s), doublet (for NMR)

TLC thin layer chromatography

dd double doublet (with NMR)

DIPEA A ', A'- D i i so p ro p y 1 c th y 1 am in

DMF A ', A'- D i m c th y 1 fo rm am i d

DMSO dimethyl sulfoxide

d. Th. Of theory (at yield)

eq. Equivalent (s)

ESI electrospray ionization (for MS)

h hour (s)

HATU <A- (7-Azabenzotriazol-1-yl) -A ', A', A "A'-tramethyluronium oxafluorophosphate

HPLC high pressure, high performance liquid chromatography

HV high vacuum

m multiplet (with NMR)

min minute (s)

MS mass spectrometry

MWCO Molecular weight cut-off

NMR nuclear magnetic resonance spectroscopy

q quartet (with NMR)

RP reverse phase (with HPLC)

RT room temperature

Rt retention time (with HPLC)

s singlet (in NMR)

SPE Solid Phase Extraction

t triplet (with NMR)

T3P propylphosphonic anhydride 50% in ethyl acetate or DMF

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran LC-MS and HPLC methods:

Method 1 (LC-MS): Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 m 50 mm x 1 mm; Eluent A: 1 1 water + 0.25 ml 99% formic acid, eluent B: 1 1 acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A - 1.2 min 5% A - 2.0 min 5% A; Oven: 50 ° C; Flow rate: 0.40 ml / min; UV detection: 210 - 400 nm.

Method 2 (LC-MS): Instrument MS: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0x50mm 3.5-Micron; Eluent A: 1 1 water + 0.01 mol ammonium carbonate, eluent B: 1 1 acetonitrile; Gradient: 0.0 min 98% A— 0.2 min 98% A—> 3.0 min 5% A— 4.5 min 5% A; Oven: 40 ° C; Flow rate: 1.75 ml / min; UV detection: 210 nm.

Method 3 (LC-MS): Instrument MS: Agilent 6200 Series TOF; Instrument HPLC: Agilent 1290 Infinity Series, column: Kinetex ^® CI 8, 50x2.1 mm, 1.7 square meters; Eluent A: 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0-0.2 min 5% B—> -3.0 min 90% B—> -3.5 min 90% B; Oven: 40 ° C, flow: 1 ml / min, UV detection: 210 nm.

Method 4 (LC-MS): Instrument: Thermo Scientific FT-MS UHPLC + system; Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 qm; Eluent A: 1 1 water + 0.01% formic acid; Eluent B: 1 1 acetonitrile + 0.01% formic acid: 0.0 min 10% B 2.5 min 95% B—> 3.5 min 95% B; Oven: 50 ° C; Flow rate: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm

Method 5 (LC-MS): Instrument: Agilent 6200 series TOF / 6500 series, Q-TOF B.06.01 (B6172 SP1); Column: Kinetex, 50 x 2.1 mm, C18 1.7 square meters; Eluent A: water + 0.1% formic acid; Eluent B: acetonitrile + 0.1% formic acid: 0.0 min 5% B - 0.2 min 5% B - 3.0 min 90% B - 3.5 min 90% B; Oven: 40 ° C; Flow rate: 1.0 ml / min; UV detection: 210 nm

Method 1 (HPLC-UV): Nucleodur Gravity ^® C18, 250 x 4 mm, 5 sqm, Eluent A: 0.2% formic acid, mobile phase B: acetonitrile, 0 min 95% A- 60 min 15% B; Oven: 20 ° C, flow: 1 ml / min, UV detection: 270 nm.

Method 2 (HPLC-UV): Phenomenex Synergi HydroRP ^®, 150x2 mm, 4 sqm, Eluent A: 0.2% trifluoroacetic acid, mobile phase B: acetonitrile, isocratic 85% A / 15% B; Oven: 20 ° C, flow: 0.375 ml / min, UV detection: 268 nm.

Method 3 (HPLC-UV): Nucleodur® Gravity CI 8, 250 x 4 mm, 5 qm, eluent A: 0.2% phosphoric acid, eluent B: acetonitrile, 0 min 0% B—> 5 min 0% B—> 35 min 100% B; Flow: 1.5 ml / min, UV detection: 210 nm. Output connections

Example 1A

tert-Butyl 4- (3,4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylate

150 g (753 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate and 120 g (903 mmol) of 1,2, 3, 4- tetrahydroisoquinoline were dissolved in 1500 ml of THF, and 239 g (1129 mmol) of sodium triacetoxyborohydride were added the temperature of the mixture was kept at about 30 ° C. The mixture was stirred at RT for about 1 h and then about 1000 ml of saturated sodium hydrogen carbonate solution were added. It was extracted with about 500 ml of ethyl acetate. The organic phase was washed with a further 500 ml of saturated sodium hydrogen carbonate solution and with 200 ml of saturated sodium chloride solution. It was then dried over sodium sulfate, filtered and concentrated. 234 g (98% of theory) of the target product were obtained, which was processed further without further purification.

LC-MS [Method 1]: R _t = 0.72 min; MS (ESIpos): m / z = 317 (M + H) ⁺

^ -NMR (400MHz, CDCE): d [ppm] = 1.47 (s, 9 H) 1.48 - 1.60 (m, 2 H) 1.75 - 1.94 (m, 3 H) 2.56 - 2.66 (m, 1 H) 2.67 - 2.81 (m, 2 H) 2.81 - 2.93 (m, 4 H) 3.78 (s, 2 H) 4.08 - 4.27 (m, 1 H) 6.98 - 7.05 (m, 1 H) 7.07 - 7.14 (m, 3 H) .

Example 2A

2- (Piperidin-4-yl) -1, 2,3,4-tetrahydroisoquinoline hydrochloride

210 g (664 mmol) of the compound from Example 1A were dissolved in 1600 ml of dichloromethane, and 830 ml (3318 mmol) of 4M hydrogen chloride in dioxane were added, the temperature of the mixture being kept at 25-30 ° C. The product began to crystallize after about 1/3 of the addition. The mixture was stirred at RT for about 20 h and then about 2000 ml of tert-butyl methyl ether were added. The deposited precipitate was filtered off with suction, washed with tert-butyl methyl ether and dried in vacuo. 185 g (97% of theory) of the target product were obtained as a white solid. LC-MS r method 21: R _t = 2.08 min; MS (ESIpos): m / z = 217 (M + H) ⁺

^ -NMR (400MHz, DMSO-d ₆ ): d [ppm] = 1.96 - 2.20 (m, 2H), 2.28 - 2.44 (m, 2H), 2.81 - 3.51 (m, 6H),

3.51 - 3.80 (m, 3H), 4.33 - 4.51 (m, 2H), 7.17 - 7.35 (m, 4H), 8.92 - 9.10 (m, 1H), 9.12 - 9.32 (m, 1H), 11.47 (br. S , 1H).

Example 18A

2- (2-Oxa-6-azaspiro [3.3] hept-6-yl) pyrimidine-5-carboxylic acid

17.7 g of methyl 2- (2-oxa-6-azaspiro [3.3] hept-6-yl) pyrimidine-5-carboxylate (75 mmol) were placed in 120 ml of ethanol, 148 ml of 1 molar sodium hydroxide solution were added and the mixture was kept overnight at RT touched. The batch was concentrated and then only dissolved in approx. 150 ml of water and then adjusted to pH 5 with 1 M hydrochloric acid. The precipitated product was filtered off with suction and washed with water. 16.3 g of product (98% of theory) were isolated.

LC-MS I method 21: R _t = 0.53 min; MS (ESIpos): m / z = 222 (M + H) ⁺

^ -NMR (400MHz, DMSO-d ₆ ): d [ppm] = 4.30 (s, 4H), 4.73 (s, 4H), 8.74 (s, 2H), 12.87 (br.s, 1H).

Example 30A

Benzyl [l - {[2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-5-yl] carbonyl} piperidin-4-yl) carbamate

11.3 g (51.2 mmol) of the compound from Example 18A and 15.0 g (64.0 mmol) of 4-Cbz-aminopiperidine (CAS 182223-54-7, commercially available e.g. Apollo Scientific product code OR301035 ) were placed in 225 ml of dichloromethane, 35.7 ml (205 mmol) of N, N-diisopropylethylamine were added and then T3P (50% by weight solution in dichloromethane, euticals) was added dropwise at a maximum of 25.degree. The mixture was stirred at RT, after 1 hour 75 ml of water were added and the mixture was stirred vigorously for 30 minutes. The organic phase was separated off, dried over sodium sulfate, then filtered and the filtrate was concentrated. The residue was in Dichloromethane was added, 100 ml of diisopropyl ether were added, dichloromethane was distilled off at a bath temperature of 320 mbar / 40 ° C. and 150 ml of diisopropyl ether were added to the suspension obtained. The mixture was stirred overnight, the solid was isolated, washed twice with 25 ml of diisopropyl ether and dried at 35 ° C. in vacuo (28 g of crude product). 16.3 g of this crude product were taken up in 100 ml of 2-propanol and stirred at RT for 0.5 h. The solid was isolated, washed twice with 15 ml of 2-propanol and dried at 50 ° C. in vacuo. 10.8 g (48% of theory) of the target compound were obtained as a solid.

LC-MS I method 11: Rt = 0.71 min; MS (ESIpos): m / z = 438 (M + H) ⁺ H NMR (400 MHz, CHLOROFORM-d) d ppm 1.26 - 1.49 (m, 2 H) 1.96 - 2.12 (m, 2 H) 2.97 - 3.21 ( m, 2 H) 3.64-388 (m, 2 H) 4.14 (br. s, 1 H), 4.34 (s, 4 H) 4.54-477 (m, 1 H) 4.86 (s, 4 H) 5.04-5.17 (m, 2 H) 7.35 (s, 5 H) 8.41 (s, 2 H)

Example 31A

(4-aminopiperidin-1-yl) [2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-5-yl] methanone

10.8 g (24.7 mmol) of the compound from Example 30A were placed in a glass pressure reactor in 200 ml of methanol, and 2 g of 10% palladium on activated carbon (K-218M, Heraeus) were added. The reactor was rendered inert, pressurized with 3 bar hydrogen and the reaction mixture was stirred at RT overnight. After inertization, it was filtered through kieselguhr, washed with methanol and the filtrate was concentrated in vacuo to give a foamy residue. 8.2 g of the target compound (> 100% of theory) are obtained as a crude product which was further reacted directly.

LC-MS rmethod 41: Rt = 0.21 min; MS (ESIpos): m / z = 404 (M + H) Execution examples

Example 8 (compound I)

[4- (3, 4-Dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl] [2- (2-oxa-6-azaspiro [3.3] hept-6-yl) pyrimidin-5-yl] methanone

A mixture of 15.5 g (70.1 mmol) of the compound from Example 18A and 20.27 g (70.1 mmol) of the compound from Example 2A in 320 ml of acetonitrile was mixed with 61.0 ml (350.3 mmol) of N, N-diisopropylethylamine and 50.05 ml (84.1 mmol) T3P (50% by weight solution in ethyl acetate) was added and the mixture was then stirred at RT for 3 h. For work-up, 100 ml of saturated sodium hydrogen carbonate solution were added and the mixture was stirred at RT for 10 min. A further 200 ml of saturated sodium hydrogen carbonate solution were then added and the mixture was extracted with 500 ml of ethyl acetate. The organic phase was washed once each with saturated sodium hydrogen carbonate solution and sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product obtained was mixed with 100 ml of methanol and heated to 55 ° C., no clear solution being formed. The mixture was cooled to RT while stirring, and 250 ml of diethyl ether were added. After 30 min, the precipitated solid was filtered off with suction, washed with a little diethyl ether and dried in the LTV. 17.2 g (59% of theory) of the target compound were obtained.

LC-MS I method 11: R _t = 0.50 min; MS (ESIpos): m / z = 420 (M + H) ⁺

^ -NMR (400MHz, DMSO-d ₆ ): d [ppm] = 1.43 - 1.60 (m, 2H), 1.77 - 1.93 (m, 2H), 2.63 - 2.73 (m, 1H), 2.77 (s, 4H) , 2.81 - 3.15 (m, 2H), 3.5 - 4.7 (br. M, 2H), 3.70 (s, 2H), 4.26 (s, 4H), 4.73 (s, 4H), 6.99 - 7.13 (m, 4H) , 8.43 (s, 2H).

Example I-A’-2

{2- [3,3-Bis (hydroxymethyl) azetidin-1-yl] pyrimidin-5-yl} [4- (3,4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl] methanone

A suspension of 20 g (48 mmol) of the compound from Example 8 in 60 ml of water was treated with conc. Sulfuric acid (5.1 ml, 95 mmol) was added and the mixture was then heated to 70 ° C. for 3.5 h. The yellow-orange solution was cooled to RT, filtered and the filtrate was then lyophilized. The lyophilizate obtained was dissolved in THF, extracted with 1N sodium hydroxide solution and washed twice with water. The organic phase was concentrated to dryness in vacuo and taken up twice in dichloromethane and again concentrated in vacuo to give a dried foam (28.6 g of crude product).

15 g of crude product were purified by means of silica gel flash chromatography (eluent dichloromethane / methanol 10% 90%), and the product fraction was concentrated to dryness in vacuo (7.3 g), suspended in tert-butyl methyl ether (100 ml) and stirred at RT overnight. The solid was isolated, washed with tert-butyl methyl ether and dried in vacuo at 35 ° C. overnight. 6.3 g (30% of theory) of the target compound were obtained as a colorless solid.

LC-MS I method 41: R _t = 0.57 min; MS (ESIpos): m / z = 438 (M + H) ⁺

(IA'-2): H NMR (400 MHz, DMSO-d6) d ppm 1.65 - 1.87 (m, 2 H) 2.02 - 2.24 (m, 2 H) 2.90 - 3.23 (br. M, 4 H) 3.31 - 3.43 (m, 1 H) 3.54 (s, 4 H) 3.60 - 3.80 (br.m, 2 H) 3.83 (s, 4 H) 4.44 - 4.50 (m, 4 H, under wide signal) 7.21 - 7.25 (m , 1 H) 7.25 - 7.39 (m, 3 H) 8.44 (s, 2 H) 9.84 (br. S, 1 H), 1H not visible (OH).

Example I-C-l

2- (l - {[2- (2-Oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-5-yl] carbonyl} piperidin-4-yl) isoquinolinium *

* This compound exists as a mixture of chloride and formate salt

7.5 g (24 mmol) of the compound from Example 31A and 8.2 g (24 mmol) 2- (2,4-dinitrophenyl) isoquinolinium chloride (prepared according to Barbier et al, J. Org. Chem, 1996, Vol. 61 , 9596 - 9598) were suspended in 60 ml of anhydrous butanol and stirred at 100 ° C. for 1 h. The red-brown solution was cooled to RT, 60 ml of water and 100 ml of tert. -Butyl methyl ether added and then filtered. The phases were separated, the aqueous phase was washed with 25 ml of tert-butyl methyl ether and the combined organic phases were extracted with 15 ml of water. The combined aqueous phases were purified by means of preparative HPLC (injection volume: 3.6 ml solution each; column: Phenomenex Luna C18 (2), 250 mm x 20.1 mm, 5 pm, eluent A: water + 0.1% formic acid, eluent B: + 0.1% Formic acid, gradient 0min = 90% A, 10min = 70% A, 10, 1min = 5% A, 15min = 5% A, 25 min = 5% A; flow 20 ml / min, UV detection: 210 nm). The product fractions were combined, concentrated in vacuo and dried under HV. 0.69 g (9% of theory) of the target compound were isolated as a mixed chloride / formate salt.

LC-MS I method 11: R _t = 0.42 min; MS (ESIpos): m / z = 416 (M) ⁺

(ICl): 'H NMR (400 MHz, DMSO-d6) d ppm 2.11 - 2.37 (m, 4 H) 2.96 - 3.76 (br. M, 4 H, under broad signal) 4.22 - 4.27 (m, 1 H) 4.22 - 4.28 (m, 4 H) 4.73 (s, 4 H) 5.05 - 5.22 (m, 1 H) 8.01 - 8.14 (m, 1 H) 8.28 (d, J = l. L Hz, 1 H) 8.36 ( br d, J = 8.1 Hz, 1 H) 8.48 - 8.54 (m, 3 H) 8.63 (d, J = 7.0 Hz, 1 H) 8.93 (d, J = 6.7 Hz, 1 H) 10.20 (s, 1 H , Formate salt). Mixture contains 4.7% by weight chloride, 3.1% by weight formate.

Example I-B-l and I-A‘-3

[4- (Isoquinolin-2 (1H) -yl) piperidin-1-yl] [2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-5-yljmethanone

(I-B-l)

[4- (4-Hydroxy-3,4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl] [2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-5 -ylmethanone (I-A'-3)

145.2 mg of the compound (I) from Example 8 were dissolved in 4.33 ml of acetonitrile. 5.31 g of Codexis ^® MCYP-RXN BUFFER (Codexis Ine., US) were dissolved in 146.25 mU of deionized water in a separate vessel. To 121.25 mU of Codexis ^® MCYP-RXN BUFFER-Uösung 3.75 mL of Acetonitrilstammlösung the compound (I) of Example 8 were added. The pH was checked (7.98). In an Erlenmeyer flask with baffles were 93.75 mg of the enzyme Codexis ^® MCYP- P1.2F02 in 25 mL of Codexis ^® MCYP-BUFFER RXN pre-dissolved solution, and then added 121.25 mL of the buffered solution of the compound (I) of Example 8. FIG. The reaction mixture was incubated at 32.5 ° C. and 150 rpm in a water bath for 24 h (substrate concentration: 2 mM, enzyme concentration: 6 mM). The precipitated proteins were removed by centrifugation and the supernatant using tangential flow filtration (Vivaflow 50 ^®, MWCO = 30 kDa, Sartorius AG, DE). The tangential flow filtration cassette was washed 3 times with 30-50 mL H2O / ACN 90/10 (v / v) and the combined phases were concentrated to a total volume of approx. 25 mL under reduced pressure. The crude product obtained was purified in several portions by means of preparative HPLC (Nucleodur ^® Gravity C18, 250x21 mm, 5 pm, 30 ml / min, ACN / 0.2% formic acid; 0 min 5% ACN, 34 min 9.5% ACN, 36 min 50% ACN, 45 min 50% ACN, 254 nm). Product-containing fractions were combined, with 0.2% aq. Formic acid diluted and eluted through 3 SPE cartridges (BondElut C18, 10 g, 60 mL volume, Agilent Technologies, Ine., US). The SPE cartridges were each filled with 50 mL 0.2% aq. Formic acid / ACN 10/90 (v / v) eluted, the eluate diluted with 200 mL ACN, concentrated under reduced pressure and dried in vacuo over P2O5. There remained (Ml) (2.6 mg, 6.3 pmol, 2.1% d.

Th., 93% purity) and M-5 (7.4 mg, 17.0 pmol, 5.7% of theory, 98.9% purity) as well as smaller amounts

(M-2).

LC-MS I method 31:

(MI): R _t = 0.75 min; MS (ESIpos): m / z = 418 (M + H) ⁺

(M-5): R _t = 0.70 min; MS (ESIpos): m / z = 436 (M + H) ⁺

HPLC-UV I method 11:

(Ml): R _t = 26.17 min, (M-5): R = 21.58 min

(MI): 'H NMR (600 MHz, DMSO-d6) d ppm 1.68-1.75 (m, 4 H), 3.16-3.22 (m, 1 H), 4.24 (m, 2 H), 4.22-4.27 (m , 4 H), 4.73 (s, 4 H), 5.21 (d, J = 6.8 Hz, 1 H), 6.39 (d, J = 6.8 Hz, 1 H), 6.75-6.83 (m, 1 H), 6.89 -6.93 (m, 1 H), 6.93-6.98 (m, l H), 7.01-7.06 (m 1 H), 8.44-8.48 (m, 2 H), not visible 2x NfOU-

ppm 1.43-1.58 (m, 2 H), 1.81-1.86 (m, 2 H), 2.43-2.48 (m, 1 H), 2.67-2.74 (m, 1 H), 2.98-3.05 (m, 1 H) , 3.57-3.59 (m, 2 H), 4.26 (s, 4 H), 4.56-4.61 (m, 1 H), 4.73 (s, 4 H), 7.02-7.07 (m, 1 H), 7.13-7.20 (m, 2 H), 7.40-7.44 (m, 1 H), 8.44 (s, 2 H), 1 H not visible (OH), not visible 2x N (CtT-CtU). Example IA'-1

2- [3,3-bis (hydroxymethyl) azetidin-1-yl] pyrimidine-5-carboxylic acid

693 mg 2- (2-Oxa-6-azaspiro [3.3] hept-6-yl) pyrimidine-5-carboxylic acid (Example 18A) (3.13 mmol,

1.0 equiv.) Were dissolved in 15 mL sulfuric acid (10% v / v) and stirred under microwave conditions at 60 ° C. for 2.5 h. The raw mixture obtained was used in the next synthesis step without further purification.

LC-MS I method 31: R _t = 0.72 min; MS (ESIpos): m / z = 240 (M + H)

2- [3-Carboxy-3- (hydroxymethyl) azetidin-1-yl] pyrimidine-5-carboxylic acid

The pH of the raw mixture from the previous synthesis step was adjusted to 2 mL aq. NaOH (50% v / v) adjusted to pH 14 and potassium permanganate (988 mg, 6.26 mmol, 2.0 eq.) Added in two portions. The dark reaction mixture was stirred for 48 h at room temperature. Any MnCf formed was filtered off after 24 hours. When the reaction was complete, solids formed again were filtered off, carefully washed with methanol, and the filtrate was acidified with formic acid and concentrated under reduced pressure. The remaining solid was suspended in 2 × with methanol and kept in an ultrasonic bath for 2 h. The combined extracts were concentrated to dryness under reduced pressure. The raw mixture obtained was used in the next synthesis step without further purification.

LC-MS rMethod 31: R _t = 0.76 min; MS (ESIpos): m / z = 254 (M + H) 2- [3- (Hydroxymethyl) -3- (methoxycarbonyl) azetidin-1-yl] pyrimidine-5-carboxylic acid

2- [3-Carboxy-3- (hydroxymethyl) azetidin-l-yl] pyrimidine-5-carboxylic acid (378 mg, 0.84 mmol, l .O equiv.) Was taken up in dry methanol (10 ml) and a small amount of NaaSCE admitted. The mixture was stirred at room temperature with thionyl chloride (244 pL, 3.35 mmol, 4.0 equiv.) Being added in 4 portions over 2 days. The mixture was concentrated to dryness under reduced pressure and the crude product was prepared using prep. HPLC purified in 3 portions (Phenomenex Aqua ^® C18, 150x21 mm, 5 pm, 25 ml / min, 0.2% formic acid / ACN = 85/15, v / v, 274 nm). Product-containing fractions were combined, diluted with 70 mL 0.2% HCOOH, passed through an SPE cartridge (BondElut C18, 20 g, Agilent Technologies, Ine., US) and eluted with a mixture of MeOH + 0.2% HCOOH (160 mL). The filtrate was concentrated to dryness and dried in vacuo. The desired ester remained as a white solid (107.2 mg, 0.40 mmol, 48%).

LC-MS I method 31: R _t = 0.72 min; MS (ESIpos): m / z = 268 (M + H) ⁺

Methyl l- (5 - {[4- (3,4-dihydroisoquinolin-2 (1H) -yl) piperidin-l-yl] carbonyl} pyrimidin-2-yl) -3-

(hydroxymethyl) azetidine-3-carboxylate

2- [3- (Hydroxymethyl) -3- (methoxycarbonyl) azetidin-1-yl] pyrimidine-5-carboxylic acid (17 mg, 63.6 pmol. 1.0 equiv.) And 2- (piperidin-4-yl) -l , 2,3,4-tetrahydroisoquinoline hydrochloride (18.4 mg, 63.3 mihoΐ. L .O equiv.) Were suspended in dry DMF (I mL). After the addition of DIPEA (55 pL, 318.1 pmol, 5.0 equiv.) And HATU (29 mg, 76.3 pmol, 1.2 equiv.), The mixture was stirred for 1 h at room temperature. The raw mixture obtained was used immediately afterwards for the final ester saponification reaction without further purification. LC-MS rMethod 31: R _t = 0.84 min; MS (ESIpos): m / z = 466 (M + H) ⁺

1- (5- {[4- (3,4-Dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl] carbonyl} pyrimidin-2-yl) -3- (hydroxymethyl) azetidine-3-carboxylic acid (M. -3)

Aqueous NaOH (0.5 mL, 1 N) was added to the raw mixture of the previous synthesis step and the mixture was stirred for a further hour at room temperature. The mixture was acidified with 1 mL HCOOH and concentrated to dryness under reduced pressure. Cleaning via prep. HPLC (Phenomenex Synergi HydroRP ^® C18, 250x10 mm, 5 pm, 7 ml / min, 0.4% TFA / ACN = 85/15, v / v, 268 nm) provided the desired product as a white solid (25.8 mg, 57.2 pmol, 90%).

LC-MS I method 31: R _t = 0.66 min; MS (ESIpos): m / z = 452 (M + H) ⁺

HPLC-UV I method 21: R, = 4.11 min

(I-A‘-l): H NMR (500 MHz, DMSO-d6) d ppm 1.70-1.84 (m, 2 H), 2.04-2.21 (m, 2 H), 3.06-3.16 (m,

2 H), 3.33-3.42 (m, 1 H), 3.65-3.71 (m, 1 H), 3.76 (br s, 1 H), 3.78 (br s, 2 H), 4.05 (d, J = 9.0 Hz , 2 H), 4.19 (d, J = 9.0 Hz, 2 H), 4.45-4.49 (m, 2 H), 7.21-7.24 (m, 1 H), 7.26-7.30 (m, 1 H), 7.30- 7.34 (m, 1 H), 8.47 (s, 2 H), 12.9 (br s, 1 H, COOH), 1 H not visible, OH, not visible 2x N (CH _? -CH2).

Example I-A‘-3

[4- (4-Hydroxy-3,4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl] [2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-5 -yl] methanone

1,2,3,4-Tetrahydroisoquinolin-4-ol hydrochloride (0.70 g, 5.12 mmol) was placed in 15 ml of THF. Tert-butyl 4-oxopiperidine-1-carboxylate (1.02 g, 5.12 mmol) and acetic acid (0.292 ml, 5.12 mmol) were added. Sodium triacetoxyborohydride (1.70 g, 8.02 mmol) was added in portions and the mixture was stirred at room temperature for 2.5 h. After the addition of saturated sodium hydrogen carbonate solution, the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate and subjected to silica gel flash chromatography (eluent dichloromethane / methanol

25%) are used. For further purification, the silica gel flash chromatography was repeated with the eluent heptane / ethyl acetate 20% 100%. 1.1 g of the intermediate compound tert-butyl 4- (4-hydroxy-3,4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylate were obtained.

LC-MS I method 51: R _t = 0.943 min; MS (ESIpos): m / z = 333 (M + H) ⁺ .

The entire amount of the intermediate was dissolved in 20 ml of dichloromethane and cooled in an ice bath. Hydrogen chloride, 4N solution in 1,4-dioxane (8.3 ml) was added and the mixture was stirred at room temperature for 16 hours. After rotary evaporation, the residue was washed with tert-butanol, dissolved in methanol and evaporated again. 0.9 g of the intermediate compound 2- (piperidin-4-yl) -l, 2,3,4-tetrahydroisoquinolin-4-ol hydrochloride were obtained.

LC-MS I method 51: R _t = 0.107 min; MS (ESIpos): m / z = 233 (M + H) ⁺ .

An aliquot of 0.69 g of the intermediate compound and 0.62 g (2.80 mmol) of 2- (2-oxa-6-azaspiro [3 3] heptan-6-yl) pyrimidine-5-carboxylic acid were dissolved in 40 ml of acetonitrile suspended. The suspension was cooled in an ice bath and 2.70 ml (15.50 mmol) N, N-diisopropylethylamine and 2.70 ml (4.56 mmol) propanephosphonic acid cyclo-anhydride, 50% by weight solution in ethyl acetate were added . The resulting clear solution was stirred at room temperature for 1 hour. The solution was washed with saturated sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate and concentrated using a rotary evaporator. The sparingly soluble residue was absorbed onto silica gel by rotary evaporation from ethyl acetate and the loaded silica gel was converted into a silica gel Flash chromatography (eluent ethyl acetate / methanol 20%

88% with 0.1 ml of triethylamine per 100 ml of eluent). 0.85 g of the desired target product with insufficient purity was obtained. After combining with the product from a test batch, the total amount of 1.08 g was preprep. HPLC (Nucleodur C18 Gravity ^® 5 pm, 250 x 21 mm "5 pm, 25 ml / min, 0.2% TEA / ACN = 80/20, v / v, 268 nm). The combined product fractions were concentrated on a rotary evaporator and solid phase extraction using a 20 g RP-18 cartridge yielded the desired product as a colorless solid (0.67 g, 1.54 mmol, 30%).

Purity HPLC-UV I method 31: 99.4%,

LC-MS I method 51: R _t = 0.697 min; MS (ESIpos): m / z = 436 (M + H) ⁺

(IA '-3): H NMR (500 MHz, DMSO-d6) d 8.44 (s, 2H), 7.47-7.38 (m, 1H), 7.20-7.16 (m, 1H), 7.16-7.12 (m, 1H ), 7.04 (d, J = 6.9 Hz, 1H), 5.16 (d, J = 7.1 Hz, 1H), 4.72 (s, 4H), 4.62-4.55 (m, 1H), 4.26 (s, 4H), 4.46 - 3.75 (br, 2H), 3.75 - 3.63 (m, 2H), 3.01 (br dd, J = 11.0, 5.0 Hz, 1H), 3.17 - 2.77 (br, 2H), 2.74 - 2.66 (m, 1H), 2.46 (br dd, J = 10.9, 7.9 Hz, 1H), 1.90 - 1.75 (m, 2H), 1.58 - 1.42 (m, 2H)

Bl evaluation of the physiological effectiveness

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

B-l) In vitro Assavs

B-lal antagonism on adrenergic receptors

Antagonism on the adrenoreceptors a.24, a ₂ u and a.2 _t : was tested on human recombinant RBL cells ((Ϊ2A), HEK-293 cells (O.2B) and human CHO cells (012c). Epinephrine was used as a stimulus (oi2A and 012c) or dexmedetomidine (O.2B). These studies were carried out at Eurofins CEREP Panlabs under standard conditions under Study ID: FR095-0003115 Report 100042683. The results for the antagonism to the adrenoreceptors 012A, Ö. ₂ B and 0.2c are shown in Table 1:

Table 1:

B-lbl binding studies on human a2-adrenergic receptors

The binding of the substances on the adrenoreceptors a.2,4, a. and 012c was determined by binding studies. The binding tests were carried out on the basis of human recombinant CHO cells for the different receptors. [ ³ H] RX 821002 served as the ligand. These studies were carried out at Eurofins CEREP Panlabs under standard conditions under Study ID: FR095-0003099 Report 100042685. The results for binding to adrenoreceptors a.2,4, oi2B and 012c are shown in Table 2:

Table 2:

Claims

Claims

1. Compound of the general formula general formula (I-A), (I-B) or the general formula (I-C)

in which

R ^{1 is} a group of the formula

stands, and

R ^{2 represents} hydrogen or hydroxyl, and their A'-oxides. Salts, solvates, salts of the A'-oxides and solvates of the A'-oxides and salts.

2. A compound according to claim 1, characterized in that it has the general formula (I-A ‘), (I-B) or the general formula (I-C)

have in which

R ^{1 is} a group of the formula

stands, and

R ^{2 represents} hydrogen or hydroxyl, and their A oxides. Salts, solvates, salts of the A-oxides and solvates of the A-oxides and salts.

3. Compound according to claim 1, characterized in that compound (IA) in the form of the N-oxide of the general formula (I-Al) is present in which the radicals RI and R2 have the meanings given above.

4. A compound according to claim 1 or 2, characterized in that compound (I-A ‘) in the form of the N-oxide of the general formula (I-A‘ 1)

is present in which the radicals RI and R2 have the meanings given above.

5. Compound according to claim 1 or 2, characterized in that they are selected from

Group containing compounds

6. Compound according to claim 1 or 2 for the treatment and / or prevention of diseases.

7. A compound according to claim 1 or 2 for use in a method for the treatment and / or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic Nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular diseases, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent neuropathies and peripheral intermittent neuropathies, and intermittent peripheral neuropathies.

8. Medicament containing a compound according to claim 1 or 2 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

9. Medicaments containing a compound according to claim 1 or 2 in combination with one or more other active ingredients selected from the group consisting of active ingredients that change lipid metabolism, antidiabetic agents, blood pressure reducers, sympathetic tone lowering agents, blood circulation-promoting and / or antithrombotic agents and antioxidants, Aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, positive inotropic compounds, calcium sensitizers, ACE inhibitors, cGMP and cAMP modulating compounds, natriuretic peptides, NO independent stimulators of guanylate cyclase, NO-independent activators of guanylate cyclase, inhibitors of human neutrophil elastase, compounds that inhibit the signal transduction cascade, compounds that modulate the energy metabolism of the heart, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory drugs, analgesics, antidepressants and other psychotropic drugs.

10. Medicament according to claim 8 or 9 for the treatment and / or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities, in particular to promote wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction , diabetic heart failure, diabetic coronary microvascular heart diseases, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemias, peripheral circulatory disorders, Raynaud's phenomenon, CREST Syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathies.

11. Process for the treatment and / or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure coronary microvascular heart diseases, peripheral and cardiac vascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome,

Microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathies, in humans and animals by administering an effective amount of at least one compound according to claim 1 or a medicament as defined in any one of claims 6 to 8.