HK1231851B - Substituted piperidinyl-tetrahydroquinolines and their use as alpha-2c adrenoreceptor antagonists - Google Patents

Description

Substituted piperidinyl tetrahydroquinolines and their use as α-2C adrenergic receptor antagonists

The present invention relates to novel substituted piperidinyl tetrahydroquinolines, to methods for their preparation, to their use in methods for treating and/or preventing diseases, and to their use in preparing medicaments for treating and/or preventing diseases, in particular cardiovascular diseases, diabetic microangiopathy, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathies.

Adrenergic receptor _α2 receptors ( _α2 -AR) belong to the G-protein coupled receptor family. They bind to the inhibitory G proteins _G1 and _G0 that are sensitive to pertussis toxin and reduce adenylate cyclase activity. They participate in the mediation of various physiological effects in different tissues after being stimulated by endogenous catecholamines (epinephrine, norepinephrine), which are released by synapses or reach the site of action via the blood. Mainly with regard to the cardiovascular system, but also in the central nervous system, α2 _- AR plays an important physiological role. Biochemical, physiological and pharmacological studies have confirmed that, in addition to various _α1 -AR subtypes, there are three _α2 -AR subtypes ( _α2A , _α2B and _α2C ) in many cardiovascular-related target cells and tissues, which makes them attractive target proteins for therapeutic intervention. However, due to the lack of highly selective ligands and/or antagonists for various _α2 -ARs, the precise physiological roles of these receptor subtypes have been difficult to elucidate so far (Gyires et al., _α2 -Adrenoceptor subtypes-mediated physiological and pharmacological actions, Neurochemistry International 55, 447-453, 2009; Tan and Limbird, The _α2- Adrenergic Receptors: Adrenergic Receptors in the 21st Century/Receptors, 2005, 241-265).

Cardiovascular changes (e.g., regulation of cardiac contractility) are regulated, on the one hand, by central regulation of sympathetic efferent nerves. Furthermore, the sympathetic efferent system regulates direct effects on vascular smooth muscle cells and endothelial cells. Thus, the sympathetic system participates in regulating cardiac output but also in controlling local perfusion in various vascular beds. This is also controlled via the _α2 -AR, which participates in regulating peripheral resistance. Thus, blood vessels are innervated by sympathetic nerve fibers distributed in the adventitia, and their distal ends have varicose veins that release norepinephrine. The released norepinephrine regulates local vascular tone via _α2 -ARs in endothelial and smooth muscle cells.

In addition to the effects on sympathetic efferent nerves, peripheral cardiovascular function is also regulated by presynaptic and postsynaptic α ₂ -AR. Smooth muscle cells and endothelial cells express different α ₂ -AR subtypes. Activation of α _2A , α _2B , and α _2C receptors on smooth muscle cells leads to contraction, thereby causing vasoconstriction (Kanagy, Clinical Science 109: 431-437, 2005). However, the distribution of various receptor subtypes in different vascular beds varies between species and between different blood vessel sizes. Thus, α _2A -AR appears to be essentially exclusively expressed in large arteries, while α _2B -AR contributes more to vascular tone in arterioles and veins. AR α _2B appears to play a role in salt-induced hypertension (Gyires et al., α ₂ -Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, 2009). Although the role of _ARα2C on hemodynamics is not fully understood, _ARα2C receptors appear to mediate venous vasoconstriction. They are also involved in the cold-induced enhancement of adrenergic receptor-induced vasoconstriction (Chotani et al., Silent _α2C adrenergic receptors enable cold-induced vasoconstriction incutaneous arteries. Am J Physiol 278:H1075-H1083, 2000; Gyires et al., _α2- Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International 55, 447-453, 2009). Cold and other factors (e.g., tissue proteins, estrogen) regulate the functional coupling of _ARα2C with intracellular signaling pathways (Chotani et al., Distinct cAMP signaling pathways differentially regulateα2C adrenenoxceptor expression: role in serum induction in human arteriolar _smooth muscle cells. Am J Physiol Heart CircPhysiol 288: H69-H76, 2005). Therefore, it is meaningful to study selective inhibitors of the AR- _α2 subtype that regulate its perfusion-regulating effects on different vascular beds under different pathophysiological conditions.

Under pathophysiological conditions, the adrenergic system can be activated, which can lead to, for example, hypertension, heart failure, increased platelet activation, endothelial dysfunction, atherosclerosis, angina pectoris, myocardial infarction, thrombosis, peripheral circulatory disorders, stroke and sexual dysfunction. Thus, for example, the pathophysiology of Raynaud's syndrome and scleroderma is largely unknown, but is associated with altered adrenergic activity. Thus, patients with spastic Raynaud's syndrome show, for example, significantly elevated expression of _ARα2 receptors on their platelets. This can be associated with the vasospasm episodes observed in these patients (Keenan and Porter, _α2- Adrenergic receptors in platelets from patients with Raynaud's syndrome, Surgery, V94(2), 1983).

Because the high efficiency of expectation and little side effect, the treatment possibility to this disease of the adrenergic system that purpose is to influence activation in organism is a kind of promising scheme.Particularly in the situation of the diabetic patient that often has too high catecholamine level, peripheral circulation disorder (microangiopathy) such as diabetic retinopathy, nephropathy or significant wound healing disorder (diabetic foot ulcer) plays an important role.In peripheral occlusive disease, diabetes is one of the most important concomitant disease, and also plays a decisive role in disease (microangiopathy and macroangiopathy) process.The higher expression of the adrenergic receptor α _2C receptor relevant with the catecholamine level of raising may participate in these pathophysiological processes in the situation of diabetic patient.

In 2011, there were 350 million people with diabetes worldwide (≈6.6% of the population), and this number is expected to double by 2028. Diabetic foot ulcers are the most common cause of hospitalization for diabetic patients. The risk of a diabetic patient developing a diabetic foot ulcer in their lifetime is 15-25%, and 15% of all diabetic foot ulcers result in amputation. Worldwide, 40-70% of all non-traumatic amputations are performed on diabetic patients. Risk factors for diabetic foot ulcers are trauma, poor metabolic control, sensory polyneuropathy, motor polyneuropathy, autonomic polyneuropathy, inappropriate footwear, infection, and peripheral arterial disease. The treatment of diabetic foot ulcers requires a multidisciplinary team and a multifactorial approach: weight loss, revascularization (in the case of peripheral arterial occlusive disease (pAVK), improved metabolic control, wound resection, dressings, dalteparin, Regranex (PDGF), and amputation. The cost of treating each diabetic foot ulcer (without amputation) is 7,000-10,000 USD. Thirty-three percent of all diabetic foot ulcers do not heal within 2 years, and there is a high recurrence rate (34% within the first year and 61% within 3 years).

It is therefore an object of the present invention to provide novel selective adrenergic receptor _α2C receptor antagonists for the treatment and/or prevention of diseases in humans and animals, such as cardiovascular diseases.

The object of the present invention is also to provide novel selective adrenergic receptor _α2C receptor antagonists for the treatment and/or prevention of peripheral circulatory disorders (microangiopathy), such as diabetic retinopathy, diabetic nephropathy and wound healing disorders (diabetic foot ulcers).

WO 2005/042517, WO 2003/020716, WO 2002/081449 and WO 2000/066559 describe structurally similar bipiperidinyl derivatives as inhibitors of CCR5 receptors, which are particularly useful for treating HIV. WO 2005/077369 describes structurally similar bipiperidinyl derivatives as inhibitors of CCR3 receptors, which are particularly useful for treating asthma. WO 94/22826 describes structurally similar piperidine compounds as active substances with peripheral vasodilatory effects.

The present invention provides a compound of formula (I) and a salt thereof, a solvate thereof and a solvate of a salt thereof,

in

R ¹ represents C ₁ -C ₆ -alkyl or C ₃ -C ₅ -cycloalkyl,

wherein the alkyl group is substituted by 1 to 2 substituents which are independently selected from the group consisting of hydroxy, C ₁ -C ₄ -alkoxy and haloalkoxy,

and

R ² represents hydrogen or C ₁ -C ₄ -alkyl,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form a 4-7 membered N-heterocyclic ring,

wherein the N-heterocycle may be substituted by 1 to 3 substituents, each independently selected from the group consisting of oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, halogen and hydroxyalkyl,

or

wherein the N-heterocycle may have two substituents, which together with the carbon atom of the N-heterocycle to which they are attached form a 4-6 membered heterocycle,

wherein the heterocycle itself may be substituted by 1 to 3 substituents, said substituents being independently selected from oxo, methyl and ethyl,

R ³ represents hydrogen, fluorine, methoxy or ethoxy,

and

R ⁴ represents hydrogen, fluorine, methoxy or ethoxy.

The compounds of the present invention are compounds of formula (I) and salts, solvates and solvates of said salts, and compounds included in formula (I) and mentioned below as embodiments and salts, solvates and solvates of said salts, as long as the compounds included in formula (I) and mentioned below are not yet salts, solvates and solvates of salts.

In the context of the present invention, the term "X acid" in any formula does not denote a stoichiometrically defined ratio of acid to the respective substance. Depending on, for example, the basicity of the respective substance, the term "X acid" denotes different ratios between the substance and the acid, such as 10:1 to 1:10; 8:1 to 1:8; 7:1 to 1:7; 5:1 to 1:5; 4.5:1 to 1:4.5; 4:1 to 1:4; 3.5:1 to 1:3.5; 3:1 to 1:3; 2.5:1 to 1:2.5; 2:1 to 1:2; 1.5:1 to 1:1.5; and 1:1.

Depending on their structure, the compounds according to the invention may exist in different stereoisomeric forms, i.e. in the form of configurational isomers or optionally as conformers (enantiomers and/or diastereomers, including those under atropisomers). Therefore, the present invention encompasses the enantiomers or diastereomers and their various mixtures. Stereoisomers can be separated from such mixtures of enantiomers and/or diastereomers in a known manner; for this purpose, chromatographic methods are preferably used, in particular HPLC chromatography on an achiral or chiral phase.

Insofar as the compounds according to the invention can exist in tautomeric forms, the present invention includes all tautomeric forms.

The present invention also includes all suitable isotopic variants of compound of the present invention.The isotopic variant of compound of the present invention is understood to refer to such compound here: wherein in compound of the present invention, at least one atom has been replaced by another atom of identical atomic number, but the atomic mass of this another atom is different from the atomic mass that usually exists or advantage exists in nature.The example of the isotope that can be mixed into the compound of the present invention is the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, 33 S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ^{131 I.} Certain isotopic variations of the compounds of the present invention (such as, in particular, those into which one or more radioactive isotopes have been incorporated) may be useful, for example, for examining the in vivo mechanism of action or the distribution of the active substance in the body; particular compounds labeled with ³ H- or ¹⁴ C-isotopes are suitable for this purpose due to their relatively easy preparation and detectability. Furthermore, due to the greater metabolic stability of the compound, the incorporation of isotopes (e.g., deuterium) may provide certain therapeutic benefits, such as an increase in in vivo half-life or a reduction in the required active dose; therefore, such modifications of the compounds of the present invention may also optionally constitute a preferred embodiment of the present invention. Isotopic variations of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example, by using corresponding isotopic modifications of various reagents and/or starting materials according to the methods described further below and in the working examples.

As salts , preferred within the scope of the present invention are physiologically acceptable salts of the compounds according to the invention. However, the invention also includes salts which are not themselves suitable for pharmaceutical applications but which can be used, for example, for isolating or purifying the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic 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 with customary bases, such as, for example and preferably, alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N -methylmorpholine, arginine, lysine, ethylenediamine, N -methylpiperidine and choline.

Designated solvates in the context of the present invention are those forms of the compounds according to the invention which form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates, in which the coordination is with water.

The present invention furthermore also includes prodrugs of the compounds according to the invention. The term "prodrug" includes compounds which themselves may be biologically active or inactive, but which are converted during their residence time in the body into compounds according to the invention (for example by metabolism or hydrolysis).

In the context of the present invention, the term "treatment" includes inhibiting, delaying, preventing, alleviating, reducing, limiting, lowering, arresting, reversing or curing a disease, illness, injury or health disorder, the development, course or progression of such conditions and/or symptoms of such conditions. The term "therapy" is understood herein as being synonymous with the term "treatment."

In the context of the present invention, the terms "control", "prevention" or "preventive measure" are used synonymously and refer to avoiding or reducing the risk of contracting, contracting, suffering from or having a disease, illness, disease, injury or health disorder, the development or progression of such conditions and/or symptoms of such conditions.

Treatment or prevention of an illness, disease, condition, injury or health disorder can be achieved partially or completely.

In the context of the present invention, unless otherwise indicated, substituents have the following definitions:

Alkyl itself and "Alk" and "alkyl" in alkoxy, alkoxyalkyl, alkylamino and alkoxycarbonyl represent straight-chain or branched alkyl residues having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, for example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy represents by way of example and preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Alkoxyalkyl represents by way of example and preferably methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl, methoxyethyl, ethoxyethyl, n-propoxyethyl, isopropoxyethyl, n-butoxyethyl and tert-butoxyethyl.

N-heterocycle in the definition of the residues R ¹ and R ² represents a saturated or partially unsaturated monocyclic residue having 4 to 7 ring atoms, including one nitrogen heteroatom and up to 3 further heteroatoms and/or heterogroups selected from S, O, N, SO and SO ₂ , wherein one of the nitrogen atoms can also form an N-oxide, for example and preferably azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine and 1,1-dioxothiomorpholine, particularly preferably azetidine, pyrrolidine, piperidine, morpholine and 1,1-dioxothiomorpholine.

The heterocycle in the definition of the residues R ¹ and R ² , which has one carbon atom in common with the N-heterocycle to which it is attached, represents a saturated or partially unsaturated monocyclic residue having 4 to 6 ring atoms and up to 4 heteroatoms and/or heterogroups selected from S, O, N, SO and SO ₂ , wherein one of the nitrogen atoms can also form an N-oxide, for example and preferably azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran and 1,1-dioxothietane, particularly preferably azetidine and oxetane and even more preferably oxetane.

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

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents C ₁ -C ₆ -alkyl or C ₃ -C ₅ -cycloalkyl,

wherein the alkyl group is substituted by 1-2 substituents, said substituents being independently selected from hydroxyl and C ₁ -C ₄ -alkoxy

and

R ² represents hydrogen or C ₁ -C ₄ -alkyl,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form a 4-7 membered N-heterocyclic ring,

wherein the N-heterocycle may be substituted by 1 to 3 substituents, each independently selected from oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy and halogen,

or

wherein the N-heterocycle may have two substituents, which together with the carbon atom of the N-heterocycle to which they are attached form a 4-6 membered heterocycle,

wherein the heterocycle itself may be substituted by 1 to 3 substituents, said substituents being independently selected from oxo, methyl and ethyl,

R ³ represents hydrogen, fluorine, methoxy or ethoxy,

and

R ⁴ represents hydrogen, fluorine, methoxy or ethoxy.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₂ -C ₆ -alkyl group,

wherein the alkyl group is substituted with one substituent selected from the group consisting of hydroxy, methoxy and ethoxy,

and

R ² represents hydrogen or

^R1 and ^R2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine or 1,1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine and 1,1-dioxothiomorpholine may be substituted by 1-2 substituents independently selected from hydroxyl, trifluoromethyl, hydroxycarbonyl, C ₁ -C ₃ -alkyl, methoxy and methoxymethyl,

or

wherein azetidine, pyrrolidine, piperidine, azepane, piperazine and morpholine may have two substituents which, together with the carbon atom of the azetidine, pyrrolidine, piperidine, azepane, piperazine and morpholine to which they are attached, form azetidine, oxetane or 1,1-dioxothietane,

wherein the azetidine, oxetane or 1,1-dioxothietane itself may be substituted by 1-2 substituents, the substituents being independently selected from methyl and ethyl,

R ³ represents hydrogen,

and

^R4 represents hydrogen, fluorine or methoxy,

or

R ³ represents hydrogen, fluorine or methoxy,

and

^R4 represents hydrogen.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₂ -C ₄ -alkyl group,

wherein the alkyl group is substituted with one substituent selected from the group consisting of hydroxy and methoxy,

and

^R2 represents hydrogen,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, morpholine or 1,1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, morpholine and 1,1-dioxothiomorpholine may be substituted by 1-2 substituents, said substituents being independently selected from hydroxycarbonyl, methyl, trifluoromethyl, methoxy and methoxymethyl,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form an azetidine,

wherein the azetidine may have two substituents, said substituents together with the carbon atom of the azetidine to which they are attached form an oxetane or a 1,1-dioxothietane,

R ³ represents hydrogen, fluorine or methoxy,

and

^R4 represents hydrogen,

or

R ³ represents hydrogen,

and

R ⁴ represents hydrogen, fluorine or methoxy.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₂ -C ₄ -alkyl group,

wherein the alkyl group is substituted with one substituent selected from the group consisting of hydroxy and methoxy,

and

^R2 represents hydrogen,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, morpholine or 1,1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, morpholine and 1,1-dioxothiomorpholine may be substituted by 1-2 substituents, said substituents being independently selected from hydroxycarbonyl and methyl,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form an azetidine,

wherein the azetidine may have two substituents, said substituents together with the carbon atom of the azetidine to which they are attached form an oxetane,

R ³ represents hydrogen,

and

^R4 represents hydrogen, fluorine or methoxy,

or

R ³ represents hydrogen, fluorine or methoxy,

and

R ⁴ represents hydrogen.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

^R1 and ^R2 together with the nitrogen atom to which they are attached form an azetidine,

wherein the azetidine may have two substituents, said substituents together with the carbon atom of the azetidine to which they are attached form an oxetane,

R ³ represents hydrogen,

and

^R4 represents hydrogen.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₁ -C ₆ -alkyl group,

wherein the alkyl group is substituted by 1 to 2 substituents which are independently selected from the group consisting of hydroxy, C ₁ -C ₄ -alkoxy and cycloalkyloxy,

and

R ² represents hydrogen or C ₁ -C ₄ -alkyl,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form a 4-7 membered N-heterocyclic ring,

wherein the N-heterocycle may be substituted by 1 to 3 substituents, each independently selected from oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy and halogen,

or

wherein the N-heterocycle may have two substituents, which together with the carbon atom of the N-heterocycle to which they are attached form a 4-6 membered heterocycle,

wherein the heterocycle itself may be substituted by 1 to 3 substituents, said substituents being independently selected from oxo, methyl and ethyl,

R ³ represents hydrogen, fluorine, methoxy or ethoxy,

and

R ⁴ represents hydrogen, fluorine, methoxy or ethoxy.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₂ -C ₆ -alkyl group,

wherein the alkyl group is substituted with one substituent selected from the group consisting of hydroxy, methoxy and ethoxy,

and

^R2 represents hydrogen,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine or 1,1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine and 1,1-dioxothiomorpholine may be substituted by 1-2 substituents independently selected from hydroxyl, hydroxycarbonyl, C ₁ -C ₃ -alkyl and methoxy,

or

wherein azetidine, pyrrolidine, piperidine, azepane, piperazine and morpholine may have two substituents which, together with the carbon atom of the azetidine, pyrrolidine, piperidine, azepane, piperazine and morpholine to which they are attached, form an azetidine or an oxetane,

wherein the azetidine or oxetane itself may be substituted by 1-2 substituents, the substituents being independently selected from methyl and ethyl,

R ³ represents hydrogen,

and

^R4 represents hydrogen, fluorine or methoxy,

or

R ³ represents hydrogen, fluorine or methoxy,

and

^R4 represents hydrogen.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₂ -C ₆ -alkyl group,

wherein the alkyl group is substituted with one substituent selected from the group consisting of hydroxy, methoxy and ethoxy,

and

^R2 represents hydrogen,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine or 1,1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine and 1,1-dioxothiomorpholine may be substituted by 1-2 substituents independently selected from hydroxyl, hydroxycarbonyl, C ₁ -C ₃ -alkyl and methoxy,

or

wherein azetidine, pyrrolidine, piperidine and azepane may have two substituents which, together with the carbon atom of the azetidine, pyrrolidine, piperidine and azepane to which they are attached, form an azetidine or an oxetane,

wherein the azetidine and oxetane themselves may be substituted by 1-2 substituents, the substituents being independently selected from methyl and ethyl,

R ³ represents hydrogen,

and

^R4 represents hydrogen, fluorine or methoxy,

or

R ³ represents hydrogen, fluorine or methoxy,

and

^R4 represents hydrogen.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₂ -C ₄ -alkyl group,

wherein the alkyl group is substituted with one substituent selected from the group consisting of hydroxy and methoxy,

and

^R2 represents hydrogen,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, morpholine or 1,1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, morpholine and 1,1-dioxothiomorpholine may be substituted by 1-2 substituents, said substituents being independently selected from oxo, hydroxyl, hydroxycarbonyl and methyl,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form an azetidine,

wherein the azetidine may have two substituents, said substituents together with the carbon atom of the azetidine to which they are attached form an oxetane,

R ³ represents hydrogen,

and

^R4 represents hydrogen.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

R ¹ represents a C ₂ -C ₆ -alkyl group,

wherein the alkyl group is substituted with one substituent selected from the group consisting of hydroxy, methoxy and ethoxy,

and

^R2 represents hydrogen.

Preferred are compounds of formula (I) and salts thereof, solvates thereof and solvates of their salts, wherein

^R1 and ^R2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, morpholine or 1,1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, morpholine and 1,1-dioxothiomorpholine may be substituted by 1-2 substituents, said substituents being independently selected from oxo, hydroxyl, hydroxycarbonyl and methyl,

or

^R1 and ^R2 together with the nitrogen atom to which they are attached form an azetidine,

The azetidine may have two substituents, which together with the carbon atom of the azetidine to which they are attached form an oxetane.

Preference is given to compounds of formula (I) in which R ² represents hydrogen.

Preferred are compounds of formula (I) wherein ^R1 and ^R2 together with the nitrogen atom to which they are attached form 2-oxa-6-azaspiro[3.3]hept-6-yl.

Preferred are compounds of formula (I) wherein R ¹ and R ² together with the nitrogen atom to which they are attached form 1,1-dioxathiamorpholin-4-yl.

Preference is given to compounds of formula (I) in which R ³ represents hydrogen.

Preference is given to compounds of formula (I) in which R ⁴ represents hydrogen.

Preferred are compounds of formula (I) wherein R ³ and R ⁴ represent hydrogen.

Independently of the respectively given combination of residues, the individual residue definitions given in the respective combination or preferred combination of residues can also be arbitrarily replaced by the residue definitions of the other combinations.

Very particular preference is given to combinations of two or more of the aforementioned preferred ranges.

The present invention also provides a method for preparing a compound of formula (I) or a salt thereof, a solvate thereof or a solvate of a salt thereof, wherein

[A] In the presence of a reducing agent, a compound of formula (II)

Reaction with a compound of formula (III)

wherein R ³ and R ⁴ have the meanings given above,

Obtaining a compound of formula (IV)

wherein R ³ and R ⁴ have the meanings given above,

or

[B] reacting the compound of formula (IV) in the presence of an acid

wherein R ³ and R ⁴ have the meanings given above,

Obtaining a compound of formula (V)

wherein R ³ and R ⁴ have the meanings given above,

or

[C] In the presence of a base, the compound of formula (VI)

in

X represents halogen, preferably fluorine, chlorine or bromine, or sulfonylmethane and,

R ⁵ represents C ₁ -C ₄ -alkyl, preferably methyl or ethyl,

Reaction with a compound of formula (VII)

wherein R ¹ and R ² have the meanings given above,

Obtaining a compound of formula (VIII)

wherein R ¹ , R ² and R ⁵ have the meanings given above,

or

[D] In the presence of a dehydrating agent, the compound of formula (IX)

wherein R ¹ and R ² have the meanings given above,

Reaction with a compound of formula (V)

wherein R ³ and R ⁴ have the meanings given above,

The compound of formula (I) is obtained.

The reaction according to process [A] is usually carried out in an inert solvent, preferably in a temperature range of -20°C to 60°C under normal pressure and optionally in the presence of a base.

Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane or tetrahydrofuran, or dimethylformamide, or acetic acid or glacial acetic acid, or dichloromethane, chloroform or 1,2-dichloroethane. Mixtures of the aforementioned solvents can also be used. Dichloromethane or tetrahydrofuran is preferred.

The base is, for example, an organic base such as a trialkylamine, for example triethylamine, N -methylmorpholine, N -methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine; preference is given to diisopropylethylamine.

The reducing agent is, for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium bis-(2-methoxyethoxy)aluminum hydride, sodium triacetoxyborohydride or borane/tetrahydrofuran; sodium triacetoxyborohydride is preferred.

The compounds of formula (II) and (III) are known or can be synthesized from appropriate starting materials by known methods.

As an alternative to the above-mentioned method [A], the preparation of the compound of formula (IV) may also include a method wherein

[E] a compound of formula (II)

Reaction with a compound of formula (III)

wherein R ³ and R ⁴ have the meanings given above,

Obtaining a compound of formula (IVa)

wherein R ³ and R ⁴ have the meanings given above,

or

[F] In the presence of a reducing agent, reacting the compound of formula (IVa)

wherein R ³ and R ⁴ have the meanings given above,

The compound of formula (IV) is obtained.

The reducing agent in the reaction according to process [E] can be, for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium bis-(2-methoxyethoxy)aluminum hydride, sodium triacetoxyborohydride, borane/tetrahydrofuran or hydrogen in the presence of a palladium catalyst.

The reaction according to process [B] is usually carried out in an inert solvent, preferably in a temperature range of -20°C to 60°C under normal pressure.

Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane or tetrahydrofuran, or dimethylformamide, or dichloromethane, chloroform or 1,2-dichloroethane. Mixtures of the solvents mentioned can also be used. Dichloromethane is preferred.

Acids are, for example, hydrogen chloride and trifluoroacetic acid; hydrogen chloride is preferred. These acids are preferably dissolved in an inert solvent and added. A preferred solvent for this is dioxane.

The reaction according to process [C] is usually carried out in an inert solvent, preferably in a temperature range of 0°C to 80°C under normal pressure.

Inert solvents are, for example, alcohols such as isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran or N-methylmorpholinone, or dimethylformamide, or dichloromethane, chloroform, 1,2-dichloroethane or acetonitrile. Acetonitrile and N-methylmorpholinone are preferred. Mixtures of the solvents mentioned can also be used.

The base is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate, or sodium hydrogen carbonate, potassium hydrogen carbonate or cesium hydrogen carbonate, or an organic base such as a trialkylamine, for example triethylamine, N -methylmorpholine, N -methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine; preference is given to potassium carbonate and sodium carbonate.

The compounds of formula (VI) and (VII) are known or can be synthesized by known methods from appropriate starting compounds.

The reaction according to process [D] is usually carried out in an inert solvent, optionally in the presence of a base, preferably in a temperature range of -30°C to 50°C under normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or chloroform, hydrocarbons such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. Mixtures of the solvents mentioned can also be used. Acetonitrile is particularly preferred.

Suitable dehydrating agents are, for example, carbodiimide compounds such as N,N' -diethyl-carbodiimide, N,N' -dipropyl-carbodiimide, N,N' -diisopropyl-carbodiimide, N,N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N' -ethylcarbodiimide hydrochloride (EDC), N -cyclohexylcarbodiimide- N' -propoxymethyl-polystyrene (PS-carbodiimide) or a carbonyl compound such as carbonyldiimidazole, or a 1,2-oxazolium compound such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2- tert-butyl -5-methylisoxazolium perchlorate, or an acylamino compound 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 benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), or N -hydroxysuccinimide, or a mixture of these with a base.

The base is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate, or sodium bicarbonate, potassium bicarbonate or cesium bicarbonate, or an organic base such as a trialkylamine, for example triethylamine, N -methylmorpholine, N -methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine; preference is given to diisopropylethylamine.

The condensation is preferably carried out using propanephosphonic anhydride.

The compound of formula (IX) can be prepared by saponifying the carboxylic acid ester in the compound of formula (VIII).

The saponification is generally carried out in an inert solvent in the presence of at least one base, preferably in a temperature range of 0°C to 90°C under normal pressure.

The base is, for example, an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide, each of which can be used in the form of an aqueous solution. Preferred are aqueous solutions of lithium hydroxide and sodium hydroxide.

Inert solvents are, for example, polar solvents such as alcohols, for example methanol, ethanol, n-propyl alcohol or isopropyl alcohol, or ethers such as ether, dioxane, tetrahydrofuran or N-methylmorpholine. Also mixtures of the solvents can be used. Preferred are mixtures of dioxane, ethanol and tetrahydrofuran with methanol.

In addition, the preparation of the compound of formula (I) according to the present invention may also comprise the following method, wherein

[G] a compound of formula (IX)

wherein R ¹ and R ² have the meanings given above,

Reaction with 4-piperidone,

Obtaining a compound of formula (X)

wherein R ¹ and R ² have the meanings given above,

or

[H] In the presence of a reducing agent, a compound of formula (X)

wherein R ¹ and R ² have the meanings given above,

Reaction with a compound of formula (III)

wherein R ³ and R ⁴ have the meanings given above,

The compound of formula (I) is obtained.

The reaction according to method [G] is carried out analogously to the reaction according to method [D].

The reducing agent in the reaction according to process [H] can be, for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium bis-(2-methoxyethoxy)aluminum hydride, sodium triacetoxyborohydride or borane/tetrahydrofuran.

In addition, the preparation of the compound of formula (I) according to the present invention may also comprise the following method, wherein

[I] In the presence of a dehydrating agent, a compound of formula (XI)

in

X represents halogen, preferably fluorine, chlorine or bromine, or sulfonylmethane,

Reaction with compound (V)

wherein R ³ and R ⁴ have the meanings given above,

Obtaining a compound of formula (XII)

in

R ³ and R ⁴ have the meanings given above and

X represents halogen, preferably fluorine, chlorine or bromine, or sulfonylmethane,

or

[J] a compound of formula (XII)

in

R ³ and R ⁴ have the meanings given above and

X represents halogen, preferably fluorine, chlorine or bromine, or sulfonylmethane,

Reaction with a compound of formula (VII)

wherein R ¹ and R ² have the meanings given above,

The compound of formula (I) is obtained.

The dehydrating agent used in the reaction according to method [I] may be, for example, those described with respect to the reaction according to method [D].

The reducing agent used in the reaction according to method [J] may be, for example, those described with respect to the reaction according to method [A].

The present invention further provides a method for preparing a compound of formula (I) or a salt thereof, a solvate thereof or a solvate of a salt thereof, wherein the method comprises a reaction according to the above method, the reaction being selected from the following combination:

[A] and [B],

[E], [F], and [B],

[C] and [D],

[A], [B], and [D],

[E], [F], [B], and [D],

[A], [B], [C], and [D], and

[E], [F], [B], [C], and [D].

The preparation of compounds of formula (I) can be illustrated by the following synthetic schemes.

Synthesis Scheme 1:

Synthesis Scheme 2:

Synthesis Scheme 3:

Synthesis Scheme 4:

Synthesis Scheme 5:

The present invention also provides compounds of formula (VIII) or (IX) and salts thereof, solvates thereof and solvates of their salts,

in

^R1 and ^R2 together with the nitrogen atom to which they are attached form an azetidine,

wherein the azetidine may have two substituents, said substituents together with the carbon atom of the azetidine to which they are attached form an oxetane,

and

R ⁵ represents C ₁ -C ₄ -alkyl, preferably methyl or ethyl.

The compounds according to the present invention have an unexpectedly useful pharmacological activity spectrum, including useful pharmacokinetic properties. They are selective adrenergic receptor _α2C receptor antagonists, which cause vasodilation and/or inhibit platelet aggregation and/or lower blood pressure and/or increase coronary or peripheral blood flow. Therefore, they are suitable for the treatment and/or prevention of diseases in humans and animals, preferably cardiovascular diseases, diabetic microangiopathy, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathies.

In particular, the compounds according to the invention exhibit a disease-selective improvement of peripheral blood flow (microcirculation and macrocirculation) under pathophysiologically altered conditions, for example as a consequence of diabetes or atherosclerosis.

The compounds according to the invention are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.

Therefore, the compounds according to the invention are suitable for the treatment of cardiovascular diseases, for example, for the treatment of hypertension, for primary and/or secondary prevention, and for the treatment of heart failure, for the treatment of stable and unstable angina, pulmonary hypertension, peripheral and cardiovascular diseases (e.g. peripheral occlusive disease), arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transient and ischemic attacks, peripheral circulatory disorders, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) and the installation of bypass, and for the treatment of ischemic syndromes, atherosclerosis, asthmatic diseases, genitourinary diseases, such as benign prostatic hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence.

Furthermore, the compounds according to the invention can be used for the treatment of primary and secondary Raynaud's phenomenon, microcirculatory disturbances, intermittent claudication, peripheral and autonomic neuropathies, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the extremities, diabetic erectile dysfunction, CREST syndrome, erythematosis, onychomycosis, tinnitus, vertigo, sudden deafness, Meniere's disease and rheumatism.

Furthermore, the compounds according to the invention are suitable for the treatment of respiratory distress syndrome and chronic obstructive pulmonary disease (COPD), acute and chronic renal failure, and for promoting wound healing, and here in particular diabetic wound healing.

In addition, the compound according to the present invention is suitable for treating and/or preventing the concomitant diseases and/or sequelae of diabetes.The example of the concomitant diseases and/or sequelae of diabetes is diabetic heart disease, for example, diabetic coronary heart disease, diabetic coronary microvascular heart disease (coronary microvascular disease, MVD), diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, hypertension, diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, apoplexy, diabetic nephropathy, diabetic erectile dysfunction, limb diabetic ulcers and diabetic foot syndrome. In addition, the compound according to the present invention is suitable for promoting diabetic wound healing, particularly for promoting the wound healing of diabetic foot ulcers.The promotion of the wound healing of diabetic foot ulcers is defined as the improvement of for example wound closure.

In addition, compound according to the present invention is also suitable for controlling cerebral blood flow, and is the effective agent for preventing and treating migraine.They are also suitable for preventing and treating the sequelae of cerebral infarction (stroke) such as apoplexy, cerebral ischemia and craniocerebral injury.Compound according to the present invention can be used for preventing and treating pain state equally.

Furthermore, the compounds according to the invention can also be used for the treatment and/or prevention of microvascular and macrovascular damage (vasculitis), reperfusion injury, arterial and venous thrombosis, edema, tumor diseases (skin cancer, liposarcoma, gastrointestinal cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureteral cancer, prostate cancer and reproductive tract cancer), central nervous system diseases and neurodegenerative diseases (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis, schizophrenia), inflammatory diseases, autoimmune diseases (Crohn's disease, ulcerative colitis, lupus erythematosus, Rheumatoid arthritis, asthma), kidney disease (glomerulonephritis), thyroid disease (hyperthyroidism), hyperhidrosis, pancreatic disease (pancreatitis), liver fibrosis, skin diseases (psoriasis, acne, eczema, neurodermatitis, dermatitis, keratitis, scarring, wart formation, frostbite), skin grafts, 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 provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, preferably thromboembolic diseases and/or thromboembolic complications.

"Thromboembolic diseases" in the sense of the present invention include in particular diseases such as ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, reocclusion and restenosis after coronary intervention (such as angioplasty, stent implantation or aortocoronary bypass), peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis and renal vein thrombosis, transient ischemic attacks and thrombotic and thromboembolic stroke and pulmonary hypertension.

Therefore, in patients with acute, intermittent or persistent cardiac arrhythmias (e.g., atrial fibrillation) and in patients undergoing cardioversion, furthermore in patients with valvular heart disease or with intravascular objects (e.g., artificial heart valves, catheters, intra-aortic balloon pumps and pacemaker probes), the substances are also suitable for the prevention and treatment of cardiogenic thromboembolism (e.g., cerebral ischemia, stroke and systemic thromboembolism and ischemia). In addition, the compounds according to the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).

Furthermore, thromboembolic complications occur in the case of microangiopathic hemolytic anemia, extracorporeal blood circulation, such as hemodialysis, hemofiltration, ventricular assist devices and artificial hearts, and heart valve prostheses.

The compounds according to the invention 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 includes more specific or related forms of the disease, such as right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage diseases, diastolic and systolic heart failure.

The compounds according to the invention are very particularly suitable for the treatment and/or prevention of cardiovascular diseases, in particular heart failure and/or circulatory disturbances and microangiopathy associated with diabetes.

The compounds according to the invention are also suitable for the primary and/or secondary prevention and treatment of the abovementioned diseases in children.

The present invention further provides the compounds according to the invention for use in a method for the treatment and/or prophylaxis of diseases, in particular the diseases mentioned above.

The present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular the diseases mentioned above.

The present invention also provides the use of the compounds according to the invention for the production of medicaments for the treatment and/or prevention of diseases, in particular the diseases mentioned above.

The present invention also provides a method for treating and/or preventing diseases, in particular the diseases mentioned above, using a therapeutically effective amount of the compounds according to the invention.

The present invention also provides adrenergic receptor α2C receptor antagonists for use in methods for treating and/or preventing complications and/or sequelae of diabetes, diabetic heart disease, diabetic coronary heart disease, diabetic coronary microvascular heart disease, diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers of the limbs, and diabetic foot ulcers, and for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers.

The present invention also provides adrenergic receptor α2C receptor antagonists for use in methods for treating and/or preventing diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, diabetic ulcers of the limbs, and diabetic foot ulcers, and for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers.

The present invention also provides a competitive adrenergic receptor α2C receptor antagonist for use in methods for treating and/or preventing complications and/or sequelae of diabetes, diabetic heart disease, diabetic coronary heart disease, diabetic coronary microvascular heart disease, diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers of the limbs, and diabetic foot ulcers, and for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers.

The present invention also provides a drug for treating and/or preventing complications and/or sequelae of diabetes, diabetic heart disease, diabetic coronary heart disease, diabetic coronary microvascular heart disease, diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers of the limbs, diabetic foot ulcers, and for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers, the drug comprising at least one adrenergic receptor α2C receptor antagonist in combination with one or more inert, non-toxic, pharmaceutically suitable adjuvants.

The present invention also provides a medicament for treating and/or preventing diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, diabetic ulcers of the limbs, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers, the medicament comprising at least one adrenergic receptor α2C receptor antagonist in combination with one or more inert, non-toxic, pharmaceutically suitable adjuvants.

The present invention also provides a drug for treating and/or preventing complications and/or sequelae of diabetes, diabetic heart disease, diabetic coronary heart disease, diabetic coronary microvascular heart disease, diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers of the limbs, diabetic foot ulcers, and for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers, the drug comprising at least one competitive adrenergic receptor α2C receptor antagonist in combination with one or more inert, non-toxic, pharmaceutically suitable adjuvants.

The present invention also provides a medicament comprising at least one adrenergic receptor α2C receptor antagonist in combination with one or more further active substances selected from the group consisting of active substances that modify lipid metabolism, antidiabetic agents, hypotensive agents, agents that reduce sympathetic tone, perfusion enhancers and/or agents that have an antithrombotic effect, as well as antioxidants, aldosterone- and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, compounds that enhance contractility, calcium Sensitizers, ACE inhibitors, compounds that regulate cGMP and cAMP, natriuretic peptides, NO-independent guanylate cyclase stimulators, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds that inhibit signal transduction cascades, compounds that regulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorexia drugs, PAF-AH inhibitors, anti-inflammatory drugs, analgesics, antidepressants and other psychotropic drugs.

The present invention also provides a medicament comprising at least one competitive adrenergic receptor α2C receptor antagonist in combination with one or more further active substances selected from the group consisting of active substances that modify lipid metabolism, antidiabetic agents, hypotensive agents, agents that reduce sympathetic tone, perfusion enhancers and/or agents that act as antithrombotic agents, as well as antioxidants, aldosterone- and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, compounds that enhance contractility , calcium sensitizers, ACE inhibitors, compounds that regulate cGMP and cAMP, natriuretic peptides, NO-independent guanylate cyclase stimulators, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds that inhibit signal transduction cascades, compounds that regulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorexia drugs, PAF-AH inhibitors, anti-inflammatory drugs, analgesics, antidepressants and other psychotropic drugs.

The present invention also provides a method for treating and/or preventing complications and/or sequelae of diabetes, diabetic heart disease, diabetic coronary heart disease, diabetic coronary microvascular heart disease, diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers of the limbs, diabetic foot ulcers, and a method for promoting diabetic wound healing and wound healing of diabetic foot ulcers in humans and animals by administering an effective amount of at least one adrenergic receptor α2C receptor antagonist or a drug containing at least one adrenergic receptor α2C receptor antagonist.

The present invention also provides a method for treating and/or preventing diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, diabetic ulcers of the limbs, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers in humans and animals by administering an effective amount of at least one adrenergic receptor α2C receptor antagonist or a drug containing at least one adrenergic receptor α2C receptor antagonist.

The present invention also provides a method for treating and/or preventing complications and/or sequelae of diabetes, diabetic heart disease, diabetic coronary heart disease, diabetic coronary microvascular heart disease, diabetic heart failure, diabetic cardiomyopathy and myocardial infarction, diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers of the limbs, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers in humans and animals by administering an effective amount of at least one competitive adrenergic receptor α2C receptor antagonist or a drug containing at least one competitive adrenergic receptor α2C receptor antagonist.

Adrenergic receptor α2C receptor antagonists within the scope of the present invention are receptor ligands or compounds that block or inhibit the biological response induced by adrenergic receptor α2C receptor agonists. Adrenergic receptor α2C receptor antagonists within the scope of the present invention can be, for example, competitive adrenergic receptor α2C receptor antagonists, non-competitive adrenergic receptor α2C receptor antagonists, inverse adrenergic receptor α2C receptor agonists or allosteric adrenergic receptor α2C receptor modulators.

The compounds according to the invention can be used alone or, if necessary, in combination with other active substances. The present invention also provides medicaments comprising the compounds according to the invention and one or more other active substances, in particular for the treatment and/or prevention of the above-mentioned diseases. Suitable active substances for combination may be mentioned by way of example and preferably: active substances which modify lipid metabolism, antidiabetics, hypotensives, agents which reduce sympathetic tone, perfusion enhancers and/or agents which have an antithrombotic effect, as well as antioxidants, aldosterone- and mineralocorticoid-receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, active substances which enhance contractility, calcium sensitizers, ACE inhibitors, compounds which regulate cGMP and cAMP, natriuretic peptides, NO-independent guanylate cyclase stimulators, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds which inhibit signal transduction cascades, compounds which regulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorexigenics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB ₄ receptor antagonists, LTB ₄ synthesis inhibitors), analgesics (aspirin), antidepressants and other psychotropic drugs.

The present invention provides, in particular, a combination of at least one compound according to the invention and at least one active substance which modifies lipid metabolism, an antidiabetic, a hypotensive active substance and/or an agent which has an antithrombotic effect.

The compounds according to the invention can preferably be combined with one or more of the following active substances:

Active substances which modify lipid metabolism, for example and preferably selected from the group consisting of: HMG-CoA reductase inhibitors from the statins, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, for example and preferably BMS-188494 or TAK-475, ACAT inhibitors, for example and preferably melinamide, patiimibe, eflumimibe or SMP-797, LDL receptor sensors, cholesterol absorption inhibitors, for example and preferably ezetimibe, tiqueside or pamaqueside, high molecular weight bile acid adsorbents, for example and preferably cholestyramine, colestipol, colesivelam, cholestagel or colestilan, bile acid reabsorption inhibitors, for example and preferably ASBT (= IBAT) inhibitors such as elobixibat (AZD-7806), S-8921, AK-105, canostamib (BARI-1741, AVE-5530), SC-435 or SC-635, MTP inhibitors, for example and preferably implitapide or JTT-130, lipase inhibitors, for example and preferably orlistat, LpL activators, fibrates, nicotinic acid, CETP inhibitors, for example and preferably torcetrapib, dalcetrapib (JTT-705) or a CETP vaccine (Avant), PPAR-γ and/or PPAR-δ agonists, for example and preferably pioglitazone or rosiglitazone and/or Endurobol (GW-501516), RXR modulators, FXR modulators, LXR modulators, thyroid hormones and/or thyroid mimetics, for example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3), ATP citrate lyase inhibitors, Lp(a) antagonists, cannabinoid receptor 1 antagonists, for example and preferably rimonabant or sulinabant (SR-147778), leptin receptor agonists, bombesin receptor agonists, histamine receptor agonists, agonists of nicotinic acid receptors, for example and preferably nicotinic acid, acipimox, acifuran or nicotinamide tartrate, and antioxidants/free radical scavengers, for example and preferably probucol, succinylcholine (AGI-1067), BO-653 or AEOL-10150;

Antidiabetic agents as mentioned in Rote Liste 2014, Chapter 12. Antidiabetic agents are preferably understood to mean insulin and insulin derivatives as well as orally effective hypoglycemic substances. Insulin and insulin derivatives include insulin of animal, human, or biotechnological origin, and mixtures thereof. Orally effective hypoglycemic substances preferably include sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, and PPAR-γ agonists. Sulfonylureas that may be mentioned as examples and preferably tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide, biguanides that may be mentioned as examples and preferably metformin, meglitinide derivatives that may be mentioned as examples and preferably repaglinide or nateglinide, glucosidase inhibitors that may be mentioned as examples and preferably miglitol or acarbose, oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK 1 receptor agonists, leptin receptor agonists, inhibitors of hepatic enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, regulators of glucose uptake and potassium channel openers, as disclosed, for example, in WO 97/26265 and WO 99/03861;

Active substances which lower blood pressure, for example and preferably are selected from the group consisting of calcium antagonists, for example and preferably nifedipine, amlodipine, verapamil or diltiazem, angiotensin AII antagonists, for example and preferably losartan, valsartan, candesartan, embusartan or telmisartan, ACE inhibitors, for example and preferably enalapril, captopril, ramipril, delapril, fosinopril, quinapril, perindopril or trandolapril, beta-blockers, for example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, metoprolol, methylprednisolone ... Pindolol, Carazalol, Sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adalolol, Landiolol, Nebivolol, Epanolol or Bucindolol, alpha-blockers, for example and preferably prazosin, ECE inhibitors, Rho kinase inhibitors and vasopeptidase inhibitors, and diuretics, for example and preferably loop diuretics such as furosemide, bumetanide or torsemide, or thiazide or thiazide-like diuretics such as chlorothiazide or hydrochlorothiazide, or A1 antagonists such as rolophylline, Tonopofylline and SLV-320;

agents that reduce sympathetic tone, such as, and preferably, reserpine, clonidine or alpha-methyldopa, or in combination with potassium channel agonists, such as, and preferably, minoxidil, diazoxide, dihydralazine or hydralazine;

an agent which acts as an antithrombotic agent, for example and preferably selected from the group consisting of platelet aggregation inhibitors, for example and preferably aspirin, clopidogrel, ticlopidine, cilostazol or dipyridamole, or anticoagulants such as thrombin inhibitors, for example and preferably ximelagatran, melagatran, bivalirudin or clexetine, GPIIb/IIIa antagonists, for example and preferably tirofiban or abciximab, factor Xa inhibitors, for example and preferably rivaroxaban, edoxaban (DU-176b), apixaban, otamixaban, fedexaban, razoxaban, fondaparinux, edaparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428, together with heparin or a low molecular weight (LMW) heparin derivative or together with a vitamin K antagonist, for example and preferably, coumarin;

aldosterone- and mineralocorticoid receptor antagonists, for example and preferably spironolactone, eplerenone or Finerenon;

Vasopressin receptor antagonists, for example and preferably, conivaptan, tovaptan, rivaptan or satavaptan (SR-121463);

organic nitrates and NO donors, for example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, or in combination with inhaled NO;

IP receptor agonists, for example and preferably, iloprost, treprostinil, beraprost and Selexipag (NS-304);

Compounds that enhance inotropic forces, for example and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine or dobutamine;

Calcium sensitizers, for example and preferably levosimendan;

compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterase (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, such as atrial natriuretic peptide (ANP, anaritide), B-type or brain natriuretic peptide (BNP, nesiritide), C-type natriuretic peptide (CNP), and urodilatin;

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

NO- and heme-independent guanylate cyclase activators, such as, inter alia, 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 that inhibit signal transduction cascades, such as tyrosine kinase inhibitors and multikinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and/or

●Compounds that affect cardiac energy metabolism, such as etomoxir, dichloroacetate, ranolazine, and trimetazidine.

Particularly preferred within the scope of the present invention are combinations comprising at least one compound according to the invention and one or more further active substances selected from the group consisting of HMG-CoA reductase inhibitors (statins), diuretics, beta-blockers, organic nitrates and NO donors, ACE inhibitors, angiotensin AII antagonists, aldosterone- and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors and anticoagulants, and their use for the treatment and/or prophylaxis of the aforementioned diseases.

Particularly preferred within the scope of the present invention are combinations comprising at least one compound according to the invention and one or more further active substances 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 of 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 compound according to the invention in a method for promoting diabetic wound healing and for treating and/or preventing diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, wherein the compound of formula (I) is additionally used in combination with one or more of the following physical and/or local therapies: wound treatment such as bandaging, wound excision, weight loss with suitable shoes, PDGF (Regranex), hyperbaric oxygen therapy, negative pressure wound therapy.

The compounds of the present invention can act systemically and/or topically. For this purpose, they can be used in a suitable manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, ear route or as an implant or stent.

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

Suitable administration forms for oral administration are forms which act according to the prior art and deliver the compound of the invention rapidly and/or in an improved form and which contain the compound of the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (uncoated or coated tablets, for example with an enteric coating or a coating which delays dissolution or an insoluble controlled release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilized powders, capsules (for example hard or soft gelatin capsules), dragees, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished while avoiding the absorption step (e.g., by intravenous, intraarterial, intracardiac, intraspinal or intralumbar routes), or while absorption is achieved (e.g., by intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal routes). Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized powders or sterile powders.

Oral administration is preferred.

In the exemplary use of the compound of formula (I) for promoting diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers, in addition to oral administration, it is also preferably administered in the form of a topical preparation.

Suitable administration forms for other administration routes are, for example, inhalation forms (including powder inhalers, nebulizers), nasal drops, nasal solutions or nasal sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration, suppositories, ear preparations or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaker mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (Milch), pastes, foams, dusting powders, implants or stents.

The compounds of the invention can be converted into the above-mentioned administration forms. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable adjuvants. These adjuvants include carrier substances (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinyl pyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, such as ascorbic acid), colorants (e.g., inorganic pigments, such as iron oxide), and flavorings and/or flavoring agents.

The invention also provides medicaments comprising at least one compound according to the invention, preferably together with one or more inert, nontoxic, pharmaceutically suitable adjuvants, and their use for the above-mentioned purposes.

In general, it has been found to be advantageous to administer an amount of about 0.1-250 mg/24 hours, preferably 0.1-50 mg/24 hours, in the case of oral administration to achieve effective results. The dosage can be divided into multiple administrations per day. An example is administration 2 or 3 times per day.

Nevertheless, it may optionally be necessary to deviate from the stated amounts, specifically depending on body weight, route of administration, individual response to the active substance, the nature of the preparation and the time point or period of administration.

The present invention also provides a compound of formula (I) as described above, which is used in a method for treating and/or preventing primary and secondary diabetic microangiopathy, diabetic wound healing, diabetic ulcers of the limbs, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathy.

The present invention also provides a compound of formula (I) as described above, which is used for treating and/or preventing primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, microcirculatory disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the limbs and CREST syndrome, as well as for diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers.

The present invention also provides a compound of formula (I) as described above for use in the preparation of a medicament for treating and/or preventing primary and secondary diabetic microangiopathy, diabetic wound healing, diabetic ulcers of the limbs, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathy.

The present invention also provides the use of the compound of formula (I) as described above for preparing a medicament for treating and/or preventing primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, microcirculatory disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the limbs and CREST syndrome, as well as for diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers.

The present invention also provides a medicament comprising a compound of formula (I) as described above in combination with one or more inert, non-toxic, pharmaceutically suitable adjuvants.

The present invention also provides a medicament comprising a compound of formula (I) as described above in combination with one or more further active substances selected from active substances that modify lipid metabolism, antidiabetic agents, hypotensive agents, agents that reduce sympathetic tone, perfusion enhancers and/or agents with antithrombotic effects, as well as antioxidants, aldosterone- and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, compounds that enhance contractility, calcium sensitizers, ACE inhibitors, compounds that regulate cGMP and cAMP, natriuretic peptides, NO-independent guanylate cyclase stimulators, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds that inhibit signal transduction cascades, compounds that regulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorexia drugs, PAF-AH inhibitors, anti-inflammatory drugs, analgesics, antidepressants and other psychotropic drugs.

The present invention also provides a drug corresponding to the above embodiment, which is used to treat and/or prevent primary and secondary diabetic microangiopathy, diabetic wound healing, diabetic ulcers of the limbs, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathy.

The present invention also provides a drug corresponding to the above embodiment, which is used to treat and/or prevent primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, microcirculatory disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the limbs and CREST syndrome, as well as for diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers.

The present invention also provides a method for treating and/or preventing primary and secondary diabetic microangiopathy, diabetic wound healing, diabetic ulcers of the limbs, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathy in humans and animals by administering an effective amount of at least one compound of formula (I) as described above or a drug as described above.

The present invention also provides a method for treating and/or preventing primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, microcirculatory disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the limbs and CREST syndrome in humans and animals by administering an effective amount of at least one compound of formula (I) as described above or a medicament as described above, as well as a method for diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers.

Unless otherwise stated, percentages in the following tests and examples are percentages by weight; parts are parts by weight. Liquid solution/liquid solution solvent ratios, dilution ratios, and concentration data are in each case based on volume. The "w/v" data means "weight/volume." For example, "10% w/v" means: 100 ml of solution or suspension contains 10 g of substance.

In the synthetic intermediates and working examples of the present invention described below, if the compounds are given in the form of salts of the corresponding bases or acids, the exact stoichiometric composition of such salts obtained by the respective preparation methods and/or purification methods is generally unknown. Unless otherwise specified, additions to names and structural formulas, such as "hydrochloride,""trifluoroacetate,""oxalate,""sodiumsalt," or "xHCl,"_{" xCF3COOH} ,"^" _xC2O42- ,""xNa ⁺ ," are not to be understood as stoichiometric with respect to such salts, but rather are merely descriptive features with respect to the salt-forming components contained therein.

This applies correspondingly to the case of synthetic intermediates and working examples which are obtained by the preparation processes and/or purification processes in the form of solvates, for example hydrates, whose stoichiometric composition (if of a defined type) is unknown.

A) Examples

abbreviation:

ca. approximately

CDI Carbonyldiimidazole

d days, doublet (in NMR)

DC thin layer chromatography

DCI Direct Chemical Ionization (in MS)

dd doublet (in NMR)

DMAP 4-dimethylaminopyridine

DMF N,N -dimethylformamide

DMSO dimethyl sulfoxide

DSC Disuccinimidyl Carbonate

d. Th. Theoretical value (yield)

eq. equivalent

ESI Electrospray ionization (in MS)

h hour

HATU O -(7-Azabenzotriazol-1-yl)- N,N,N',N' -tetramethyluronium hexafluorophosphate

HPLC High-pressure, high-performance liquid chromatography

HV High Vacuum

LDA lithium diisopropylamide

m multiplet (in NMR)

min

MS

NMR nuclear magnetic resonance spectroscopy

PYBOP Benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate

q quartet (in NMR)

RP Reversed Phase (in HPLC)

RT Room temperature

_Rt retention time (in HPLC)

s singlet (in NMR)

t triplet (in NMR)

T3P 50% propanephosphonic anhydride in ethyl acetate or DMF

THF Tetrahydrofuran.

LC-MS and HPLC methods:

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

Method 2 (LC-MS): Instrument: Waters ACQUITY SQD UPLC system; Column: Waters AcquityUPLC HSS T3 1.8 µ 50 mm x 1 mm; Mobile phase A: 1 l water + 0.25 ml 99% formic acid, Mobile phase B: 1 l acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Incubator: 50°C; Flow rate: 0.40 ml/min; UV detection: 210 – 400 nm.

Method 3 (LC-MS): Instrument: Waters ACQUITY SQD UPLC system; Column: Waters AcquityUPLC HSS T3 1.8 µ 30 x 2 mm; Mobile phase A: 1 l water + 0.25 ml 99% formic acid, Mobile phase B: 1 l acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Incubator: 50°C; Flow rate: 0.60 ml/min; UV detection: 208 – 400 nm.

Method 4 (LC-MS): Instrument: Micromass Quattro Premier with Waters UPLCAcquity; Column: Thermo Hypersil GOLD 1.9 µ 50 mm x 1 mm; Mobile phase A: 1 l water + 0.5 ml 50% formic acid, Mobile phase B: 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; Constant temperature oven: 50°C; Flow rate: 0.33 ml/min; UV detection: 210 nm.

Method 5 (LC-MS): MS instrument type: Waters (Micromass) Quattro Micro; HPLC instrument type: Agilent 1100 series; column: Thermo Hypersil GOLD 3 µ 20 mm x 4 mm; mobile phase A: 1 l water + 0.5 ml 50% formic acid, mobile phase B: 1 l acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow rate: 2.5 ml) →5.00 min 100% A; thermostat: 50°C; flow rate: 2 ml/min; UV detection: 210 nm.

Method 6 (LC-MS): MS instrument type: Waters ZQ; HPLC instrument type: Agilent 1100 series; UV DAD; column: Thermo Hypersil GOLD 3 µ 20 mm x 4 mm; mobile phase A: 1 l water + 0.5 ml 50% formic acid, mobile phase B: 1 l acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100%; constant temperature oven: 55°C; flow rate: 2 ml/min; UV detection: 210 nm.

Method 7 (LC-MS): MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.0 x 50 mm 3.5 micron; mobile phase A: 1 l water + 0.01 mol ammonium carbonate, mobile phase B: 1 l acetonitrile; gradient: 0.0 min 98% A → 0.2 min 98% A → 3.0 min 5% A→ 4.5 min 5% A; thermostat: 40°C; flow rate: 1.75 ml/min; UV detection: 210 nm.

Method 8 (LC-MS): MS instrument: Waters (Micromass) Quattro Micro; HPLC instrument: Agilent 1100 series; column: YMC-Triart C18 3 µ 50 x 3 mm; mobile phase A: 1 l water + 0.01 mol ammonium carbonate, mobile phase B: 1 l acetonitrile; gradient: 0.0 min 100% A → 2.75 min 5% A → 4.5 min 5% A; thermostat: 40°C; flow rate: 1.25 ml/min; UV detection: 210 nm.

Method 9 (preparative HPLC): Column: Waters XBridge, 50 x 19 mm, 10 µm, mobile phase A: water + 0.5% ammonium hydroxide, mobile phase B: acetonitrile, 5 min = 95% A, 25 min = 50% A, 38 min = 50% A, 38,1 min = 5% A, 43 min = 5% A, 43.01 min = 95% A, 48.0 min = 5% A; flow rate 20 ml/min, UV detection: 210 nm.

NMR data were assigned unless the signal was hidden by solvent.

Starting compound

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, maintaining the mixture at approximately 30°C. Stirring was carried out at room temperature for approximately 1 hour, followed by the addition of approximately 1000 ml of saturated sodium bicarbonate solution. Extraction was then carried out with approximately 500 ml of ethyl acetate. The organic phase was washed with a further 500 ml of saturated sodium bicarbonate solution and 200 ml of saturated sodium chloride solution. The mixture was subsequently dried over sodium sulfate, filtered, and concentrated. This gave 234 g (98% of theory) of the target compound, which was processed further without further purification.

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 a 4M solution of hydrogen chloride in dioxane were added, maintaining the mixture at 25-30°C. After approximately one-third of the mixture had been added, the product began to crystallize. The mixture was stirred at room temperature for approximately 20 hours, followed by the addition of approximately 2000 ml of tert-butyl methyl ether. The resulting precipitate was filtered off with suction, washed with tert-butyl methyl ether, and dried in vacuo. 185 g (97% of theory) of the target compound were obtained as a white solid.

Example 3A

tert-Butyl 4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate

Dissolve 1.40 g (7.03 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate, 1.58 g (8.43 mmol) of 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride, and 2.45 ml (14.05 mmol) of N,N-diisopropylethylamine in 50 ml of dichloromethane and add approximately 1.5 g of molecular sieves (4 Å). Stir the suspension at room temperature for 1 hour. Then, add 2.23 g (10.54 mmol) of sodium triacetoxyborohydride and stir at room temperature for approximately 18 hours. For workup, dilute with approximately 50 ml of dichloromethane and wash twice with approximately 100 ml of saturated sodium bicarbonate solution. Extract the combined aqueous phases once with approximately 50 ml of dichloromethane and then with approximately 500 ml of ethyl acetate. Wash the organic phase with an additional 500 ml of saturated sodium bicarbonate solution and 200 ml of saturated sodium chloride solution. The combined organic phases were then dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by chromatography on silica gel (elution with cyclohexane/ethyl acetate 5:1 to 2:1). This gave 1.58 g (67% of theory) of the target compound.

Example 4A

7-Fluoro-2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

1.58 g (4.72 mmol) of the compound from Example 3A was dissolved in approximately 30 ml of dichloromethane, and 7.1 ml (28.35 mmol) of a 4M solution of hydrogen chloride in dioxane was added. The mixture was stirred at room temperature for approximately 20 h, after which approximately 100 ml of diethyl ether was added. The resulting precipitate was filtered off with suction, washed with diethyl ether, and dried under HV. This gave 1.17 g (81% of theory) of the target compound as a white solid.

Example 5A

tert-Butyl 4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate

Dissolve 1.73 g (8.66 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate, 1.95 g (10.39 mmol) of 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride, and 3.02 ml (17.32 mmol) of N,N-diisopropylethylamine in 50 ml of dichloromethane and add approximately 10 g of molecular sieves (4 Å). Stir the suspension at room temperature for 1 hour. Then, add 2.75 g (12.99 mmol) of sodium triacetoxyborohydride and stir at room temperature for approximately 18 hours. For workup, dilute with approximately 50 ml of dichloromethane and wash twice with approximately 100 ml of saturated sodium bicarbonate solution. Extract the combined aqueous phases once with approximately 50 ml of dichloromethane and then with approximately 500 ml of ethyl acetate. Wash the organic phase with an additional 500 ml of saturated sodium bicarbonate solution and 200 ml of saturated sodium chloride solution. The combined organic phases were then dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by chromatography on silica gel (elution with cyclohexane/ethyl acetate 2:1 to 1:1). This gave 2.73 g (94% of theory) of the target compound.

Example 6A

6-Fluoro-2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

2.73 g (8.16 mmol) of the compound from Example 5A were dissolved in approximately 60 ml of dichloromethane, and 10.2 ml (40.82 mmol) of a 4M solution of hydrogen chloride in dioxane were added. The mixture was stirred at room temperature for approximately 20 h, after which approximately 100 ml of diethyl ether were added. The resulting precipitate was filtered off with suction, washed with diethyl ether, and dried under HV. This gave 2.24 g (89% of theory) of the target compound as a white solid.

Example 7A

tert-Butyl 4-(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate

Analogously to the compound from Example 5A, 3.27 g (16.42 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate, 3.93 g (10.39 mmol) of 7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, and 5.72 ml (32.84 mmol) of N,N-diisopropylethylamine were reacted with 5.22 g (24.63 mmol) of sodium triacetoxyborohydride. This gave 5.33 g (92% of theory) of the target compound.

Example 8A

7-Methoxy-2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

5.33 g (15.17 mmol) of the compound from Example 7A were reacted analogously to the compound from Example 6A with 22.75 ml (91.01 mmol) of a 4M solution of hydrogen chloride in dioxane. This gave 4.39 g (91% of theory) of the target compound as a white solid.

Example 9A

tert-Butyl 4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate

Analogously to the compound from Example 5A, 2.59 g (13.02 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate and 2.55 g (15.62 mmol) of 6-methoxy-1,2,3,4-tetrahydroisoquinoline were reacted with 4.14 g (19.53 mmol) of sodium triacetoxyborohydride. This gave 4.28 g (91% of theory) of the target compound.

Example 10A

6-Methoxy-2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

In analogy to the compound from Example 6A, 4.28 g (11.86 mmol) of the compound from Example 9A were reacted with 17.79 ml (71.15 mmol) of a 4M solution of hydrogen chloride in dioxane. This gave 3.50 g (92% of theory) of the target compound as a white solid.

Example 11A

Ethyl 2-[(2-methoxyethyl)amino]pyrimidine-5-carboxylate

0.42 ml (4.8 mmol) of 2-methoxyethylamine was added dropwise to a suspension of 1.00 g (4.34 mmol) of ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate and 1.80 g (13.0 mmol) of potassium carbonate in 10 ml of acetonitrile. After stirring at room temperature for 4 hours, the reaction mixture was concentrated and the residue was dissolved in dichloromethane and water. The phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 95:5 - 70:30), resulting in 485 mg (50% of theory) of the title compound.

Example 12A

2-[(2-methoxyethyl)amino]pyrimidine-5-carboxylic acid

10.8 ml of 1N sodium hydroxide solution were added to a solution of 485 mg (2.15 mmol) of ethyl 2-[(2-methoxyethyl)amino]pyrimidine-5-carboxylate in 10 ml of dioxane and stirred at room temperature for 4 h. For workup, the reaction mixture was concentrated and acidified with 1N hydrochloric acid. The resulting precipitate was filtered, washed twice with water, and dried under HV. 280 mg (66% of theory) of the title compound were isolated.

Example 13A

(rac) -2-[(1-methoxybutan-2-yl)amino]pyrimidine-5-carboxylic acid ethyl ester

Analogously to the compound from Example 11A, 493 mg (4.8 mmol) of 1-methoxy-2-aminobutane, 1.00 g (4.34 mmol) of ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate and 1.80 g (13.0 mmol) of potassium carbonate were reacted in 10 ml of acetonitrile. 412 mg (37% of theory) of the title compound were isolated.

Example 14A

(rac) -2-[(1-methoxybutan-2-yl)amino]pyrimidine-5-carboxylic acid

412 mg (1.63 mmol) of the compound from Example 13A were reacted analogously to the compound from Example 12A. 280 mg (76% of theory) of the title compound were isolated.

Example 15A

(rac) -2-[(1-hydroxybutan-2-yl)amino]pyrimidine-5-carboxylic acid ethyl ester

Analogously to the compound from Example 11A, 0.45 ml (4.8 mmol) of DL-2-amino-1-butanol, 1.00 g (4.34 mmol) of ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate and 1.80 g (13.0 mmol) of potassium carbonate were reacted in 10 ml of acetonitrile. 485 mg (46% of theory) of the title compound were isolated.

Example 16A

(rac) -2-[(1-hydroxybutan-2-yl)amino]pyrimidine-5-carboxylic acid

1.4 mg (4.05 mmol) of 3N sodium hydroxide solution was added to a solution of 485 mg (2.03 mmol) of the compound from Example 15A in 5.0 ml of ethanol and stirred at room temperature overnight. For workup, the reaction mixture was acidified with 1N HCl. The resulting precipitate was filtered, washed twice with water, and dried under high pressure. The aqueous phase was then extracted twice with 30 ml of ethyl acetate each time, and the organic phase was dried over magnesium sulfate, filtered, and concentrated. A total of 250 mg (58% of theory) of the title compound was isolated.

Example 17A

2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidine-5-carboxylic acid methyl ester

14.70 g (85.18 mmol) of methyl 2-chloropyrimidine-5-carboxylate was dissolved in 200 ml of acetonitrile, and 41.20 mg of potassium carbonate (298.14 mmol) was added. Subsequently, 24.17 g (127.77 mmol) of 2-oxa-6-azaspiro[3.3]heptane oxalate, prepared according to Angew. Chem. Int. Ed. 2008, 47, 4512–4515, was added, and the mixture was stirred at 60°C for approximately 16 hours. The mixture was then stirred in water and extracted three times with 200 ml of ethyl acetate each time. The aqueous phase was then extracted once more with approximately 200 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was stirred in approximately 200 ml of diethyl ether. The precipitated solid was filtered off with suction, washed with a little diethyl ether, and dried under HV. This gave 17.70 g (88% of theory) of the target compound.

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 initially placed in 120 ml of ethanol, 148 ml of 1 molar sodium hydroxide solution were added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, then initially dissolved in approximately 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) was isolated.

Example 19A

2-[(2R)-2-(tert-Butoxycarbonyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid ethyl ester

818 mg (4.78 mmol) of tert-butyl D-proline ester were added dropwise to a suspension of 1.00 g (4.34 mmol) of ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate and 2.40 g (17.4 mmol) of potassium carbonate in 10 ml of acetonitrile. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, filtered, the residue washed with ethyl acetate/dichloromethane, and the filtrate concentrated. The crude product was purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 95:5 to 70:30), resulting in 564 mg (40% of theory) of the title compound.

Example 20A

2-[(2R)-2-(tert-Butoxycarbonyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid

8.6 ml of 1N lithium hydroxide solution were added to a solution of 564 mg (1.76 mmol) of the compound from Example 19A in 20 ml of THF/methanol (5:1) and stirred at room temperature overnight. For workup, the reaction mixture was concentrated, acidified with 6N hydrochloric acid, and concentrated. The resulting residue was triturated with water. The precipitate was filtered, washed with water, and dried in a vacuum drying oven at 50°C. 400 mg (78% of theory) of the title compound were isolated.

Example 21A

1-(5-{[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]carbonyl}pyrimidin-2-yl)-D-proline tert-butyl ester

100 mg (0.341 mmol) of the compound from Example 20A and 99 mg (0.341 mmol) of the compound from Example 2A were reacted with 0.42 ml (2.4 mmol) of N,N-diisopropylethylamine and 0.24 ml (0.41 mmol) of T3P (50% by weight solution in ethyl acetate) in analogy to the compound from Example 1. 97 mg (58% of theory) of the title compound were isolated.

Example 22A

Methyl 2-(1,1-dioxathiamorpholin-4-yl)pyrimidine-5-carboxylate

55 mg of methyl 2-chloropyrimidine-5-carboxylate (0.32 mmol) and 43 mg of thiomorpholine-1,1-dioxide (0.32 mmol) were initially placed in 1 ml of N-methylmorpholinone, and 40 mg of sodium carbonate (0.38 mmol) was added. The mixture was then stirred at 100°C for 20 h. The mixture was stirred with water, and the precipitated product was filtered off with suction and washed with water. 62 mg (72% of theory) of the target compound were isolated.

Example 23A

2-(1,1-Dioxathiamorpholin-4-yl)pyrimidine-5-carboxylic acid

69 mg (0.25 mmol) of the compound from Example 22A were dissolved in 2 ml of methanol/THF 1/1, followed by the addition of 0.25 ml of 2N sodium hydroxide solution (0.50 mmol). Stir at 70°C for 1 h. The mixture was concentrated and taken up in water. It was then acidified with 1N aqueous hydrochloric acid solution and extracted twice with approximately 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was dried under HV. This gave 52 g (79% of theory) of the title compound, which was reacted further without further purification.

Example 24A

Methyl 2-[-2,6-dimethylmorpholin-4-yl]pyrimidine-5-carboxylate ( cis-isomer )

150 mg of methyl 2-chloropyrimidine-5-carboxylate (0.87 mmol) and 150 mg of 2,6-dimethylmorpholine (1.30 mmol) were initially placed in 3 ml of acetonitrile, and 420 mg of potassium carbonate (3.04 mmol) were added. The mixture was subsequently stirred at 60°C for 20 h. The mixture was stirred with water and then extracted twice with approximately 20 ml of ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1 to 5:1). 124 mg (57% of theory) of the target compound were isolated.

Example 25A

2-[-2,6-Dimethylmorpholin-4-yl]pyrimidine-5-carboxylic acid ( cis- isomer)

124 mg (0.49 mmol) of the compound from Example 24A were initially placed in 2 ml of methanol/THF (1:1), followed by the addition of 0.49 ml of 2N sodium hydroxide solution. Stir at 70°C for 1 h. The mixture was concentrated and taken up in water. It was then acidified with 1N aqueous hydrochloric acid solution and extracted twice with approximately 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was dried under HV. This gave 106 g (91% of theory) of the title compound, which was reacted further without further purification.

Example 26A

2-[-2,6-dimethylmorpholin-4-yl]pyrimidine-5-carboxylic acid methyl ester ( trans- isomer)

150 mg of methyl 2-chloropyrimidine-5-carboxylate (0.87 mmol) and 150 mg of 2,6-dimethylmorpholine (1.30 mmol) were initially placed in 3 ml of acetonitrile, and 420 mg of potassium carbonate (3.04 mmol) were added. The mixture was then stirred at 60°C for 20 h. The mixture was stirred with water and then extracted twice with approximately 20 ml of ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1 to 5:1). 38 mg of product (17% of theory) were isolated.

Example 27A

2-[-2,6-Dimethylmorpholin-4-yl]pyrimidine-5-carboxylic acid ( trans- isomer)

35 mg (0.14 mmol) of the compound from Example 26A were initially placed in 2 ml of methanol/THF 1:1, followed by the addition of 0.14 ml (0.28 mmol) of 2N sodium hydroxide solution. Stir at 70°C for 1 h. The mixture was concentrated and dissolved in water. Subsequently, it was acidified with 1N aqueous hydrochloric acid solution and extracted twice with approximately 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was dried under HV. This gave 27 g (78% of theory) of the title compound, which was reacted further without further purification.

Example 28A

Methyl 2-(2,2-dimethylmorpholin-4-yl)pyrimidine-5-carboxylate

75 mg of methyl 2-chloropyrimidine-5-carboxylate (0.44 mmol) and 99 mg of 2,2-dimethylmorpholine hydrochloride (0.65 mmol) were initially placed in 3 ml of acetonitrile, and 300 mg of potassium carbonate (2.17 mmol) were added. The mixture was then stirred at 60°C for 20 h. The mixture was stirred with water and then extracted twice with approximately 20 ml of ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1 to 5:1), resulting in 104 mg of product (95% of theory).

Example 29A

Methyl-2-(2,2-dimethylmorpholin-4-yl)pyrimidine-5-carboxylic acid

104 mg (0.41 mmol) of the compound from Example 28A were initially placed in 2 ml of methanol/THF 1/1, followed by the addition of 0.41 ml (0.82 mmol) of 2N sodium hydroxide solution. Stir at 70°C for 1 h. The mixture was concentrated and dissolved in water. Subsequently, it was acidified with 1N aqueous hydrochloric acid solution and extracted twice with approximately 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was dried under HV. This gave 86 g (88% of theory) of the title compound, which was reacted further without further purification.

Working Examples

Example 1

[4-(3,4-Dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}methanone

0.35 ml (2.0 mmol) of N,N-diisopropylethylamine and 0.20 ml (0.34 mmol) of T3P (50% by weight solution in ethyl acetate) were added to a mixture of 56 mg (0.28 mmol) of the compound from Example 12A and 72 mg (0.29 mmol) of the compound from Example 2A in 2.4 ml of acetonitrile, followed by stirring at room temperature overnight. For workup, 1 ml of saturated sodium bicarbonate solution was added, stirred for 15 minutes, filtered through an Extrelut cartridge, eluted with dichloromethane, and the filtrate was concentrated. The crude product obtained was purified by preparative HPLC [Method 9], resulting in 47 mg (41% of theory) of the title compound.

Example 2

(rac) -[4-(7-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]{2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}methanone

56 mg (0.249 mmol) of the compound from Example 13A and 76.4 mg (0.294 mmol) of the compound from Example 4A were reacted with 0.30 ml (1.7 mmol) of N,N-diisopropylethylamine and 0.17 ml (0.30 mmol) of T3P (50% by weight solution in ethyl acetate) in analogy to the compound from Example 1. 56.0 mg (51% of theory) of the title compound were isolated.

Example 3

(rac) -[4-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]{2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}methanone

56 mg (0.249 mmol) of the compound from Example 13A and 76.4 mg (0.294 mmol) of the compound from Example 6A were reacted with 0.30 ml (1.7 mmol) of N,N-diisopropylethylamine and 0.17 ml (0.30 mmol) of T3P (50% by weight solution in ethyl acetate) in analogy to the compound from Example 1. 61 mg (55% of theory) of the title compound were isolated.

Example 4

(rac) -{2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}[4-(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]methanone

56 mg (0.25 mmol) of the compound from Example 13A and 79 mg (0.29 mmol) of the compound from Example 8A were reacted with 0.30 ml (1.7 mmol) of N,N-diisopropylethylamine and 0.17 ml (0.30 mmol) of T3P (50% by weight solution in ethyl acetate) in a similar manner to the compound from Example 1. 67 mg (59% of theory) of the title compound were isolated.

Example 5

(rac) -{2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}[4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]methanone

56 mg (0.25 mmol) of the compound from Example 13A and 79 mg (0.29 mmol) of the compound from Example 10A were reacted with 0.30 ml (1.7 mmol) of N,N-diisopropylethylamine and 0.17 ml (0.30 mmol) of T3P (50% by weight solution in ethyl acetate) in analogy to the compound from Example 1. 52 mg (46% of theory) of the title compound were isolated.

Example 6

(rac) -[4-(3,4-Dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]{2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}methanone

56 mg (0.25 mmol) of the compound from Example 13A and 63 mg (0.29 mmol) of the compound from Example 2A were reacted with 0.30 ml (1.7 mmol) of N,N-diisopropylethylamine and 0.17 ml (0.30 mmol) of T3P (50% by weight solution in ethyl acetate) in analogy to the compound from Example 1. 52 mg (46% of theory) of the title compound were isolated.

Example 7

(rac) -[4-(3,4-Dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]{2-[(1-hydroxybutan-2-yl)amino]pyrimidin-5-yl}methanone

0.29 ml (1.7 mmol) of N,N-diisopropylethylamine and 0.17 ml (0.28 mmol) of T3P (50% by weight solution in ethyl acetate) were added to a mixture of 50 mg (0.24 mmol) of the compound from Example 16A and 60 mg (0.24 mmol) of the compound from Example 2A in 2.0 ml of acetonitrile, followed by stirring at room temperature overnight. For workup, 1 ml of saturated sodium bicarbonate solution was added, stirred for 15 minutes, filtered through an Extrelut cartridge, eluted with dichloromethane, and the filtrate concentrated. The crude product obtained was purified by preparative HPLC [Method 9], resulting in 53 mg (54% of theory) of the title compound.

Example 8

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

61.0 ml (350.3 mmol) of N,N-diisopropylethylamine and 50.05 ml (84.1 mmol) of T3P (50% by weight solution in ethyl acetate) were added to a solution of 15.5 mg (70.1 mmol) of the compound from Example 18A and 20.27 mg (70.1 mmol) of the compound from Example 2A in 320 ml of acetonitrile, followed by stirring at room temperature for 3 hours. For workup, 100 ml of saturated sodium bicarbonate solution was added, and the mixture was stirred at room temperature for 10 minutes. An additional 200 ml of saturated sodium bicarbonate solution was then added, and the mixture was extracted with 500 ml of ethyl acetate. The organic phase was washed once with saturated sodium bicarbonate solution and once with sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. 100 ml of methanol was added to the crude product and heated to 55°C; this did not produce a clear solution. The mixture was cooled to room temperature with stirring, and 250 ml of diethyl ether was added. After 30 min, the precipitated solid was filtered off with suction, washed with a little diethyl ether and dried under HV. This gave 17.2 g (59% of theory) of the target compound.

Example 9

[4-(7-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-5-yl]methanone

0.28 ml (1.6 mmol) of N,N-diisopropylethylamine and 0.16 ml (0.27 mmol) of T3P (50% by weight solution in ethyl acetate) were added to a solution of 58 mg (0.23 mmol) of the compound from Example 18A and 69 mg (0.23 mmol) of the compound from Example 4A in 1.9 ml of acetonitrile, followed by stirring at room temperature overnight. For workup, 1 ml of saturated sodium bicarbonate solution was added, stirred for 15 minutes, filtered through an Extrelut cartridge, eluted with dichloromethane, and the filtrate was concentrated. The crude product obtained was purified by preparative HPLC [Method 9], resulting in 30 mg (29% of theory) of the title compound.

Example 10

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

0.28 ml (1.6 mmol) of N,N-diisopropylethylamine and 0.16 ml (0.27 mmol) of T3P (50% by weight solution in ethyl acetate) were added to a mixture of 58 mg (0.23 mmol) of the compound from Example 18A and 72 mg (0.23 mmol) of the compound from Example 10A in 1.9 ml of acetonitrile, followed by stirring at room temperature overnight. For workup, 1 ml of saturated sodium bicarbonate solution was added, stirred for 15 minutes, filtered through an Extrelut cartridge, eluted with dichloromethane, and the filtrate concentrated. The resulting crude product was purified by preparative HPLC [Method 9], resulting in 30 mg (29% of theory) of the title compound.

Example 11

1-(5-{[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]carbonyl}pyrimidin-2-yl)-D-proline hydrochloride

0.46 ml of a 4N hydrogen chloride solution in dioxane was added to a solution of 90 mg (0.183 mmol) of the compound from Example 21A in 3.5 ml of dichloromethane and stirred at room temperature overnight. 0.46 ml of a 4N hydrogen chloride solution in dioxane was subsequently added and stirred until the starting material had reacted completely. The reaction mixture was then concentrated and the resulting residue was ground with ether. The solid was filtered out and dried under HV to give 82 mg (94% of theoretical value) of the title compound.

Example 12

[4-(3,4-Dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(1,1-dioxathiamorpholin-4-yl)pyrimidin-5-yl]methanone

51 mg (0.20 mmol) of the compound from Example 23A and 57 mg (0.20 mmol) of the compound from Example 2A were initially placed in 2 ml of acetonitrile, and 0.17 ml of N,N-diisopropylethylamine (0.99 mmol) was added. Subsequently, 0.14 ml (0.24 mmol) of T3P (50% by weight solution in ethyl acetate) was added dropwise, and the mixture was stirred at room temperature overnight. After concentration, the residue was diluted with 20 ml of ethyl acetate, and approximately 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 minutes, the mixture was diluted with water and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate concentrated. The resulting crude product was purified by preparative HPLC [Method 9]. 62 mg (68% of theory) of the target compound were isolated.

Example 13

[4-(3,4-Dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(2,6-dimethylmorpholin-4-yl)pyrimidin-5-yl]methanone (cis-isomer)

106 mg (0.45 mmol) of the compound from Example 25A and 130 mg (0.45 mmol) of the compound from Example 2A were placed in 2 ml of acetonitrile, and 0.39 ml of N,N-diisopropylethylamine (2.23 mmol) was added. Subsequently, 0.32 ml (0.54 mmol) of T3P (50% by weight solution in ethyl acetate) was added dropwise, and the mixture was stirred at room temperature overnight. After concentration, the residue was diluted with 20 ml of ethyl acetate, and approximately 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 minutes, the mixture was diluted with water and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate concentrated. The resulting crude product was purified by preparative HPLC [Method 9]. 125 mg (58% of theory) of the target compound were isolated.

Example 14

[4-(3,4-Dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(2,6-dimethylmorpholin-4-yl)pyrimidin-5-yl]methanone (trans-isomer)

27 mg (0.11 mmol) of the compound from Example 27A and 33 mg (0.11 mmol) of the compound from Example 2A were initially placed in 2 ml of acetonitrile, and 0.10 ml of N,N-diisopropylethylamine (0.57 mmol) was added. Subsequently, 0.08 ml (0.14 mmol) of T3P (50% by weight solution in ethyl acetate) was added dropwise, and the mixture was stirred at room temperature overnight. After concentration, the residue was diluted with 20 ml of ethyl acetate, and approximately 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 minutes, the mixture was diluted with water and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate concentrated. The resulting crude product was purified by preparative HPLC [Method 9]. 32 mg (65% of theory) of the target compound were isolated.

Example 15

[4-(3,4-Dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(2,2-dimethylmorpholin-4-yl)pyrimidin-5-yl]methanone

86 mg (0.36 mmol) of the compound from Example 29A and 105 mg (0.36 mmol) of the compound from Example 2A were initially placed in 2 ml of acetonitrile, and 0.32 ml of N,N-diisopropylethylamine (1.81 mmol) was added. Subsequently, 0.26 ml (0.44 mmol) of T3P (50% by weight solution in ethyl acetate) was added dropwise, and the mixture was stirred at room temperature overnight. After concentration, the residue was diluted with 20 ml of ethyl acetate, and approximately 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 minutes, the mixture was diluted with water and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate concentrated. The resulting crude product was purified by preparative HPLC [Method 9]. 116 mg (73% of theory) of the target compound were isolated.

B) Assessment of Physiological Efficacy

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

B-1) In vitro assay

B-1a) Antagonism against adrenergic receptors

Antagonism against adrenergic receptor _α1A was tested using a recombinant human _α1A receptor CHO cell line that also recombinantly expresses mtAeq (mitochondrial aequorin). Antagonism against adrenergic receptor α2A was tested using a recombinant human _α2A -Gα16 receptor fusion protein CHO cell line (PerkinElmer Life Sciences) that also recombinantly expresses _mtAeq . Antagonism against adrenergic receptor _α2B was tested using a recombinant human _α2B receptor CHO cell line (PerkinElmer LifeSciences) that also recombinantly expresses mtAeq. Antagonism against adrenergic receptor _α2C was tested using a recombinant human _α2C receptor CHO cell line that also recombinantly expresses a chimeric G protein (Gαqi3) and mtOb (mitochondrial obelin).

Cells were cultured in Dulbecco's modified Eagle's medium/NUT mixture F12 containing L-glutamine at 37°C and 5% _CO2 , and the mixture F12 also contained 10% (v/v) inactivated fetal bovine serum, 1 mM sodium pyruvate, 0.9 mM sodium bicarbonate, 50 U/ml penicillin, 50 μg/ml streptomycin, 2.5 μg/ml amphotericin B, and 1 mg/ml geneticin. Cells were passaged using an enzyme-free Hank's cell dissociation buffer. All cell culture reagents used were obtained from Invitrogen (Carlsbad, USA).

Luminescence measurements were performed in white 384-well microtiter plates. 2,000 cells were plated per well in a 25 µl volume and cultured for one day at 30°C and 5% CO₂ in cell culture _medium containing coelenterazine ( _α2A and _α2B : 5 µg/ml; α1a _/c and _α2C : 2.5 µg/ml). Serial dilutions (10 µl) of the test substances were added to the cells. Five minutes later, norepinephrine was added to the cells (35 µl; final concentration: 20 nM (α1a _/c and _α2C ) or 200 nM ( _α2A and _α2B ), and the emitted light was measured for 50 seconds in a light-tight box using a CCD (charge-coupled device) camera (Hamamatsu Corporation, Shizuoka, Japan). Test substances were tested up to a maximum concentration of 10 µM. _IC50 values were calculated from the appropriate dose-effect curves. The results for antagonism against adrenergic receptor _α2C are shown in Table 1:

Table 1:

B-1b) Binding studies at human α1- and α2-adrenergic receptors

To prepare cell membranes containing human _α1- and _α2 -adrenergic receptors, CHO cells stably overexpressing _α1- and _α2 -adrenergic receptors were lysed and subjected to differential centrifugation. After lysis in binding buffer (50 mM tris(hydroxymethyl)aminomethane/1 N hydrochloric acid, 5 mM magnesium chloride, pH 7.4) using an Ultra Turrax (Jahnke & Kunkel, Ika-Werk), the homogenate was centrifuged at 1000 g for 10 min at 4°C. The resulting pellet was discarded, and the supernatant was centrifuged at 20,000 g for 30 min at 4°C. The supernatant was discarded, and the pellet was resuspended in binding buffer and stored at -70°C until binding assay. For the binding assay, the radioligands ³ H-MK-912 (2.2-3.2 TBq/mmol, PerkinElmer) (0.4 nM for α _2C -adrRez and 1 nM for α _2A -adrRez), 0.25 nM ³ H-prazosin (α _1AC -adrRez; 2.6-3.3 TBq/mmol, PerkinElmer), 0.25 nM ³ H-rauwolfiacin (α _2B -adrRez, 2.6-3.2 TBq/mmol, PerkinElmer) were incubated with 5-20 μg of cell membranes in binding buffer (total experimental volume 0.2 ml) in the presence of the test substances at 30° C. for 60 min in 96-well filter plates (FC/B glass fiber, Multiscreen Millipore). After terminating the incubation by aspirating the unbound radioactive material, the plates were washed with binding buffer and subsequently dried at 40°C for 1 hour. Liquid scintillant (Ultima Gold, PerkinElmer) was then added and the radioactivity retained on the plates was measured in a liquid scintillation counter (Microβ, Wallac). Nonspecific binding was defined as the radioactivity in the presence of 1-10 μM MWB-4101 (α _2C -adrRez and α _2A -adrRez), prazosin (α _2B -adrRez and α _1AC -adrRez) (all from Sigma), and typically <25% of the total radioactivity bound. Binding data (IC ₅₀ and dissociation constant K _i ) were determined using the program GraphPad Prism Version 4.0.

B-2) In vivo assay

B-2a) Relaxation measurements on isolated rat tail arteries

Male Wistar rats (200-250 g) were euthanized with carbon dioxide. Tail arteries were prepared and incubated at 4°C for 17 h in Krebs-Henseleit buffer (composition by mmol/l: NaCl 112, KCl 5.9, CaCl ₂ 2.0, MgCl ₂ 1.2, NaH ₂ PO ₄ 1.2, NaHCO ₃ 25, glucose 11.5). The arteries were cut into 2 mm long rings, transferred to an organ bath containing 5 ml of Krebs-Henseleit buffer, and connected to a wire myograph (DMT, Denmark). The buffer was warmed to 27°C and supplied with 95% O ₂ , 5% CO ₂ . Before each experiment, the responsiveness of the test product was measured by adding potassium-containing Krebs-Henseleit solution (50 mmol/l KCl). After a 60-minute equilibration period, constriction of the vascular rings was induced with 30 nmol/l UK 14.304. The test substances were then added cumulatively in increasing concentrations. Relaxation was expressed as a reduction in the UK 14.304-induced constriction.

B-2b) Hemodynamics in CHF rats

Male old Wistar, ZDF/Crl-Lepr fa/fa, SHR-SP, or Sprague Dawley rats (Charles River; 250–300 g) were anesthetized with 5% isoflurane in an anesthesia cage, intubated, and artificially ventilated (rate: 60 breaths/min; inspiratory: expiratory ratio: 50:50; positive end-expiratory pressure: 1 cm _H₂O ; tidal volume: 10 ml/kg body weight; FIO₂ _: 0.5; 2% isoflurane). Body temperature was maintained at 37–38°C using a heating pad. Buprenorphine (Temgesic) at a dose of 0.05 mg/kg was administered subcutaneously as an analgesic. For hemodynamic measurements, the rats were tracheotomized and artificially ventilated (rate: 60 breaths/min; inspiratory: expiratory ratio: 50:50; positive end-expiratory pressure: 1 cm _H₂O ; tidal volume: 10 ml/kg body weight; FIO₂ _: 0.5). Anesthesia was maintained by isoflurane inhalation anesthesia. Left ventricular pressure was determined via the left carotid artery using a Millar microtip catheter (Millar SPR-320 2F). Systolic left ventricular pressure (sLVP), end-diastolic ventricular pressure (LVEDP), contractility (+dPdt), and relaxation force (-dPdt) were determined as derived parameters. After hemodynamic measurements, the heart was removed and the ratio of the right ventricle to the left ventricle (including the septum) was determined. In addition, plasma samples were obtained to determine plasma biomarkers and plasma substance levels.

B-2c) Measurement of blood flow and blood pressure in rats

Use 2.5% isoflurane in oxygen/laughing gas mixture (40:60) to anesthetize 250-350 g weight Wistar rats (Hsd Cpb:Wu) or 330-520 g weight ZDF rats (ZDF/Crl-Lepr fa/fa). In order to determine the blood flow in the carotid artery and femoral artery, the anesthetized rats are placed in a supine position and the left carotid artery and right femoral artery are carefully exposed. By placing a flow probe (Transonic Flowprobe) at the blood vessels, blood flow is measured. By introducing a PE50 arterial catheter into the left femoral artery, blood pressure and heart rate are determined (Transducer Ref. 5203660: deriving from Braun CH). The substance is administered as a bolus or continuous infusion via an intravenous catheter in the left femoral vein.

After preparing the animals, a 5 min baseline interval was waited. The infusion of the ARα2C antagonist was then started. At steady state (32 min after the start of the experiment), the femoral flow (% difference) was determined relative to the initial flow.

The compound of Example 8 demonstrated a dose-dependent increase in femoral flow in diabetic ZDF fa/fa animals at doses of 0.1, 0.3, and 1 µg/kg. In Wistar rats, no increase in femoral flow was observed up to 1 µg/kg/min. No changes in blood pressure or heart rate were observed. Placebo: 10% ethanol/40% PEG400/50% NaCl. Data (mean values) are shown in Table 2:

Table 2:

B-2d) Determination of substances that enhance perfusion (hemodynamics)

To reduce perfusion, the right external iliac artery is ligated under sterile conditions in anesthetized (e.g., by inhalation of isoflurane, enflurane) rats (e.g., ZDF/Crl-Lepr fa/fa). Depending on the degree of collateralization in the animal, the femoral artery may also need to be ligated to reduce perfusion. Following the procedure or prophylactically, the test animals are treated with the test substance orally, intragastrically (via a gastric tube or ingested with food or drinking water), intraperitoneally, intravenously, intraarterially, intramuscularly, by inhalation, or subcutaneously. The test substance is administered enterally or parenterally, once or more daily for up to 50 weeks, or continuously via a subcutaneously implanted osmotic micropump (e.g., Alzet pump). During the experiment, microperfusion and temperature of the lower limbs are recorded. Here, a temperature-sensitive laser Doppler probe (Periflux) is glued to the paw under anesthesia to measure microperfusion and skin temperature. According to the experimental protocol, samples such as blood (intermediate diagnostics) and other body fluids, urine or organs are taken for other in vitro examinations, or blood pressure and heart rate are measured via a catheter in the carotid artery to record hemodynamics. At the end of the experiment, the animals are euthanized.

B-2e) Determination of substances that enhance perfusion (microcirculation)

In diabetic (ZDFfa/fa) and healthy rats (Wistar), a laser Doppler probe was fixed to the sole of the foot under anesthesia (isoflurane anesthetic) for measuring the microcirculation of the skin. The test animals were treated orally with the test substance once. During the experiment, the microperfusion and temperature of the lower limbs were continuously recorded. Here, a temperature-sensitive laser Doppler probe (Periflux, O2C) was bonded to the paw to measure microperfusion and skin temperature. 30 minutes after oral administration of the test substance, microcirculation measurements were measured on both paws. From these data, mean values were calculated and compared with animals treated with placebo. It was shown that the test substance showed a minimum effective dose (MED) when significantly improving microcirculation compared to placebo (vehicle = 10% EtOH + 30% PEG400 + 60% water for injection; 1 ml/kg), and the multiple of microcirculation improvement compared to placebo at this dose. The MED (ttest) for a significant increase in skin temperature was also provided.

Table 3 shows the microcirculation data for the adrenergic receptor α _2C receptor antagonist of the compound of Example 8 and the comparative substance ORM12741 (AR α 2c receptor antagonist from Orion):

Table 3:

B-2f) Determination of perfusion-enhancing substances (kinesiology ) in the running wheel test

In order to determine motor function, the running behavior of mice (for example the mice of eNOS knockout, wild-type mice C-57B16 or ApoE knockout) was checked on a running wheel. In order to accustom mice to using the running wheel automatically, 4-5 weeks before the experiment started, animals were individually put into a cage with a running wheel and trained. 2 weeks before the experiment started, the motion of mice on the running wheel was recorded by a computer by photoelectric elements, and the distance that various running parameters were for example run every day, each distance involved, and their time distribution in a day were determined. According to their natural running behavior, animals were randomly divided into groups (8-12 animals) (control group, false group and one to multiple material groups). After the start-up phase of 2 weeks, in order to reduce the perfusion in the hind leg, the femoral artery on both sides was ligated under anesthesia under aseptic conditions (for example, anesthetized by inhaling isoflurane). After the procedure, or otherwise prophylactically, the test animals are treated with the test substance orally, intragastrically (via a gastric tube or ingested with food or drinking water), intraperitoneally, intravenously, intraarterially, intramuscularly, by inhalation, or subcutaneously. The test substance is administered enterally or parenterally, once or more daily for up to 5 weeks, or continuously via a subcutaneously implanted osmotic minipump. The animals' tumbling behavior is observed and recorded for several weeks following the procedure. At the conclusion of the experiment, the animals are painlessly sacrificed. Samples, such as blood and other body fluids or organs, are removed for other in vitro examinations according to the experimental protocol (S. Vogelsberger Neue Tiermodelle für die Indikation Claudicatio Intermittens (Pocket Book), Publisher: VVB Laufersweiler Verlag (March 2006), ISBN-10: 383595007X, ISBN-13: 978-3835950078).

B-2g) Determination of substances that enhance perfusion (occlusion pressure measurement)

To reduce perfusion, the right external iliac artery is ligated under sterile conditions in anesthetized rats (e.g., ZDF rats) (e.g., anesthetized by inhalation of isoflurane). Depending on the degree of collateralization in the animal, the femoral artery may also need to be ligated to reduce perfusion. Following the procedure or prophylactically, the test animals are treated with the test substance orally, intragastrically (via a gastric tube or ingested with food or drinking water), intraperitoneally, intravenously, intraarterially, intramuscularly, by inhalation, or subcutaneously. The test substance is administered enterally or parenterally, once or more daily for up to 5 weeks, or continuously via a subcutaneously implanted osmotic minipump (e.g., an Alzet pump). The occlusion pressure of the animals is measured after the procedure (subsequently randomized) and weekly for up to 2 months thereafter. Here, under anesthesia, an inflatable bandage is placed around the rat's hind leg, and a temperature-controlled laser Doppler probe (Periflux) is glued to the paw. The bandage is inflated until the laser Doppler probe no longer measures blood flow. The pressure of the bandage is then gradually reduced, and the pressure at which blood flow is detected again is measured. Depending on the experimental protocol, samples such as blood (intermediate diagnostics) and other body fluids or organs are removed for other in vitro examinations. At the end of the experiment, the animals are painlessly sacrificed (S. Vogelsberger Neue Tiermodelle für die Indikation Claudicatio Intermittens (Pocket Book), Publisher: VVB Laufersweiler Verlag (March 2006), ISBN-10: 383595007X, ISBN-13: 978-3835950078).

B-2h) Examination of substances that affect wound healing (ulcer model)

To induce superficial wounds, diabetic mice (db/db, i.e., BKS.Cg-m Dock7m +/+ Leprdb/J mice) were anesthetized with isoflurane. A continuous injury (10 mm x 10 mm) was made on a sterilized skin area on the left rib. The animals were then randomly assigned to different experimental groups. In all groups, the wound was covered with a dressing (Systagenix Wound Management, UK). Every day (from the first day after the wound was inflicted), the animals were treated with the given dose of the substance by gavage (200 μl, vehicle = 10% EtOH + 30% PEG400 + 60% water for injection). On days 4, 8, 12, 16, and 20, the animals were anesthetized, the dressing was removed, and the wound size was measured using digital photographs. The photographs were evaluated by an automated calibrated planar method.

The results are shown in Figure 1 as the remaining wound size during the course of the experiment. For this purpose, all individual values are expressed as a percentage relative to the individual animals on the day the wound was inflicted. Mean values +/- SEM are shown.

B-2i) Examination of substances that affect renal function

In animals with acute or disease-induced renal damage (e.g., STZ rats, ZDF rats, ZDF rats with DOCA implants, UUO renal damage model, glomerulonephritis model, diabetes, atherosclerosis), diuresis is performed regularly before or during continuous treatment with the test substance. The test animals are treated orally, intragastrically (via a gastric tube or by ingestion of food or drinking water), intraperitoneally, intravenously, intraarterially, intramuscularly, by inhalation, or subcutaneously with the test substance. The test substance is administered enterally or parenterally, once or more daily, or continuously via a subcutaneously implanted osmotic minipump (e.g., Alzet pump). Plasma and urine parameters are determined throughout the duration of the experiment.

B-2j) Hemodynamics in anesthetized dogs

^Mongrel® dogs of both sexes weighing 25-35 kg, either healthy or in heart failure (Marshall BioResources, Marshall Farms Inc; Clyde, NY; USA) were used. Anesthesia was initiated by slow intravenous administration of 25 mg/kg sodium thiopental ( ^Trapanal® ) and 0.15 mg/kg alcuronium ( ^Alloferin® ) and maintained during the experiment with a continuous infusion of 0.04 mg/kg*h fentanyl ( ^Fentanyl® ), 0.25 mg/kg*h droperidol ( ^{Dihydrobenzperidol®} ), and 15 µg/kg/h alcuronium ( ^Alloferin® ). After intubation, the animals were ventilated with a ventilator at a constant respiratory volume to achieve an end-tidal _CO2 concentration of approximately 5%. Ventilation was performed using room air enriched with approximately 30% oxygen (normoxia). In order to measure hemodynamic parameters, a liquid-filled catheter is implanted in the femoral artery for measuring blood pressure. A Swan- ^Ganz® catheter with two chambers is floated into the pulmonary artery via the jugular vein (the distal chamber is used to measure pulmonary artery pressure, and the proximal chamber is used to measure central venous pressure). With the help of a temperature sensor at the tip of the catheter, continuous cardiac output (CCO) is determined. By placing a flow probe (Transonic Flowprobe) at each blood vessel, blood flow is measured in different vascular beds such as the coronary artery, carotid artery, or femoral artery. After a micro-tip catheter ( ^Millar® Instruments) is introduced into the left ventricle via the carotid artery, the pressure in the left ventricle is measured, and dP/dt is derived therefrom as a measure of contractility. The substance is administered intravenously via the femoral vein or intraduodenally as a cumulative dose/activity curve (bolus injection or continuous infusion). The hemodynamic signal is recorded and evaluated with the help of a pressure receiver/amplifier and ^PONEMAH® (as data acquisition software).

In order to induce heart failure, under aseptic conditions, pacemaker is implanted in dog. After induction of anesthesia by sodium pentobarbital (15-30mg kg ^-1 intravenously), then intubation and ventilation (room air subsequently; Sulla 808, Dräger ^® , Germany), by continuous infusion of pentobarbital (1-5 mg kg ^-1 h ^-1 ) and fentanyl (10-40μg kg ^-1 h ^-1 ) maintain anesthesia. Pacemaker cable (Setrox S60 ^® , Biotronik, Germany) is implanted and placed in right ventricle via the incision of the left jugular vein. Described cable is connected to pacemaker (Logos ^® , Biotronik, Germany), described pacemaker is located in the small subcutaneous bag between shoulder blades. After surgical intervention, ventricular pacing was started 7 days later, to obtain heart failure with a frequency of 220 beats/min within the time of 10-28 days.

B-2k) Determination of antidepressant effects in the forced swim test in rats

Rats forced to swim in a confined chamber from which they cannot escape adapt, after an initial period of increased activity, by adopting a characteristic rigid posture and performing only the movements absolutely necessary to keep their heads above water. Many clinically active antidepressants can reduce this immobility (e.g., Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol. Sci. 2002; 23:238-245). The methods used here are based on those of Porsolt et al. (Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur. J. Pharmacol. 1978; 47379-91; and Porsolt RD, Brossard G, Hautbois C, Roux S. Rodent models of depression-forced swimming and tail suspension behavioral despair tests in rats and mice. Curr. Protoc. Neurosci. 2001; Chapter 8: Unit 8.10A, 1-10) and De Vry et al. (De Vry J, Maurel S, Schreiber R, de Beun R, Jentzsch KR. Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism. Eur. Neuropsychopharmacology 1999; 9:461-468). During two 24h intervals (training and testing), rats were forced to swim in a narrow cylinder filled with water from which they could not escape. A training treatment (duration 15 min) was performed before substance treatment, and behavior was not recorded to familiarize the rats with the 5-minute test treatment 24 h later. During the two treatments, rats were individually placed in a cylinder filled with water, which was visually separated from each other. After the treatment, the rats were taken out of the water and dried. About 24, 5, and 1 h before the test treatment, rats were treated with the test substance or vehicle solution; the first administration was performed immediately after the training treatment. Compared with a single administration, the 3 substance administrations before the test treatment resulted in more stable pharmacological results. The test treatment was electronically recorded using a video surveillance camera, and after storage, a computer offline analysis was used. For each animal, behavior was analyzed by 3-4 independent observers, who scored the total time of immobility in seconds during the 5-minute test treatment period.

Passive behavior or immobility is defined as a rat that floats in an upright position in the water and makes only small movements to keep its head above the water or to maintain its body in a stable position of balance. In contrast, active behavior is characterized by active swimming movements, such as vigorous movements of the front or hind legs and/or tail, climbing or diving.

For each animal and treatment group, the mean of the duration of immobility determined by the observer was calculated. Differences in the duration of immobility between the groups were examined by ANOVA or appropriate nonparametric test statistics, with p < 0.05 as a significance level.

B-21) Radiotelemetry measurement of blood pressure and heart rate in conscious rats

A commercially available telemetry system from Data Sciences International (DSI), USA, was used for the following measurements on awake rats. The system consists of three main components: (1) an implantable transmitter (Physiotel® Telemetry Transmitter), (2) a receiver (Physiotel® Receiver) connected via a multiplexer (DSI Data Exchange Matrix), and (3) a data acquisition computer. The telemetry device continuously records blood pressure, heart rate, and body movements of awake animals in their habitual environment.

The study was conducted on adult female Wistar rats weighing >200 g. After transmitter implantation, the animals were individually housed in type III Makrolon® cages. They had free access to standard chow and water. A day/night rhythm was established in the laboratory by alternating room lighting.

Transmitter implantation:

The telemetry transmitters used (PA-C40, DSI) were surgically implanted in the experimental animals under sterile conditions at least 14 days before the initial experiment.

For implantation, fasting animals were anesthetized with isoflurane (IsoFlo®, Abbott, 5% initial, 2% maintenance), and a wide area of the abdomen was shaved and disinfected. After opening the abdominal cavity along the linea alba, the system's fluid-filled measuring catheter was inserted cranially into the descending aorta above the bifurcation and secured with tissue adhesive (VetBonD™, 3M). The transmitter housing was secured intraperitoneally to the abdominal wall musculature, and the wound was closed layer by layer. Postoperatively, antibiotics (Ursocyclin® 10%, 60 mg/kg subcutaneously, 0.06 ml/100 g body weight, Serumwerk Bernburg AG, Germany) were administered to prevent infection, and analgesics (Rimadyl®, 4 mg/kg subcutaneously, Pfizer, Germany) were administered.

Substances and solutions:

Unless otherwise stated, the test substances were administered orally to a group of animals (n = 6) in each case. The test substances were dissolved in a suitable solvent mixture in an amount corresponding to 2 ml/kg body weight. A vehicle-treated group of animals (placebo/vehicle = diethylene glycol monoethyl ether, ^Transcutol® , 2 ml/kg p.o.) served as a control.

Experimental procedure:

The telemetry device was constructed for 24 animals.

Each rat living in the apparatus is assigned a dedicated receiving antenna (RPC-1 Receiver, DSI). The implanted transmitter can be externally activated via a mounted magnetic switch and switched to transmission during the experimental run-in. The transmitted signal can be collected online and processed accordingly using a data acquisition system (Dataquest™ A.R.T. for Windows, DSI).

In standard practice, the following items are measured for 10 seconds each: (1) systolic blood pressure (SBP), (2) diastolic blood pressure (DBP), (3) mean arterial pressure (MAP), (4) heart rate (HR), and (5) activity (ACT). These parameters are measured within 24 hours after administration.

The acquisition of measurements was repeated at 5-minute intervals under computer control. In the graphs, the source data obtained as absolute values were corrected using the most recently measured atmospheric pressure (Ambient Pressure Reference Monitor, APR-1, DSI).

evaluate:

After the experiment, the data were analyzed using analysis software (Dataquest™ A.R.T. 4.1 Analysis). The average value (4 absolute values) of the pre-run (i.e., before substance administration) was taken as the blank value and compared with the measured absolute value to obtain the deviation expressed as a percentage. The data were smoothed over a predefined period by determining the average value (15-minute average).

literature:

K. Witte, K. Hu, J. Swiatek, C. Müssig, G. Ertl, and B. Lemmer, Experimental heart failure in rats: effects on cardiovascular circadian rhythms and onmyocardialβ-adrenergic signaling, Cardiovasc. Res. 47 (2): 203-405, 2000.

result:

The results of comparing the compound of Example 8 with Orion's adrenergic receptor _α2C receptor antagonist (ORM-12741), which has been used in trials for the treatment of Alzheimer's disease and Raynaud's syndrome, are shown in Figures 2-5.

Example 8 showed no hemodynamic effects (hypertension, heart rate) up to an oral dose of 1 mg/kg; a slight transient increase in heart rate was observed at 3 and 10 mg/kg. In contrast, the comparator ORM-12741, Orion's adrenergic _α2C receptor antagonist, showed additional blood pressure reduction at 10 mg/kg.

Description of the drawings:

Figure 1: B-2h) Testing of substances that affect wound healing (ulcer model). Remaining wound area in dbdb mice relative to placebo-treated animals (%). Mean ± SEM (n=10).

Figure 2: B-21) Deviation of the heart rate in % versus time [h] after substance administration; Example 8

Figure 3: B-21) Deviation in mean arterial blood pressure in % versus time [h] after substance administration; Example 8

Figure 4: B-21) Deviation of the heart rate in % versus time [h] after substance administration; comparative example ORM12741

Figure 5: B-21) Deviation in mean arterial blood pressure in % versus time [h] after substance administration; comparative example ORM12741

C) Working Examples 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) (available from BASF, Germany) and 2 mg of magnesium stearate.

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

Production:

A mixture of the compound of Example 1, lactose, and starch was granulated with a 5% solution of PVP in water (m/m). After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture was compressed in a conventional tablet press (for tablet form, see above).

Oral suspension:

Composition:

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

10 ml of oral suspension correspond to a single dose of 100 mg of the compound according to the invention.

Production:

Rhodigel was suspended in ethanol, and the compound of Example 1 was added to the suspension. Water was added with stirring, and the mixture was stirred for approximately 6 h until the Rhodigel had completely swollen.

Solutions for intravenous administration:

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 was dissolved in water with polyethylene glycol 400 under stirring. The solution was sterile filtered (pore size 0.22 μm) and dispensed aseptically into heat-sterilized infusion bottles. The infusion bottles were closed with infusion stoppers and crimped caps.

Claims (14)

1. Compounds of formula (I) and their salts, in ^R1 represents _C2 - _C6 -alkyl. The alkyl group is substituted by one of the following substituents: hydroxyl, methoxy, and ethoxy. and ^R2 represents hydrogen. or ^R1 and ^R2, together with the nitrogen atoms they are attached to, form azaheptanes, pyrrolidines, piperidines, azaheptanes, piperazines, morpholines, thiomorpholines, 1-oxothiomorpholines, or 1,1-dioxothiomorpholines. Among them, aziridine, pyrrolidine, piperidine, aziridine, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine, and 1,1-dioxothiomorpholine can be substituted with 1-2 substituents, wherein the substituents are independently selected from hydroxyl, trifluoromethyl, hydroxycarbonyl, _C1 - _C3 -alkyl, methoxy, and methoxymethyl. or Azahexacyclobutane, pyrrolidine, piperidine, azaheptanane, piperazine, and morpholine may have two substituents, which, together with the carbon atoms of the azahexacyclobutane, pyrrolidine, piperidine, azaheptanane, piperazine, and morpholine they are connected to, form azahexacyclobutane, oxacyclobutane, or 1,1-dioxothiohexacyclobutane. The aforementioned azahexacyclobutane, oxacyclobutane, or 1,1-dioxothiohexacyclobutane may be substituted with 1-2 substituents. The substituents are independently selected from methyl and ethyl groups. R ³ represents hydrogen and R ⁴ represents hydrogen, fluorine, or methoxy. or R ³ represents hydrogen, fluorine, or methoxy. and ^R4 represents hydrogen. 2. The compound of formula (I) according to claim 1 and its salt, wherein ^R1 represents _C2 - _C4 -alkyl. The alkyl group is substituted by one of the following substituents: hydroxyl and methoxy. and ^R2 represents hydrogen. or ^R1 and ^R2, together with the nitrogen atoms they are attached to, form nitrogen-containing heterocyclic butanes, pyrrolidines, morpholines, or 1,1-dioxothiomorpholines. Among them, azacyclobutane, pyrrolidine, morpholine, and 1,1-dioxothiomorpholine can be substituted with 1-2 substituents, wherein the substituents are independently selected from hydroxycarbonyl, methyl, trifluoromethyl, methoxy, and methoxymethyl. or ^R1 and ^R2, together with the nitrogen atoms they are attached to, form nitrogen-containing heterocyclic butanes. The azahexacyclic butane may have two substituents, which, together with the carbon atom of the azahexacyclic butane to which they are connected, form oxohexacyclic butane or 1,1-dioxothiohexacyclic butane. R ³ represents hydrogen, fluorine, or methoxy. and ^R4 represents hydrogen. or ^R3 represents hydrogen. and R ⁴ represents hydrogen, fluorine, or methoxy. 3. The compound of formula (I) and its salt according to any one of claims 1-2, wherein... ^R1 represents _C2 - _C4 -alkyl. The alkyl group is substituted by one of the following substituents: hydroxyl and methoxy. and ^R2 represents hydrogen. or ^R1 and ^R2, together with the nitrogen atoms they are attached to, form nitrogen-containing heterocyclic butanes, pyrrolidines, morpholines, or 1,1-dioxothiomorpholines. Among them, azacyclobutane, pyrrolidine, morpholine, and 1,1-dioxothiomorpholine can be substituted with 1-2 substituents, which are independently selected from hydroxycarbonyl and methyl groups. or ^R1 and ^R2, together with the nitrogen atoms they are attached to, form nitrogen-containing heterocyclic butanes. The azahexacyclic butane may have two substituents, which, together with the carbon atom of the azahexacyclic butane to which they are connected, form an oxacyclobutane. R ³ represents hydrogen, fluorine, or methoxy. and ^R4 represents hydrogen. or ^R3 represents hydrogen. and R ⁴ represents hydrogen, fluorine, or methoxy. 4. The compound of formula (I) and its salt according to any one of claims 1-3, wherein ^R1 and ^R2, together with the nitrogen atoms they are attached to, form nitrogen-containing heterocyclic butanes. The azahexacyclic butane has two substituents, which, together with the carbon atom of the azahexacyclic butane to which they are connected, form an oxacyclobutane. ^R3 represents hydrogen. and ^R4 represents hydrogen. 5. A method for preparing the compound of formula (I) according to claim 1 or a salt thereof, wherein [A] In the presence of a reducing agent, the compound of formula (II) is... Reaction with compounds of formula (III) Wherein ^R3 and ^R4 have the meanings given in claim 1, The compound of formula (IV) was obtained. Wherein ^R3 and ^R4 have the meanings given in claim 1, and [B] In the presence of an acid, the compound of formula (IV) reacts. Wherein ^R3 and ^R4 have the meanings given in claim 1, The compound of formula (V) is obtained. Wherein ^R3 and ^R4 have the meanings given in claim 1, and [C] In the presence of a base, the compound of formula (VI) is... in X represents a halogen, preferably fluorine, chlorine, or bromine, or sulfonylmethane and... R ⁵ represents _C1 - _C4 -alkyl, preferably methyl or ethyl. Reaction with compounds of formula (VII), Wherein ^R1 and ^R2 have the meanings given in claim 1, The compound of formula (VIII) is obtained. Wherein ^R1 and ^R2 have the meanings given in claim 1, and ^R5 is as defined above. and [D] In the presence of a dehydrating agent, the compound of formula (IX) is... Wherein ^R1 and ^R2 have the meanings given in claim 1, Reaction with compounds of formula (V) Wherein ^R3 and ^R4 have the meanings given in claim 1, Compound of formula (I) was obtained. 6. Compounds of formula (VIII) or (IX) and their salts, in ^R1 and ^R2, together with the nitrogen atoms they are attached to, form nitrogen-containing heterocyclic butanes. The azahexacyclic butane has two substituents, which, together with the carbon atom of the azahexacyclic butane to which they are connected, form an oxacyclobutane. and R ⁵ represents _C1 - _C4 -alkyl. 7. The compound according to claim 6 and its salt, wherein... R ⁵ represents methyl or ethyl. 8. A drug comprising a compound of formula (I) as defined in any one of claims 1-4, in combination with one or more inert, non-toxic, and pharmaceutically suitable adjuvants. 9. A medicament comprising a compound of formula (I) as defined in any one of claims 1-4, in combination with one or more other active substances selected from active substances that alter lipid metabolism, antidiabetic drugs, antihypertensive agents, agents that reduce sympathetic tension, perfusion enhancers and/or agents that have antithrombotic effects, as well as antioxidants, aldosterone- and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, compounds that enhance contractility, calcium sensitizers, etc. Chemicals, ACE inhibitors, compounds that regulate cGMP and cAMP, natriuretic peptides, NO-independent guanylate cyclase stimulants, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds that inhibit signal transduction cascades, compounds that regulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorexia nervosa, PAF-AH inhibitors, anti-inflammatory drugs, analgesics, antidepressants, and other psychotropic drugs. 10. Use of at least one compound of formula (I) as defined in any one of claims 1-4 or a drug as defined in any one of claims 8-9 in the preparation of a drug for the treatment and/or prevention of the following diseases in humans and animals: primary and secondary diabetic microangiopathy, diabetic wound healing, diabetic ulcers of the extremities, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermittent claudication, and peripheral and autonomic neuropathy. 11. The use according to claim 10, wherein the drug is used to promote wound healing of diabetic foot ulcers. 12. A medicament comprising a compound as defined in claim 1 in combination with one or more additional active compounds selected from rivaroxaban, iloprost, and inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4, and/or 5, comprising an effective amount of any one of claims 1 to 4. 13. Use of the compound of any one of claims 1 to 4 in the preparation of a medicament for treating and/or preventing peripheral occlusive diseases. 14. Use of the compound of any one of claims 1 to 4 in the preparation of a medicament for treating and/or preventing peripheral and cardiovascular diseases, peripheral circulatory disorders or intermittent claudication.