HK1231851A1

HK1231851A1 - Substituted piperidinyl-tetrahydroquinolines and their use as alpha-2c adrenoreceptor antagonists

Info

Publication number: HK1231851A1
Application number: HK17105241.7A
Authority: HK
Inventors: Eva Maria Becker-Pelster; Philipp BUCHGRABER; Anja BUCHMÜLLER; Karen Engel; Volker Geiss; Andreas GÖLLER; Herbert Himmel; Raimund Kast; Andreas Knorr; Dieter Lang; Gorden Redlich; Carsten Schmeck; Hanna Tinel; Frank Wunder
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2013-12-19
Filing date: 2014-12-16
Publication date: 2017-12-29

Description

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

The present invention relates to novel substituted piperidinyl tetrahydroquinolines, to a process for their preparation, to their use in a method for the treatment and/or prophylaxis of diseases, and to their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular diseases, diabetic microangiopathies, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microangiopathies, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemias, peripheral circulatory disorders, raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathies.

Adrenergic receptor α₂Receptor (α)₂-AR) belongs to the family of G-protein coupled receptors. They bind pertussis toxin-sensitive inhibitory G protein G_iAnd G₀They are involved in the mediation of various physiological effects in different tissues after stimulation by endogenous catecholamines (epinephrine, norepinephrine), which are released by synapses or reach the site of action via the blood α, mainly in terms of the cardiovascular system, but also in the central nervous system₂Biochemical, physiological and pharmacological studies have demonstrated, except for the various α₁In addition to the AR subtype, there are 3 α species in many cardiovascular-related target cells and tissues₂The AR subtype (α)_2A、α_2BAnd α_2C) However, because of the lack of variety α₂Highly selective ligands and/or antagonists of the AR, so that it has hitherto been difficult to elucidate the precise physiological tasks of said receptor subtypes (Gyires et al, α)₂-adrenocepter subtypes-mediated physiological, pharmacological actions, Neurochemistry International55, 447-453, 2009; Tan and Limbird, The α_2-Adrenergic Receptors: Adrenergic Receptorsin the 21st Century/Receptors，2005，241-265)。

Thus, the sympathetic system is involved in the regulation of the output properties of the heart, but also in the control of local perfusion of different vascular beds₂Thus, the blood vessels are innervated by sympathetic nerve fibers distributed in the adventitia, and their periphery has varicose veins to release noradrenaline via α in endothelial cells and smooth muscle cells₂The AR regulates the respective local vascular tone.

In addition to the effects on sympathetic efferent nerves, peripheral cardiovascular function is also affected by presynaptic and postsynaptic α₂Smooth muscle cells and endothelial cells express different α₂α on smooth muscle cells of AR subtype_2A、α_2BAnd α_2CActivation of receptors leads to contraction, thereby causing vasoconstriction (Kanagy, Clinical Science 109:431-437, 2005.) however, the distribution of various receptor subtypes varies among species and among different vascular sizes in different vascular beds α_2AThe AR appears to be expressed substantially exclusively in the aorta, whereas α_2BAR contributes more to the vascular tone in arterioles and veins AR α_2BAppear to play a role in salt-induced hypertension (Gyires et al, α)₂-adrenocepter subtypes-mediated physiological, pharmacological actions, Neurochemistry International55, 447-453, 2009 although AR α is not fully understood_2CEffects on hemodynamics, however, AR α_2CThey are also involved in the cold-induced enhancement of adrenoreceptor-induced vasoconstriction (Chotani et al, Silent α)_2Cadrenergic receptors enable cold-induced vasoconstriction incuTaneous artifacts, Am J Physiol 278: H1075-H1083, 2000; Gyires et al, α₂-Adrenoceptor subtypes-mediated physiological, pharmacological actions, Neurochemistry International55, 447-453, 2009 cold and other factors (e.g. tissue proteins, estrogens) regulate AR α_2CFunctional coupling to intracellular signalling pathways (Chotani et al, Distingt cAMP signaling pathway differential regulation α_2Calcohol in serum expression in human organic small blood cell, Am J Physiol Heart Physiol 288: H69-H76, 2005.) thus, AR- α, the perfusion-regulating effect of different vascular beds under different pathophysiological conditions, was studied₂Selective inhibitors of the subtype are of interest.

Under pathophysiological conditions, the adrenergic system can be activated, which can lead to, for example, hypertension, heart failure, increased platelet activation, endothelial function disorders, atherosclerosis, angina pectoris, myocardial infarction, thrombosis, peripheral circulation disorders, stroke, and sexual dysfunction₂Expression of receptors (receptoren) on their platelets this can be correlated with the onset of vasospasm observed in these patients (Keenan and Porter, α)₂-Adrenergic receptors in platelets frompatients with Raynaud´s syndrome，Surgery，V94(2),1983)。

The therapeutic possibility of such diseases aimed at influencing the activated adrenergic system in the organism is a promising approach due to the expected high efficiency and small side effects. Peripheral circulation disorders (microangiopathies) such as diabetic retinopathy, nephropathy or significant wound healing disorders (diabetic foot ulcers) play an important role, in particular in the case of diabetic patients who often have excessively high catecholamine levels. Among peripheral occlusive diseases, diabetes is the most important concomitantOne of the sexual disorders, and also plays a decisive role in the progression of the disease (microangiopathy and macroangiopathy.) adrenergic receptors α associated with elevated catecholamine levels_2CHigher expression of the receptor may be involved in these pathophysiological processes in the case of diabetic patients.

In 2011, there are 3.5 billion diabetic patients in the world (6.6% of the population), and this number is expected to double as of 2028. Diabetic foot ulcers are the most common cause of hospitalization of diabetic patients. The risk of a diabetic patient developing a diabetic foot ulcer throughout life is 15-25%, with 15% of all diabetic foot ulcers resulting in amputation. 40-70% of all non-invasive amputations are performed in diabetics throughout the world. Risk factors for diabetic foot ulcers are trauma, poor metabolic control, sensory polyneuropathy, motor polyneuropathy, autonomic polyneuropathy, improper footwear, infection, and peripheral arterial disease. Treatment of diabetic foot ulcers requires a multidisciplinary team and the use of a multifactorial regimen: weight loss, revascularization (in the case of the peripheral arterial occlusive disease pAVK), improved metabolic control, wound excision, dressings, dalteparin, regranex (pdgf), and amputation. The cost of treatment for each diabetic foot ulcer (without amputation) was 7000-10000 USD. 33% of all diabetic foot ulcers do not heal within 2 years, and there is a high recurrence rate (34% in the first year, 61% in 3 years).

Accordingly, it is an object of the present invention to provide a novel selective adrenergic receptor α_2CReceptor antagonists for the treatment and/or prevention of diseases in humans and animals, e.g. cardiovascular diseases.

It is also an object of the present invention to provide novel selective adrenergic receptors α_2CReceptor antagonists for the treatment and/or prevention of peripheral circulation disorders (microangiopathies), 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 the CCR5 receptor, which are particularly useful in the treatment of HIV. WO 2005/077369 describes structurally similar bipiperidinyl derivatives as inhibitors of the CCR3 receptor, which are particularly useful in the treatment of asthma. WO94/22826 describes structurally similar piperidines as active substances with peripheral vasodilatory action.

The present invention provides compounds of formula (I) and salts thereof, solvates thereof and solvates of the salts thereof,

wherein

R¹Represents C₁-C₆-alkyl or C₃-C₅-a cycloalkyl group,

wherein alkyl is substituted with 1-2 substituents independently selected from hydroxy, C₁-C₄-alkoxy and haloalkoxy groups,

and

R²represents hydrogen or C₁-C₄-an alkyl group,

or

R¹And R²Together with the nitrogen atom to which they are attached form a 4-7 membered N-heterocyclic ring,

wherein the N-heterocycle may be substituted with 1 to 3 substituents independently selected from oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-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 commonly attached, form a 4-6 membered heterocycle,

wherein the heterocycle itself may be substituted by 1 to 3 substituents which are independently of one another selected from oxo, methyl and ethyl,

R³represents hydrogen, fluorine, methoxy or ethoxy,

and

R⁴represents 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 encompassed by formula (I) and mentioned below as embodiments and salts, solvates and solvates of said salts, provided that the compounds encompassed by formula (I) and mentioned below are not already salts, solvates and solvates of salts.

Within the scope of the present invention, the term "x acids" in any formula does not denote the stoichiometrically defined ratio of acid to the respective substance. The term "x-acid" denotes different ratios between substance and 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 conformational isomers (enantiomers and/or diastereomers, including those under atropisomers). Thus, the present invention includes enantiomers or diastereomers and various mixtures thereof. Stereoisomerically identical components can be separated from such mixtures of enantiomers and/or diastereomers in a known manner; preference is given to using chromatographic methods for this purpose, in particular HPLC chromatography on achiral or chiral phases.

As long as the compounds according to the invention can exist in tautomeric forms, the invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variations of the compounds of the present invention. Isotopic variations of the compounds of the present invention are understood herein to mean compounds which: wherein at least one atom has been replaced within a compound of the invention with another atom of the same atomic number, but having an atomic mass different from the atomic mass usually found or predominant in nature. Examples of isotopes that can be incorporated into the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. certain isotopic variations of the compounds of the present invention (such as, inter alia, those into which one or more radioactive isotopes have been incorporated) can be useful, for example, for examining the mechanism of action or the distribution of active species in vivo; due to comparatively easy manufacturability and detectability, use³H-or¹⁴C-isotopically labelled specific compounds are suitable for this purpose. In addition, due to the greater metabolic stability of the compounds, the incorporation of isotopes (e.g., deuterium) may produce certain therapeutic benefits, such as increased in vivo half-life or reduction in the requisite active dose; thus, such modifications of the compounds of the present invention may also optionally constitute preferred embodiments 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 employing the respective isotopic modifications of the various reactants and/or starting materials according to the methods described further below and in the working examples.

AsSalt (salt)Preference is given in the scope of the invention to the physiological properties of the compounds according to the inventionAn acceptable salt. However, the invention also includes salts which are not suitable per se for pharmaceutical use but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, for example and with preference, 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 with preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, methyl ethyl ketone, ethyl methyl ketone, ethyl methyl ethyl ketone, ethyl propyl ketone,N-methylmorpholine, arginine, lysine, ethylenediamine,N-methylpiperidine and choline.

Are named in the context of the present inventionSolvatesThose 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 particular form of solvates in which the coordination is with water.

The invention furthermore encompasses prodrugs of the compounds of the invention. The term "prodrug" includes such compounds: which may be biologically active or inactive per se, but which is converted (e.g. by metabolism or hydrolysis) to a compound according to the invention during in vivo residence.

Within the scope of the present invention, the term "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, limiting, reducing, arresting, reversing or curing the development, process or progression of a disease (Krankheit), disease (Leiden), disease (Erkrankung), injury or health disorder, such a condition and/or symptoms of such a condition. Herein, the term "therapy" is understood to be synonymous with the term "treatment".

Within the scope of the present invention, the terms "prevention", "prophylaxis" or "prophylactic measure" are used synonymously and mean avoiding or reducing the risk of developing or progressing from, infection with, suffering from or having a disease (Krankheit), a disease (Leiden), a disease (Erkrankung), an injury or health disorder, such a state and/or symptoms of such a state.

Treatment or prevention of disease (Krankheit), disease (Leiden), disease (Erkrankung), injury or health disorder may be partially or fully effected.

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

alkyl in alkoxy, alkoxyalkyl, alkylamino and alkoxycarbonyl is itself and "Alk" and "alkyl"Represents a straight-chain or branched alkyl residue having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as, and preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy radicalFor example and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

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

At residue R ¹ And R ² The N-heterocyclic ring in the definition of (1) represents saturated or partially unsaturated having 4 to 7 ring atomsMonocyclic residue, said ring atoms comprising one nitrogen heteroatom and up to 3 residues selected from S, O, N, SO and SO₂And/or a hetero group, in which one nitrogen atom may also form an N-oxide, such as, 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.

At residue R ¹ And R ² Has a common carbon atom to the N-heterocycle to which it is attachedAn episaturated and partially unsaturated monocyclic residue having 4 to 6 ring atoms and up to 4 ring atoms selected from S, O, N, SO and SO₂And/or a hetero group in which one nitrogen atom may also form an N-oxide, such as and preferably azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and 1, 1-dioxothietane, particularly preferably azetidine and oxetane, and still more preferably oxetane.

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

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

R¹Represents C₁-C₆-alkyl or C₃-C₅-a cycloalkyl group,

wherein alkyl is substituted with 1-2 substituents independently selected from hydroxy and C₁-C₄-alkoxy radical

And

R²represents hydrogen or C₁-C₄-an alkyl group,

or

wherein the N-heterocycle may be substituted with 1 to 3 substituents independently selected from oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, C₁-C₄Alkyl radical, C₁-C₄-an alkoxy group and a halogen,

or

R³represents hydrogen, fluorine, methoxy or ethoxy,

and

R⁴represents hydrogen, fluorine, methoxy or ethoxy.

R¹Represents C₂-C₆-an alkyl group,

wherein alkyl is substituted with 1 substituent selected from the group consisting of: a hydroxyl group, a methoxy group and an ethoxy group,

and

R²represents hydrogen or

R¹And R²Together 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 with 1-2 substituentsThe substituents are independently of one another selected from the group consisting of hydroxy, trifluoromethyl, hydroxycarbonyl, C₁-C₃-alkyl, methoxy and methoxymethyl groups,

or

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

wherein the azetidine, oxetane or 1, 1-dioxothietane may themselves be substituted by 1-2 substituents independently of one another selected from methyl and ethyl,

R³represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen, fluorine or methoxy,

or

R³Represents hydrogen, fluorine or methoxy,

and

R⁴represents hydrogen.

R¹Represents C₂-C₄-an alkyl group,

wherein alkyl is substituted with 1 substituent selected from the group consisting of: a hydroxyl group and a methoxy group,

and

R²represents hydrogen, and is selected from the group consisting of,

or

R¹And R²Together with the nitrogen atom to which they are attached form an azetidine,Pyrrolidine, morpholine or 1, 1-dioxothiomorpholine,

wherein azetidine, pyrrolidine, morpholine and 1, 1-dioxothiomorpholine may be substituted with 1-2 substituents independently selected from the group consisting of hydroxycarbonyl, methyl, trifluoromethyl, methoxy and methoxymethyl,

or

R¹And R²Together with the nitrogen atom to which they are attached form azetidines,

wherein the azetidine may have two substituents which, together with the carbon atom of the azetidine to which they are commonly attached, form an oxetane or a1, 1-dioxothietane,

R³represents hydrogen, fluorine or methoxy,

and

R⁴represents hydrogen, and is selected from the group consisting of,

or

R³Represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen, fluorine or methoxy.

R¹Represents C₂-C₄-an alkyl group,

and

R²represents hydrogen, and is selected from the group consisting of,

or

R¹And R²Together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, morpholine or 1, 1-dioxoA group of thiomorpholine compounds selected from the group consisting of thiomorpholine,

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

or

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

R³represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen, fluorine or methoxy,

or

R³Represents hydrogen, fluorine or methoxy,

and

R⁴represents hydrogen.

R³represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen.

R¹Represents C₁-C₆-an alkyl group,

wherein alkyl is substituted with 1-2 substituents independently selected from hydroxy, C₁-C₄-alkoxy and cycloalkyloxy radicals,

and

R²represents hydrogen or C₁-C₄-an alkyl group,

or

R³represents hydrogen, fluorine, methoxy or ethoxy,

and

R⁴represents hydrogen, fluorine, methoxy or ethoxy.

R¹Represents C₂-C₆-an alkyl group,

and

R²represents hydrogen, and is selected from the group consisting of,

or

wherein azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine and 1, 1-dioxothiomorpholine may be substituted with 1-2 substituents independently of one another selected from hydroxy, hydroxycarbonyl, C₁-C₃-an alkyl group and a methoxy group,

or

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

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

R³represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen, fluorine or methoxy,

or

R³Represents hydrogen, fluorine or methoxy,

and

R⁴represents hydrogen.

R¹Represents C₂-C₆-an alkyl group,

and

R²represents hydrogen, and is selected from the group consisting of,

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 commonly attached, form an azetidine or oxetane,

wherein the azetidines and oxetanes may themselves be substituted with 1-2 substituents independently selected from methyl and ethyl,

R³represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen, fluorine or methoxy,

or

R³Represents hydrogen, fluorine or methoxy,

and

R⁴represents hydrogen.

R¹Represents C₂-C₄-an alkyl group,

and

R²represents hydrogen, and is selected from the group consisting of,

or

R¹And R²Together 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 with 1-2 substituents independently selected from oxo, hydroxy, hydroxycarbonyl and methyl,

or

R³represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen.

R¹Represents C₂-C₆-an alkyl group,

and

R²represents hydrogen.

or

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

Preferred are compounds of formula (I) wherein R²Represents hydrogen.

Preferred are compounds of formula (I) wherein R¹And R²Together with the nitrogen atom to which they are attached form a 2-oxa-6-azaspiro [3.3]]Hept-6-yl.

Preferred are compounds of formula (I) wherein R¹And R²Together with the nitrogen atom to which they are attached form a1, 1-dioxathiomorpholin-4-yl group.

Preferred are compounds of formula (I) wherein R³Represents hydrogen.

Preference is given to compounds of the formula (I)A compound of formula (I) wherein R⁴Represents hydrogen.

Preferred are compounds of formula (I) wherein R³And R⁴Represents hydrogen.

Independent of the combination of the residues given in each case, the individual residue definitions given in the respective combinations or preferred combinations of residues are also arbitrarily replaced by the residue definitions of the other combinations.

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

The invention also provides a process for the preparation of a compound of formula (I) or a salt thereof, a solvate thereof or a solvate of a salt thereof, wherein

[A] Reacting a compound of formula (II) in the presence of a reducing agent

With compounds of the formula (III)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

to give a compound of the formula (IV)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

or

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

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

to give a compound of the formula (V)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

or

[C] Reacting a compound of formula (VI) in the presence of a base

Wherein

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

R⁵represents C₁-C₄-an alkyl group, preferably a methyl or ethyl group,

with compounds of the formula (VII)

Wherein R is¹And R²Having the meaning given above, it is preferred that,

to give a compound of the formula (VIII)

Wherein R is¹、R²And R⁵With the above supplyThe meaning of the above-mentioned is,

or

[D] Reacting a compound of formula (IX) in the presence of a dehydrating agent

Wherein R is¹And R²Having the meaning given above, it is preferred that,

with compounds of the formula (V)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

to obtain the compound of formula (I).

The reaction according to process [ A ] is generally carried out in an inert solvent, preferably at a temperature in the range from-20 ℃ to 60 ℃ under atmospheric 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, trichloromethane or 1, 2-dichloroethane. Mixtures of the solvents mentioned may also be used. Preferred are dichloromethane or tetrahydrofuran.

The base is, for example, an organic base such as a trialkylamine, e.g. triethylamine,N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine; diisopropylethylamine is preferred.

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

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

As an alternative to the above-mentioned process [ A ], the preparation of the compound of the formula (IV) may further include a process in which

[E] Reacting a compound of formula (II)

With compounds of the formula (III)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

to give a compound of the formula (IVa)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

or

[F] Reacting a compound of formula (IVa) in the presence of a reducing agent

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

to give the compound of formula (IV).

The reducing agent in the reaction according to the process [ E ] may 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 at a temperature in the range of-20 ℃ to 60 ℃ 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, trichloromethane or 1, 2-dichloroethane. Mixtures of the solvents mentioned may also be used. Preferred is dichloromethane.

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

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

Inert solvents are, for example, alcohols such as isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran or N-methylmorpholone, or dimethylformamide, or dichloromethane, trichloromethane, 1, 2-dichloroethane or acetonitrile. Preferred are acetonitrile and N-methylmorpholone. Mixtures of the solvents mentioned may 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; preferred are potassium carbonate and sodium carbonate.

The compounds of the formulae (VI) and (VII) are known or can be synthesized by known methods from suitable starting compounds.

The reaction according to process [ D ] is generally carried out in an inert solvent, optionally in the presence of a base, preferably at a temperature in the range of-30 ℃ to 50 ℃ at atmospheric pressure.

The inert solvent is, for example, a halogenated hydrocarbon such as dichloromethane or trichloromethane, a hydrocarbon such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. Mixtures of the solvents mentioned may also be used. Acetonitrile is particularly preferred.

Suitable dehydrating agents are, for example, carbodiimide-based 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 carbonyl compounds such as carbonyldiimidazole, or 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-Tert-butyl radical-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride (T3P), or isobutyl chloroformate, or bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl) -N,N,N',N'Tetramethyluronium Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridinyl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium Hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), orN-hydroxysuccinimide, or mixtures of these with bases.

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; diisopropylethylamine is preferred.

The condensation is preferably carried out using propane phosphonic anhydride.

The compound of formula (IX) may be prepared by saponification of a carboxylic acid ester in the compound of formula (VIII).

The saponification is generally carried out in the presence of at least one base in an inert solvent, preferably at a temperature ranging from 0 ℃ to 90 ℃ under atmospheric pressure.

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

Inert solvents are, for example, polar solvents such as alcohols, for example methanol, ethanol, N-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran or N-methylmorpholine. Mixtures of the solvents mentioned may also be used. Preferred are dioxane, ethanol and a mixture of tetrahydrofuran and methanol.

Furthermore, the preparation of the compounds of the formula (I) according to the invention can also comprise a process in which

[G] Reacting a compound of formula (IX)

Wherein R is¹And R²Having the meaning given above, it is preferred that,

reacting with 4-piperidone to obtain the intermediate,

to give a compound of the formula (X)

Wherein R is¹And R²Having the meaning given above, it is preferred that,

or

[H] Reacting a compound of formula (X) in the presence of a reducing agent

Wherein R is¹And R²Having the meaning given above, it is preferred that,

with compounds of the formula (III)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

to obtain the compound of formula (I).

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

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

[I] Reacting a compound of formula (XI) in the presence of a dehydrating agent

Wherein

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

with a compound of formula (V)

Wherein R is³And R⁴Having the meaning given above, it is preferred that,

to give a compound of the formula (XII)

Wherein

R³And R⁴Have the meanings given above and

or

[J] Reacting a compound of formula (XII)

Wherein

R³And R⁴Have the meanings given above and

with compounds of the formula (VII)

Wherein R is¹And R²Having the meaning given above, it is preferred that,

to obtain the compound of formula (I).

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

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

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

[A] and [ B ],

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

[C] and [ D ],

[A] the components of the formulae (A), (B) and (D),

[E] the compounds of formula (I), (B) and (D),

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

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

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

wherein

and is

R⁵Represents C₁-C₄-alkyl, preferably methyl or ethyl.

The compounds according to the invention have an unpredictable useful spectrum of pharmacological activity, including useful pharmacokinetic properties, they are selective adrenergic receptors α_2CA receptor antagonist which results in vasodilation and/or inhibits platelet aggregation and/or reduces blood pressure and/or increases coronary or peripheral blood flow. They are therefore suitable for the treatment and/or prophylaxis of diseases in humans and animals, preferably cardiovascular diseases, diabetic microangiopathies, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microangiopathies, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemias, peripheral circulation disorders, leisurely, in humans and animalsNorrhea, CREST syndrome, microcirculatory disturbance, intermittent claudication, and peripheral and autonomic neuropathy.

In particular, the compounds according to the invention show a disease-selective improvement of the 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 as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.

The compounds according to the invention are therefore suitable for the treatment of cardiovascular diseases, for example for the treatment of hypertension, for primary and/or secondary prophylaxis, and for the treatment of heart failure, for the treatment of stable and unstable angina pectoris, pulmonary hypertension, peripheral and cardiovascular diseases (e.g. peripheral occlusive diseases), arrhythmias, for the treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transient and ischaemic attacks, peripheral circulatory disorders, for the prevention of restenosis, such as after thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA) and bypass installation, and for the treatment of ischemic syndromes, atherosclerosis, asthma diseases, genitourinary diseases such as 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, microcirculation disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the extremities, diabetic erectile dysfunction, CREST syndrome, red spot (erythrimatosis), onychomycosis, tinnitus, dizziness, 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.

Furthermore, the compounds according to the invention are suitable for the treatment and/or prophylaxis of diseases and/or sequelae which are associated with diabetes. Examples of concomitant diseases and/or sequelae of diabetes are diabetic heart diseases, such as 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, stroke, diabetic nephropathy, diabetic erectile dysfunction, diabetic ulcers of the extremities and diabetic foot syndrome. Furthermore, the compounds according to the invention are suitable for promoting the healing of diabetic wounds, in particular for promoting the healing of wounds of diabetic foot ulcers. Promotion of wound healing of diabetic foot ulcers is defined, for example, as improvement in wound closure.

In addition, the compounds according to the present invention are also suitable for controlling cerebral blood flow and are effective agents for preventing and treating migraine. They are also suitable for the prophylaxis and prophylaxis of the sequelae of cerebral infarctions (cerebral stroke) such as stroke, cerebral ischemia and craniocerebral injury. The compounds according to the invention can likewise be used for the prophylaxis and treatment of painful states.

In addition, the compounds according to the invention can also be used for the treatment and/or prophylaxis of microvascular and macrovascular injuries (vasculitis), reperfusion injuries, arterial and venous thrombosis, edema, tumor diseases (skin cancer, liposarcoma, gastrointestinal tract cancer, liver cancer, pancreatic cancer, lung cancer, kidney cancer, ureteral cancer, prostate cancer and cancer of the genital tract), diseases of the central nervous system 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 diseases (glomerulonephritis), thyroid diseases (hyperthyroidism), hyperhidrosis (hyperhidrosis), pancreatic diseases (pancreatitis), liver fibrosis, skin diseases (psoriasis), liver diseases, diabetes mellitus (stroke, diabetes mellitus, diabetes, Acne, eczema, neurodermatitis, dermatitis, keratitis, scar formation, wart formation, chilblain), skin grafts, viral diseases (HPV, HCMV, HIV), cachexia, osteoporosis, avascular osteonecrosis, gout, incontinence, for wound healing in patients suffering from sickle cell anemia, and for angiogenesis.

The invention furthermore 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 disorders" in the sense of the present invention include, inter alia, disorders such as ST-elevated myocardial infarction (STEMI) and non-ST-elevated myocardial infarction (non-STEMI), stable angina, unstable angina, reocclusion and restenosis following coronary interventions such as angioplasty, stent implantation or aortic coronary bypass, peripheral arterial occlusive disorders, pulmonary embolism, deep vein thrombosis and renal vein thrombosis, transient ischemic attacks and thrombotic and thromboembolic strokes and pulmonary hypertension.

Thus, the substances are also suitable for the prevention and treatment of cardiogenic thromboembolisms (e.g. cerebral ischemia, stroke and systemic thromboembolism and ischemia) in patients with acute, intermittent or persistent cardiac arrhythmias (e.g. atrial fibrillation) and in patients receiving cardioversion, but also in patients with heart valve diseases or with intravascular objects (e.g. artificial heart valves, catheters, intra-aortic balloon counterpulsation and pacemaker probes). In addition, the compounds according to the invention are suitable for the treatment of Disseminated Intravascular Coagulation (DIC).

In addition, 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 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 insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary insufficiency, 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 prophylaxis of cardiovascular diseases, in particular heart failure and/or circulatory disorders and microangiopathies associated with diabetes.

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

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

The invention also provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

The invention also provides the use of a compound according to the invention for the production of a medicament for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

The invention also provides methods for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases, using a therapeutically effective amount of a compound according to the invention.

The invention also provides adrenergic receptor alpha 2C receptor antagonists for use in methods of treating and/or preventing concomitant diseases and/or sequelae of diabetes, diabetic 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 in the extremities, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers.

The invention also provides adrenergic receptor alpha 2C receptor antagonists for use in methods of treatment and/or prevention of diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, diabetic ulcers of the extremities, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers.

The invention also provides competitive adrenergic receptor alpha 2C receptor antagonists for use in methods of treating and/or preventing concomitant diseases and/or sequelae of diabetes, diabetic 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 in the extremities, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers.

The invention also provides a medicament for the treatment and/or prevention of concomitant diseases and/or sequelae of diabetes, diabetic 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 extremities, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers, said medicament comprising at least one adrenergic receptor alpha 2C receptor antagonist in combination with one or more inert, non-toxic, pharmaceutically suitable adjuvants.

The invention also provides a medicament for the treatment and/or prevention of diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, diabetic ulcers of the extremities, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers, said medicament comprising at least one adrenergic receptor alpha 2C receptor antagonist in combination with one or more inert, non-toxic pharmaceutically suitable adjuvants.

The invention also provides a medicament for the treatment and/or prevention of concomitant diseases and/or sequelae of diabetes, diabetic 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 extremities, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers, said medicament comprising at least one competitive adrenergic receptor α 2C receptor antagonist in combination with one or more inert, non-toxic, pharmaceutically suitable adjuvants.

The invention also provides a medicament comprising at least one antagonist of the alpha 2C receptor of the adrenergic receptor in combination with one or more other active substances selected from the group consisting of active substances which alter lipid metabolism, antidiabetics, hypotensive agents, agents which reduce sympathetic tone, perfusion enhancers and/or agents acting as antithrombotic agents and antioxidants, aldosterone-and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrate and NO donors, IP receptor agonists, inotropic compounds, calcium sensitizers, ACE inhibitors, compounds which modulate cGMP and cAMP, natriuretic peptides, NO-independent stimulators of guanylate cyclases, NO-independent activators of guanylate cyclases, inhibitors of human neutrophil elastase, compounds which inhibit the signal transduction cascade, Compounds that modulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory agents, analgesics, antidepressants and other psychotropic agents.

The invention also provides a medicament comprising at least one competitive adrenergic receptor alpha 2C receptor antagonist in combination with one or more other active substances selected from the group consisting of active substances which alter lipid metabolism, antidiabetics, hypotensives, agents which reduce sympathetic tone, perfusion enhancers and/or agents which act as antithrombotic agents as well as antioxidants, aldosterone-and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, inotropic compounds, calcium sensitizers, ACE inhibitors, compounds which modulate cGMP and cAMP, natriuretic peptides, NO-independent guanylate cyclase stimulators, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds which inhibit the signal transduction cascade, Compounds that modulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory agents, analgesics, antidepressants and other psychotropic agents.

The invention also provides a method for the treatment and/or prevention of concomitant diseases and/or sequelae of diabetes, diabetic 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 function disorder, diabetic ulcers of the extremities, 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 alpha 2C receptor antagonist or a medicament comprising at least one adrenergic receptor alpha 2C receptor antagonist.

The present invention also provides a method for the treatment and/or prophylaxis of diabetic microangiopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microangiopathy, diabetic ulcers of the extremities, 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 alpha 2C receptor antagonist or a medicament comprising at least one adrenergic receptor alpha 2C receptor antagonist.

The invention also provides a method for the treatment and/or prevention of concomitant diseases and/or sequelae of diabetes, diabetic 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 function disorder, diabetic ulcers of the extremities, 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 alpha 2C receptor antagonist or a medicament comprising at least one competitive adrenergic receptor alpha 2C receptor antagonist.

Adrenergic receptor alpha 2C receptor antagonists are within the scope of the present invention receptor ligands or compounds that block or inhibit the biological response induced by adrenergic receptor alpha 2C receptor agonists. An adrenergic receptor alpha 2C receptor antagonist can be, for example, a competitive adrenergic receptor alpha 2C receptor antagonist, a non-competitive adrenergic receptor alpha 2C receptor antagonist, a reverse adrenergic receptor alpha 2C receptor agonist, or an allosteric adrenergic receptor alpha 2C receptor modulator within the scope of the invention.

The compounds according to the invention can be used alone or, if desired, in combination with other active substances. The invention also provides medicaments comprising a compound according to the invention and one or more further active substances, which are used, inter alia, for the treatment and/or prophylaxis of the abovementioned diseases. Mention may be made, by way of example and preferably, as suitable combination actives: active substances which alter lipid metabolism, antidiabetics, hypotensives, agents which reduce sympathetic tone, perfusion enhancers and/or agents which act as antithrombotic agents, as well as antioxidants, aldosterone-and mineralocorticoid-receptor antagonists, vasopressin receptor antagonists, organic nitrate and NO donors, IP receptor agonists, inotropic active substances, calcium sensitizers, ACE inhibitors, compounds which modulate cGMP and cAMP, natriuretic peptides, NO-independent guanylate cyclase stimulators, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds which inhibit the signal transduction cascade, compounds which modulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, Anti-inflammatory agent (COX inhibitor, LTB)₄Receptor antagonists, LTB₄Synthetic inhibitors), analgesics (aspirin), antidepressants, and other psychotropic agents.

The invention provides, inter alia, a combination of at least one compound according to the invention and at least one active substance which alters lipid metabolism, an antidiabetic, 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 alter lipid metabolism, for example and preferably selected from: HMG-CoA reductase inhibitors from statins, such as, and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, such as, and preferably, BMS-188494 or TAK-475, ACAT inhibitors, such as, and preferably, melinamide, Patibobu, Ellumobu or SMP-797, LDL receptor sensors, cholesterol absorption inhibitors, such as, and preferably, ezobu, Tiquina or pamoside, polymeric bile acid adsorbents, such as, and preferably, cholestyramine, colestipol, colesevelam (Coliolvam), colestipol (Cholestel) or colestiolane, bile acid reabsorption inhibitors, such as, and preferably, ASBT (= IBElobiAT) inhibitors such as, AZD-7806 ™, S-8921, AK-105, Carnomab (BARI-1741, AVE-5530), SC-435 or SC-635, an MTP inhibitor, such as, and preferably, Enptapi or JTT-130, a lipase inhibitor, such as, and preferably, orlistat, an LpL activator, a fibrate, nicotinic acid, a CETP inhibitor, such as, and preferably, Toxotrepirimid, Dazetricip (JTT-705) or a CETP vaccine (Avant), a PPAR-gamma and/or a PPAR-agonist, such as, and preferably, pioglitazone or rosiglitazone and/or Endurobol (GW-501516), a R modulator, a FXR modulator, a LXR modulator, a thyroid hormone and/or a thyroid mimetic, such as, and preferably, D-thyroxine or 3,5,3' -triiodothyronine (T3), an ATP citrate lyase inhibitor, lp (a) antagonists, cannabinoid receptor 1-antagonists, such as and preferably, rimonabant or suliban (SR-147778), leptin receptor agonists, bombesin receptor agonists, histamine receptor agonists, agonists of the nicotinic acid receptor, such as and preferably, nicotinic acid, acipimox, acifran or nicotinyl tartrate, and antioxidants/radical scavengers, such as and preferably, probucol, succinobucol (AGI-1067), BO-653 or AEOL-10150;

● antidiabetics mentioned in Rote Liste 2014, chapter 12. Antidiabetic agents are preferably understood to mean insulin and insulin derivatives as well as orally active hypoglycemic active substances. Herein, insulin and insulin derivatives include insulin of animal, human or biotechnological origin and mixtures thereof. Orally active hypoglycemic actives preferably include sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors and PPAR-gamma agonists. Sulfonylureas which may be mentioned, for example and preferably, are tolbutamide, glyburide, glimepiride, glipizide or gliclazide, biguanides which may be mentioned, for example and preferably, metformin, meglitinide derivatives which may be mentioned, for example and preferably, repaglinide or nateglinide, glucosidase inhibitors which may be mentioned, for example and preferably, miglitol or acarbose, oxadiazolidone, thiazolidinedione, GLP 1 receptor agonist, glucagon antagonist, insulin sensitizer, CCK 1 receptor agonist, leptin receptor agonist, inhibitors of hepatic enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake and potassium channel openers, for example, those disclosed in WO 97/26265 and WO 99/03861;

● hypotensive active substances, for example and preferably selected from: calcium antagonists, such as, and preferably, nifedipine, amlodipine, verapamil or diltiazem, angiotensin AII antagonists, such as, and preferably, losartan, valsartan, candesartan, emblosartan or telmisartan, ACE inhibitors, such as, and preferably, enalapril, captopril, ramipril, delapril, fosinopril, quinapril (Quinopril), perindopril or Tolidopril, beta-blockers, such as, and preferably, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bucindolol, nadolol, mepindolol, carandolol, cararanolol (Carazalol), sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adadilol, landiolol, nebivolol, lanalol, and timolol, Epoxolol or bucindolol, alpha receptor blockers, e.g. and preferably, prazosin, ECE inhibitors, Rho kinase inhibitors and vasopeptidase inhibitors, and diuretics, e.g. and preferably, loop diuretics such as furosemide, bumetanide or torasemide, or thiazine-like diuretics such as chlorothiazide or hydrochlorothiazide, or a1 antagonists such as rolophylline, Tonopofylline and SLV-320;

● a sympathetic tone-lowering agent, such as and preferably reserpine, clonidine or alpha-methyldopa, or in combination with a potassium channel agonist, such as and preferably minoxidil, diazoxide, dihydralazine or hydralazine;

● act as antithrombotic agents, for example and preferably selected from: platelet aggregation inhibitors, such as, and preferably, aspirin, clopidogrel, ticlopidine, cilostazol or dipyridamole, or anticoagulants such as thrombin inhibitors, such as, and preferably, ximelargol, melagatran, bivalirudin or coxsackiel, GPIIb/IIIa antagonists, such as, and preferably, tirofiban or abciximab, factor Xa inhibitors, such as, and preferably, rivaroxaban, idoxaban (DU-176b), apixaban, otaxaban, fidaxababan, razan, fondaparinux, edaparin, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV, SSR-126512 or SSR-128428, together with heparin or a Low Molecular Weight (LMW) heparin derivative or together with a vitamin K antagonist, such as, and preferably, coumarin;

● aldosterone-and mineralocorticoid receptor antagonists, such as, and preferably, spironolactone, eplerenone, or Finorenon;

● vasopressin receptor antagonists, such as, and preferably, conivaptan, trovatan, rivastigmine or sativaptan (SR-121463);

● organic nitrate and NO donors, such as, and preferably, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, or in combination with inhaled NO;

● IP receptor agonists such as, and preferably, iloprost, treprostinil, beraprost, and Selexipag (NS-304);

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

● calcium sensitizers such as, and preferably, levosimendan;

● 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 natriuretic peptide" 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 particular in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

● guanylate cyclase activators which are independent of NO and heme, 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 cevelestol and DX-890 (relatran);

● inhibit signal transduction cascades, such as tyrosine kinase inhibitors and multiple kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and/or

● for example, compounds that affect cardiac energy metabolism such as etomoxider, dichloroacetate, ranolazine and trimetazidine.

Within the scope of the present invention, particular preference is given to 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 for the treatment and/or prevention of the abovementioned 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 heparins, antidiabetics, ACE inhibitors, diuretics and antibiotics and their use in methods for promoting diabetic wound healing and for the treatment and/or prevention of diabetic ulcers in 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 the treatment and/or prevention of 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 one or more of the following physical and/or topical therapies: wound management such as bandaging, wound excision, weight loss with appropriate shoes, pdgf (regranex), hyperbaric oxygen therapy, negative pressure wound therapy.

The compounds of the invention may act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic routes or as implants or stents.

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

Administration forms suitable for oral administration are those which: which function according to the prior art and deliver the compounds of the invention rapidly and/or in improved form and which contain the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with enteric coatings or coatings which delay dissolution or which control the release of the compounds according to the invention) rapidly disintegrating in the oral cavity, or films/wafers, films/lyophilised powders, capsules (for example hard or soft gelatine capsules), dragees, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished while avoiding the step of absorption (e.g., by intravenous, intraarterial, intracardiac, intraspinal, or intravertebral routes), or while absorption is being accomplished (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 or sterile powders.

Oral administration is preferred.

In an exemplary use of the compounds of formula (I) for promoting diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers, administration in the form of a topical formulation is preferred in addition to oral administration.

Suitable administration forms for other routes of administration are, for example, inhalation pharmaceutical forms (including powder inhalers, nebulizers), nasal drops, nasal solutions or nasal sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration, suppositories, otic or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake 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 administration forms described above. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. Such adjuvants include carrier substances (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifying and dispersing agents or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), 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 flavouring 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, non-toxic, pharmaceutically suitable adjuvants, and the use thereof for the above-mentioned purposes.

In general, it has proven advantageous to administer amounts of about 0.1 to 250 mg/24 hours, preferably 0.1 to 50 mg/24 hours, in the case of oral administration, in order to achieve effective results. The dose may be divided into multiple administrations per day. Examples are 2 or 3 administrations per day.

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

The present invention also provides a compound of formula (I) as described above for use in a method of treatment and/or prevention of primary and secondary diabetic microangiopathies, diabetic wound healing, diabetic ulcers of the extremities, particularly for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction disease, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemia, 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 for use in a method of treatment and/or prevention of primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemias, peripheral circulation disorders, raynaud's phenomenon, microcirculation disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the extremities and CREST syndrome, as well as for use in 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 the treatment and/or prevention of primary and secondary diabetic microangiopathies, diabetic wound healing, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microangiopathy, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemia, 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 a compound of formula (I) as described above for the preparation of a medicament for the treatment and/or prevention of primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulation disorders, raynaud's phenomenon, microcirculation disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the extremities and CREST syndrome, and for diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers.

The 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 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 the group consisting of active substances which alter lipid metabolism, antidiabetics, hypotensive agents, agents which reduce sympathetic tone, perfusion enhancers and/or agents acting antithrombotic as well as antioxidants, aldosterone-and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrates and NO donors, IP receptor agonists, inotropic compounds, calcium sensitizers, ACE inhibitors, compounds which modulate cGMP and cAMP, natriuretic peptides, NO-independent stimulators of guanylate cyclases, NO-independent activators of guanylate cyclase, inhibitors of human neutrophil elastase, compounds which inhibit the signal transduction cascade, compounds which modulate cardiac energy metabolism, Chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectic agents, PAF-AH inhibitors, anti-inflammatory agents, analgesics, antidepressants and other psychotropic agents.

The invention also provides medicaments corresponding to the above embodiments for the treatment and/or prophylaxis of primary and secondary diabetic microangiopathies, diabetic wound healing, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction disease, 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 invention also provides medicaments corresponding to the above embodiments for the treatment and/or prevention of primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemia, peripheral circulation disorders, raynaud's phenomenon, microcirculation disorders, intermittent claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the extremities and CREST syndrome, as well as for the healing of diabetic wounds, in particular for the promotion of the healing of wounds of diabetic foot ulcers.

The invention also provides a method for the treatment and/or prophylaxis of primary and secondary diabetic microangiopathies, diabetic wound healing, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular 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 medicament as described above.

The invention also provides a method for the treatment and/or prophylaxis of primary and secondary heart failure, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemia, peripheral circulatory disorders, raynaud's phenomenon, microcirculatory disorders, intermittent claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic nephropathy, diabetic retinopathy, diabetic ulcers of the extremities and CREST syndrome, and for diabetic wound healing, in particular for promoting wound healing of diabetic foot ulcers, 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.

Unless otherwise indicated, the percentage data in the following tests and examples are percentages by weight; parts are parts by weight. The solvent ratio, dilution ratio and concentration data of the liquid solution/liquid solution are in each case based on volume. The data "w/v" refers to "weight/volume". For example, "10% w/v" means: 100 ml of solution or suspension contained 10 g of material.

In the synthetic intermediates and working examples of the invention described below, if the compounds are given in the form of the corresponding base or acid salts, the exact stoichiometric composition of such salts obtained by the respective preparation and/or purification methods is generally unknown. Unless specified in more detail, additions to names and structural formulae, such as "hydrochloride", "trifluoroacetate", "oxalate", "sodium salt" or "x HCl", "x CF₃COOH"，“xC₂O₄ ^2-”、"x Na⁺"with respect to such salts should not be understood as being stoichiometric, but merely having the descriptive characteristics with respect to the salt-forming components contained therein.

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

A) Examples of the embodiments

Abbreviations:

ca. about

CDI carbonyl diimidazole

d days, doublet (in NMR)

DC thin layer chromatography

DCI direct chemical ionization (in MS)

dd doublet (in NMR)

DMAP 4-dimethylaminopyridine

DMFN,N-dimethylformamide

DMSO dimethyl sulfoxide

DSC disuccinimidyl carbonate

d. Th. theoretical values (in yield)

eq. equivalent

ESI electrospray ionization (in MS)

h hours

HATUO- (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 for

MS mass spectrometry

NMR nuclear magnetic resonance spectroscopy

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

q quartet (in NMR)

RP reverse phase (in HPLC)

RT Room temperature

R_tRetention time (in HPLC)

s singlet (in NMR)

t triplet (in NMR)

50% propane phosphonic anhydride of T3P in ethyl acetate or DMF

THF tetrahydrofuran.

LC-MS and HPLC methods:

method 1 (LC-MS)Instrument: Waters ACQUITY SQD UPLC System, column: waters AcquisytUPLC HSS T31.8 μ 50 mm x 1 mm, mobile phase A1 l water + 0.25 ml 99% formic acid, mobile phase B1 l acetonitrile + 0.25 ml 99% formic acid, gradient: 0.0 min90% A → 1.2 min 5% A → 2.0 min 5% A, incubator: 50 ℃ and flow rate: 0.40 ml/min, UV detection of 210 and 400 nm.

Method 2 (LC-MS):Instrument-Waters ACQUITY SQD UPLC System, column: waters AcquisytUPLC HSS T31.8 μ 50 mm x 1 mm, mobile phase A1 l water + 0.25 ml 99% formic acid, mobile phase B1 l acetonitrile + 0.25 ml 99% formic acid, gradient: 0.0 min90% A → 1.2 min 5% A →2.0 min 5% A, incubator: 50 ℃ and flow rate: 0.40 ml/min, UV detection of 210 and 400 nm.

Method 3 (LC-MS):Instrument-Waters ACQUITY SQD UPLC System, column: waters AcquisytUPLC HSS T31.8 μ 30 x 2 mm, mobile phase A1 l water + 0.25 ml 99% formic acid, mobile phase B1 l acetonitrile + 0.25 ml 99% formic acid, gradient: 0.0 min90% A → 1.2 min 5% A → 2.0 min 5% A incubator: 50 ℃ and flow rate: 0.60 ml/min, UV detection: 208-.

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 A1 l water +0.5 ml50% formic acid, mobile phase B1 l acetonitrile +0.5 ml50% formic acid, gradient: 0.0 min90% A → 0.1 min90% A → 1.5 min 10% A → 2.2 min 10% A, incubator: 50 ℃ and flow rate: 0.33 ml/min, UV detection 210 nm.

Method 5 (LC-MS):MS instrument type: waters (Micromass) Quattro Micro, HPLC instrument type: agilent1100 series; column: thermo Hypersil GOLD 3 μm 20 mm x 4mm, mobile phase A: 1l water +0.5 ml50% formic acid, mobile phase B: 1l acetonitrile +0.5 ml50% formic acid, gradient: 0.0 min100% A → 3.0min 10% A → 4.0 min 10% A → 4.01 min100% A (flow rate: 2.5 ml) → 5.00 min100% A, an incubator: 50 ℃ and flow rate: 2 ml/min, and UV detection at 210 nm.

Method 6 (LC-MS):MS instrument type: waters ZQ, HPLC Instrument type: agilent1100 series; UV DAD, column: thermo Hypersil GOLD 3 μm 20 mm x 4mm, mobile phase A: 1l water +0.5 ml50% formic acid, mobile phase B: 1l acetonitrile +0.5 ml50% formic acid, gradient: 0.0 min100% A → 3.0min 10% A → 4.0 min 10% A → 4.1 min100%, oven: 55 ℃, flow rate: 2 ml/min, and UV detection at 210 nm.

Method 7 (LC-MS) MS instrument Waters (Micromass) QM HPLC instrument Agilent1100 series; column: agilent ZORBAX extended-C183.0 x 50 mm 3.5 micron, mobile phase A: 1l water +0.01 mol ammonium carbonate, mobile phase B: 1l acetonitrile, gradient: 0.0 min 98% A → 0.2min 98% A → 3.0min 5% A → 4.5 min 5% A, incubator: 40 ℃, flow rate: 1.75 ml/min, UV detection 210 nm.

Method 8 (LC-MS):MS instrument Waters (Micromass) Quattro Micro, HPLC instrument Agilent1100 series; column: YMC-Triart C183 mu m 50 x 3mm, mobile phase A: 1l water +0.01 mol ammonium carbonate, mobile phase B: 1l acetonitrile, gradient: 0.0 min100% A → 2.75 min 5% A → 4.5 min 5% A, incubator: 40 ℃, 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, 38,1min = 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 the solvent.

Starting compounds

Example 1A

4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylic acid tert-butyl ester

150 g (753 mmol) of tert-butyl 4-oxopiperidine-1-carboxylate and 120 g (903 mmol) of 1,2,3, 4-tetrahydroisoquinoline are dissolved in 1500 ml of THF, and 239 g (1129 mmol) of sodium triacetoxyborohydride are added, with the temperature of the mixture being maintained at about 30 ℃. Stir at room temperature for about 1h, then add about 1000 ml of saturated sodium bicarbonate solution. Extracted with about 500 ml ethyl acetate. The organic phase is washed with a further 500 ml of saturated sodium bicarbonate solution and with 200ml of saturated sodium chloride solution. Then dried over sodium sulfate, filtered and concentrated. 234 g (98% of theory) of the target compound are obtained, which are 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 are dissolved in 1600 ml of dichloromethane and 830ml (3318 mmol) of a 4M solution of hydrogen chloride in dioxane are added, the temperature of the mixture being maintained at 25-30 ℃. After addition of about 1/3, the product began to crystallize. Stirring was carried out at room temperature for about 20 h, followed by the addition of about 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 expected compound are obtained as a white solid.

Example 3A

4- (7-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylic acid tert-butyl ester

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 are dissolved in 50 ml of dichloromethane and approximately 1.5 g of molecular sieve (4A) are added. The suspension was stirred at room temperature for 1 h. Then 2.23 g (10.54 mmol) of sodium triacetoxyborohydride was added and stirred at room temperature for about 18 h. For work-up, it is diluted with about 50 ml of dichloromethane and then washed 2 times with about 100 ml of saturated sodium bicarbonate solution. The combined aqueous phases were extracted 1 time with about 50 ml dichloromethane. Extracted with about 500 ml ethyl acetate. The organic phase is washed with a further 500 ml of saturated sodium bicarbonate solution and with 200ml of saturated sodium chloride solution. The combined organic phases were then dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 5:1-2: 1). 1.58 g (67% of theory) of the target compound are obtained.

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 are dissolved in about 30ml of dichloromethane and 7.1 ml (28.35 mmol) of a 4M solution of hydrogen chloride in dioxane are added. Stirring was carried out at room temperature for about 20 h, followed by addition of about 100 ml of diethyl ether. The resulting precipitate is filtered off with suction, washed with diethyl ether and dried under HV. 1.17 g (81% of theory) of the title compound are obtained as a white solid.

Example 5A

4- (6-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylic acid tert-butyl ester

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 are dissolved in 50 ml of dichloromethane and approximately 10 g of molecular sieve (4A) are added. The suspension was stirred at room temperature for 1 h. Then 2.75 g (12.99 mmol) of sodium triacetoxyborohydride are added and stirred at room temperature for about 18 h. For work-up, it is diluted with about 50 ml of dichloromethane and then washed 2 times with about 100 ml of saturated sodium bicarbonate solution. The combined aqueous phases were extracted 1 time with about 50 ml dichloromethane. Extracted with about 500 ml ethyl acetate. The organic phase is washed with a further 500 ml of saturated sodium bicarbonate solution and with 200ml of saturated sodium chloride solution. The combined organic phases were then dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 2:1-1: 1). 2.73 g (94% of theory) of the target compound are obtained.

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 are dissolved in about 60 ml of dichloromethane and 10.2 ml (40.82 mmol) of a 4M solution of hydrogen chloride in dioxane are added. Stirring was carried out at room temperature for about 20 h, followed by addition of about 100 ml of diethyl ether. The resulting precipitate is filtered off with suction, washed with diethyl ether and dried under HV. 2.24 g (89% of theory) of the title compound are obtained as a white solid.

Example 7A

4- (7-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylic acid tert-butyl ester

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

Example 8A

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

In analogy to the compound from example 6A, 5.33 g (15.17 mmol) of the compound from example 7A were reacted with 22.75 ml (91.01 mmol) of a solution of 4M hydrogen chloride in dioxane. 4.39 g (91% of theory) of the title compound are obtained as a white solid.

Example 9A

4- (6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylic acid tert-butyl ester

In analogy to the compound from example 5A, 2.59 g (13.02 mmol) tert-butyl 4-oxopiperidine-1-carboxylate and 2.55 g (15.62 mmol) 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline are reacted with 4.14 g (19.53 mmol) sodium triacetoxyborohydride. 4.28 g (91% of theory) of the title compound are obtained.

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 solution of 4M hydrogen chloride in dioxane. 3.50 g (92% of theory) of the title compound are obtained as a white solid.

Example 11A

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

0.42 ml (4.8 mmol) of 2-methoxyethylamine is added dropwise to a suspension of 1.00g (4.34 mmol) of ethyl 2- (methylsulfonyl) pyrimidine-5-carboxylate and 1.80 g (13.0 mmol) of potassium carbonate in10 ml of acetonitrile. After stirring at room temperature for 4h, 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 is purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 95:5-70:30), whereby 485 mg (50% of theory) of the title compound are isolated.

Example 12A

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

10.8 ml of 1N sodium hydroxide solution are added to a solution of 485 mg (2.15 mmol) of ethyl 2- [ (2-methoxyethyl) amino ] pyrimidine-5-carboxylate in10 ml of dioxane and stirred at room temperature for 4 h. For work-up, the reaction mixture is concentrated and acidified with 1N hydrochloric acid. The resulting precipitate is filtered off, washed 2 times with water and dried under HV. 280mg (66% of theory) of the title compound are isolated.

Example 13A

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

In analogy to the compound from example 11A 493 mg (4.8 mmol) 1-methoxy-2-aminobutane, 1.00g (4.34 mmol) ethyl 2- (methylsulfonyl) pyrimidine-5-carboxylate and 1.80 g (13.0 mmol) potassium carbonate are reacted in10 ml acetonitrile. 412 mg (37% of theory) of the title compound are isolated.

Example 14A

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

In analogy to the compound from example 12A, 412 mg (1.63 mmol) of the compound from example 13A were reacted. 280mg (76% of theory) of the title compound are isolated.

Example 15A

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

In analogy to the compound from example 11A, 0.45 ml (4.8 mmol) DL-2-amino-1-butanol, 1.00g (4.34 mmol) ethyl 2- (methylsulfonyl) pyrimidine-5-carboxylate and 1.80 g (13.0 mmol) potassium carbonate were reacted in10 ml acetonitrile. 485 mg (46% of theory) of the title compound are 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 are 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 work-up, the reaction mixture was acidified with 1N HCl. The resulting precipitate is filtered, washed 2 times with water and dried under HV. The aqueous phase is then extracted 2 times with 30ml of ethyl acetate each time, and the organic phase is dried over magnesium sulfate, filtered and concentrated. A total of 250 mg (58% of theory) of the title compound are 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 are dissolved in 200ml of acetonitrile and 41.20mg of potassium carbonate (298.14 mmol) are 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 stirred at 60 ℃ for about 16 h. Subsequently, the mixture was stirred in water and extracted 3 times with 200ml of ethyl acetate each time. The aqueous phase is then extracted 1 more time with approximately 200ml of dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is stirred in about 200ml of diethyl ether. The precipitated solid is filtered off with suction, washed with a little diethyl ether and dried under HV. 17.70 g (88% of theory) of the title compound are obtained.

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 (75mmol) were initially taken in 120 ml of ethanol and 148 ml of 1 molar sodium hydroxide solution were added and stirred at room temperature overnight. The mixture is concentrated and then first dissolved in approximately 150 ml of water and then adjusted to pH 5 with 1M hydrochloric acid. The precipitated product is filtered off with suction and washed with water. 16.3 g of product are isolated (98% of theory).

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 are added dropwise to a suspension of 1.00g (4.34 mmol) of ethyl 2- (methylsulfonyl) pyrimidine-5-carboxylate and 2.40 g (17.4 mmol) of potassium carbonate in10 ml of acetonitrile. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, filtered, the residue washed with ethyl acetate/dichloromethane and the filtrate concentrated. The crude product is purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 95:5-70:30), whereby 564 mg (40% of theory) of the title compound are isolated.

Example 20A

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

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

Example 21A

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

In analogy to the compound from example 1, 100 mg (0.341 mmol) of the compound from example 20A, 99mg (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). 97 mg (58% of theory) of the title compound are isolated.

Example 22A

2- (1, 1-Dioxathiomorpholin-4-yl) pyrimidine-5-carboxylic acid methyl ester

55 mg of methyl 2-chloropyrimidine-5-carboxylate (0.32 mmol) and 43 mg of thiomorpholine-1, 1-dioxide (0.32 mmol) are initially taken in1 ml of N-methylmorpholone and 40 mg of sodium carbonate (0.38 mmol) are added. Followed by stirring at 100 ℃ 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 are isolated.

Example 23A

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

69 mg (0.25 mmol) of the compound from example 22A are dissolved in 2ml of methanol/THF 1/1, and 0.25 ml of 2N sodium hydroxide solution (0.50 mmol) are subsequently added. Stirring was carried out at 70 ℃ for 1 h. The mixture was concentrated and dissolved in water. It is subsequently acidified with 1N aqueous hydrochloric acid and extracted 2 times with approximately 20ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is dried under HV. 52 g (79% of theory) of the title compound are obtained, which are reacted further without further purification.

Example 24A

2- [ -2, 6-dimethylmorpholin-4-yl]Pyrimidine-5-carboxylic acid methyl ester (Cis-isomers)

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

Example 25A

2- [ -2, 6-dimethylmorpholin-4-yl]Pyrimidine-5-carboxylic acid (C)Cis-alpha-carboxylic acid derivativesIsomers)

124 mg (0.49 mmol) of the compound from example 24A are initially taken in 2ml of methanol/THF 1:1, and 0.49 ml of 2N sodium hydroxide solution are subsequently added. Stirring was carried out at 70 ℃ for 1 h. The mixture was concentrated and dissolved in water. It is subsequently acidified with 1N aqueous hydrochloric acid and extracted 2 times with approximately 20ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is dried under HV. 106 g (91% of theory) of the title compound are obtained, which are reacted further without further purification.

Example 26A

2- [ -2, 6-dimethylmorpholin-4-yl]Pyrimidine-5-carboxylic acid methyl ester (Trans-Isomers)

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

Example 27A

2- [ -2, 6-dimethylmorpholin-4-yl]Pyrimidine-5-carboxylic acid (C)Trans-Isomers)

35 mg (0.14 mmol) of the compound from example 26A are initially taken in 2ml of methanol/THF 1:1, and 0.14 ml (0.28 mmol) of 2N sodium hydroxide solution are subsequently added. Stirring was carried out at 70 ℃ for 1 h. The mixture was concentrated and dissolved in water. Subsequently, it was acidified with 1N aqueous hydrochloric acid solution and extracted 2 times with about 20ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is dried under HV. 27 g (78% of theory) of the title compound are obtained, which are reacted further without further purification.

Example 28A

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

75 mg of methyl 2-chloropyrimidine-5-carboxylate (0.44 mmol) and 99mg of 2, 2-dimethylmorpholine hydrochloride (0.65mmol) are initially taken in 3 ml of acetonitrile and 300 mg of potassium carbonate (2.17 mmol) are added. Subsequently, stirring was carried out at 60 ℃ for 20 h. The mixture was stirred with water and then extracted 2 times with approximately 20ml of ethyl acetate. The organic phase was dried over sodium sulfate, then filtered and concentrated. The crude product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1-5:1) to isolate 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 are initially taken in 2ml of methanol/THF 1/1, and 0.41 ml (0.82 mmol) of 2N sodium hydroxide solution are subsequently added. Stirring was carried out at 70 ℃ for 1 h. The mixture was concentrated and dissolved in water. Subsequently, it was acidified with 1N aqueous hydrochloric acid solution and extracted 2 times with about 20ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is dried under HV. 86 g (88% of theory) of the title compound are obtained, which are 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 (0.29mmol) of the compound from example 2A in 2.4 ml of acetonitrile, followed by stirring at room temperature overnight. For work-up, 1 ml of saturated sodium bicarbonate solution was added, stirred for 15 min, filtered through an Extrelut cartridge, eluted with dichloromethane and the filtrate was concentrated. The crude product obtained is purified by means of preparative HPLC [ method 9], whereby 47 mg (41% of theory) of the title compound are isolated.

Example 2

(rac)- [4- (7-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl]{2- [ (1-Methoxybutan-2-yl) amino group]Pyrimidin-5-yl } methanones

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

Example 3

(rac)- [4- (6-fluoro-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl]{2- [ (1-Methoxybutan-2-yl) amino group]Pyrimidin-5-yl } methanones

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

Example 4

(rac)- {2- [ (1-Methoxybutan-2-yl) amino group]Pyrimidin-5-yl } [4- (7-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl]Ketone

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

Example 5

(rac)- {2- [ (1-Methoxybutan-2-yl) amino group]Pyrimidin-5-yl } [4- (6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl]Ketone

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

Example 6

(rac)- [4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl]{2- [ (1-Methoxybutan-2-yl) amino group]Pyrimidin-5-yl } methanones

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

Example 7

(rac)- [4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl]{2- [ (1-hydroxybutan-2-yl) amino]Pyrimidin-5-yl } methanones

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

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 and stirred at room temperature for 3 h. For work-up, 100 ml of saturated sodium bicarbonate solution were added and stirred at room temperature for 10 min. Subsequently, another 200ml of saturated sodium bicarbonate solution was added and extracted with 500 ml of ethyl acetate. The organic phase was washed 1 time with saturated sodium bicarbonate solution and sodium chloride solution each, dried over sodium sulfate, filtered and concentrated. 100 ml of methanol was added to the crude product and heated to 55 ℃ whereby no clear solution was produced. It is cooled to room temperature with stirring and 250 ml of diethyl ether are added. After 30min, the precipitated solid is filtered off with suction, washed with a little diethyl ether and dried under HV. 17.2 g (59% of theory) of the target compound are obtained.

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 (0.23mmol) of the compound from example 18A and 69 mg (0.23mmol) of the compound from example 4A in 1.9 ml of acetonitrile, followed by stirring at room temperature overnight. For work-up, 1 ml of saturated sodium bicarbonate solution was added, stirred for 15 min, filtered through an Extrelut cartridge, eluted with dichloromethane and the filtrate was concentrated. The crude product obtained is purified by means of preparative HPLC [ method 9], whereby 30mg (29% of theory) of the title compound are isolated.

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 (0.23mmol) of the compound from example 18A and 72 mg (0.23mmol) of the compound from example 10A in 1.9 ml of acetonitrile, and the mixture was stirred at room temperature overnight. For work-up, 1 ml of saturated sodium bicarbonate solution was added, stirred for 15 min, filtered through an Extrelut cartridge, eluted with dichloromethane and the filtrate was concentrated. The crude product obtained is purified by means of preparative HPLC [ method 9], whereby 30mg (29% of theory) of the title compound are isolated.

Example 11

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

0.46ml of a 4N solution of hydrogen chloride in dioxane were 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. Subsequently, 0.46ml of a 4N solution of hydrogen chloride in dioxane was added again and stirred until the starting materials were completely reacted. The reaction mixture was then concentrated and the resulting residue was triturated with ether. The solid is filtered off and dried under HV, whereby 82 mg (94% of theory) of the title compound are obtained.

Example 12

[4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl ] [2- (1, 1-dioxathiomorpholin-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 are initially taken in 2ml of acetonitrile and 0.17ml of N, N-diisopropylethylamine (0.99 mmol) are added. Subsequently, 0.14 ml (0.24mmol) of T3P (50 wt.% solution in ethyl acetate) was added dropwise and stirred at room temperature overnight. After concentration, the residue was diluted with 20ml of ethyl acetate and about 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 min, it is diluted with water and extracted 2 times with 20ml portions of ethyl acetate. The combined organic phases were dried over sodium sulfate, then filtered, and the filtrate was concentrated. The crude product obtained is purified by means of preparative HPLC [ method 9 ]. 62 mg (68% of theory) of the target compound are isolated.

Example 13

[4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl][2- (2, 6-dimethylmorpholin-4-yl) pyrimidin-5-yl]Ketone(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 are initially taken in 2ml of acetonitrile and 0.39 ml of N, N-diisopropylethylamine (2.23 mmol) are added. Subsequently, 0.32 ml (0.54 mmol) of T3P (50 wt% solution in ethyl acetate) was added dropwise and stirred at room temperature overnight. After concentration, the residue was diluted with 20ml of ethyl acetate and about 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 min, it is diluted with water and extracted 2 times with 20ml portions of ethyl acetate. The combined organic phases were dried over sodium sulfate, then filtered, and the filtrate was concentrated. The crude product obtained is purified by means of preparative HPLC [ method 9 ]. 125 mg (58% of theory) of the target compound are isolated.

Example 14

[4- (3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl][2- (2, 6-dimethylmorpholin-4-yl) pyrimidin-5-yl]Ketone(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 are initially taken in 2ml of acetonitrile and 0.10 ml of N, N-diisopropylethylamine (0.57 mmol) are added. Subsequently, 0.08 ml (0.14 mmol) of T3P (50 wt% solution in ethyl acetate) was added dropwise and stirred at room temperature overnight. After concentration, the residue was diluted with 20ml of ethyl acetate and about 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 min, it is diluted with water and extracted 2 times with 20ml portions of ethyl acetate. The combined organic phases were dried over sodium sulfate, then filtered, and the filtrate was concentrated. The crude product obtained is purified by means of preparative HPLC [ method 9 ]. 32 mg (65% of theory) of the target compound are 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 are initially taken in 2ml of acetonitrile and 0.32 ml of N, N-diisopropylethylamine (1.81 mmol) are added. Subsequently, 0.26 ml (0.44 mmol) of T3P (50 wt% solution in ethyl acetate) was added dropwise and stirred at room temperature overnight. After concentration, the residue was diluted with 20ml of ethyl acetate and about 10 ml of saturated aqueous sodium bicarbonate solution was added. After 10 min, it is diluted with water and extracted 2 times with 20ml portions of ethyl acetate. The combined organic phases were dried over sodium sulfate, then filtered, and the filtrate was concentrated. The crude product obtained is purified by means of preparative HPLC [ method 9 ]. 116 mg (73% of theory) of the target compound are isolated.

B) Evaluation 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:

in vitroB-1) determination

B-1a) antagonism against adrenergic receptors

Use of recombinant human α_1AReceptor CHO cell line tested against adrenergic receptor α_1ASaid cell line additionally recombinantly expressing mtAeq (mitochondrial aequorin.) use of recombinant human α_2AThe CHO cell line (PerkinElmer Life Sciences) of the G α 16 receptor fusion protein tested against the adrenergic receptor α_2ASaid cell line additionally expressing mtAeq recombinantly using recombinant human α_2BReceptor CHO cell line (PerkinElmer Life Sciences) tested for the adrenergic receptor α_2BSaid cell line additionally expressing mtAeq recombinantly using recombinant human α_2CReceptor CHO cell line tested against adrenergic receptor α_2CThe cell line additionally recombinantly expressing a chimeric G protein (G α qi3) and mtOb (mitochondrial Obelin).

Cells were cultured in Dulbecco's modified eagle's medium/NUT mixture F12 containing L-glutamine at 37 ℃ and 5% CO₂Cultivation, the mixture F12 additionally contained 10% (v/v) inactivated fetal bovine serum, 1 mM sodium pyruvate, 0.9mM sodium bicarbonate, 50U/ml penicillin, 50 μ g/ml streptomycin, 2.5 μ g/ml amphotericin B, and 1 mg/ml geneticin. Cells were passaged with enzyme-free hank's based cell dissociation buffer. All cell culture reagents used were obtained from Invitrogen (Carlsbad, USA).

Luminescence measurements were performed on white 384-well microtiter plates. 2000 cells/well were plated in a volume of 25 μ l and at 30 ℃ and 5% CO₂The lower part of the body contains coelenterazine (α)_2AAnd α_2B: 5µg/ml；α_1a/cAnd α_2C2.5 mug/ml) in cell culture medium.1 day serial dilutions of test substance (10 μ l) were added to the cells.5 minutes later, norepinephrine was added to the cells (35 μ l; final concentration: 20 nM (α)_1a/cAnd α_2C) Or 200 nM (α)_2AAnd α_2B) And emitted light was measured for 50 seconds in an opaque box using a CCD (charge coupled device) camera (Hamamatsu Corporation, Shizuoka, japan). Test substances were tested to a maximum concentration of 10 μ M. Calculation of IC from appropriate dose-Effect curves₅₀Values for α targeting adrenergic receptors_2CThe results of antagonism are shown in table 1:

table 1:

B-1B) binding studies at human α 1-and α 2-adrenergic receptors

To prepare a food having person α₁-and α₂-cell membranes of adrenergic receptors, will stably overexpress α₁-and α₂-CHO cell lysis of adrenergic receptors followed by differential centrifugation. Using an Ultra Turrax (Jahnke)&After Kunkel, Ika-Werk) lysis in binding buffer (50 mM tris (hydroxymethyl) aminomethane/1N hydrochloric acid, 5mM magnesium chloride, pH 7.4), the homogenate was centrifuged at 1000 g for 10 min at 4 ℃. The resulting precipitate was discarded and the supernatant was centrifuged at 20000 g for 30min at 4 ℃. The supernatant was discarded and the pellet resuspended in binding buffer and stored at-70 ℃ prior to the binding assay. For binding assays, radioligands are used³H-MK-912 (2.2-3.2 TBq/mmol, Perkinelmer) (for α)_2C0.4 nM for adrRez, and α for_2A1 nM for-adrRez), 0.25 nM³H-prazosin (α)_1AC-adrRez；2.6 - 3.3 TBq/mmol，PerkinElmer)、0.25 nM³H-rauwolfine (α)_2B-adrRez, 2.6-3.2 TBq/mmol, Perkinelmer) with 5-20 μ g cell membranes in binding buffer (total volume of experiment 0.2ml) in the presence of test substance at 30 ℃ for 60 min in 96-well filter plates (FC/B glass fibers, Multiscreen Millipore). After termination of the incubation by aspiration of unbound radioactive material, the plates are removedThe plates were washed with binding buffer and then dried at 40 ℃ for 1 hour then liquid scintillant (Ultima Gold, PerkinElmer) was added and the radioactivity retained on the plates was measured in a liquid scintillation counter (Micro β, Wallac.) nonspecific binding was defined as being at 1-10 μ MWB-4101 (α μ M MWB-4101)_2CadrRez and α_2AadrRez), prazosin (α)_2BadrRez and α_1AC-adrRez) (all from Sigma) in the presence of radioactivity, and usually<25% of the total radioactivity bound. Binding data (IC) was determined using the program GraphPad Prism Version 4.0₅₀And dissociation constant K_i)。

In vivoB-2) determination

B-2a) measurement of relaxation on isolated rat tail artery

Male Wistar rats (200-250 g) were euthanized with carbon dioxide. The tail artery was prepared and incubated in Krebs-Henseleit buffer for 17 h at 4 ℃ (composition in mmol/l: NaCl 112, KCl 5.9, CaCl)₂2.0MgCl₂1.2，NaH₂PO₄1.2，NaHCO₃25, glucose 11.5). The arteries were cut into 2 mm long loops, transferred to organ baths containing 5ml of Krebs-Henseleit buffer, and connected to a wire myograph (DMT, Denmark). The buffer was warmed to 27 ℃ and supplied with 95% O₂、5%CO₂. Prior to each experiment, the preparations were tested for responsiveness by adding a Krebs-Henseleit solution containing potassium (50 mmol/l KCl). After an equilibration period of 60 minutes, the contraction of the vascular ring was induced with 30 nmol/l UK 14.304. The test substance is then added cumulatively at increasing concentrations. Relaxation was shown as a reduction in UK 14.304-induced contraction.

B-2B) hemodynamic CHF rats

Male old Wistar, ZDF/Crl-Lepr fa/fa, SHR-SP or Sprague Dawley rats (Charles river; 250-₂O; tidal volume: 10 ml ofPer kg body weight; FIO_2:0.5; 2% isoflurane). Body temperature was maintained at 37-38 ℃ with a heating pad. Buprenorphine (Temgesic) 0.05 mg/kg was administered subcutaneously as an analgesic. For hemodynamic measurements, rats were tracheotomized and artificially ventilated (frequency: 60 breaths/min; inspiration to expiration ratio: 50: 50; positive end-expiratory pressure: 1 cm H₂O; tidal volume: 10 ml/kg body weight; FIO_2:0.5). Anesthesia was maintained by isoflurane inhalation anesthesia. The left ventricular pressure was determined via the left carotid artery using a Millar microcapillary catheter (Millar SPR-3202F). Systolic left ventricular pressure (sLVP), end diastolic ventricular pressure (LVEDP), systolic force (+ dPdt), and relaxed 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 biomarker and plasma substance levels.

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

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

After preparation of the animals, wait for a 5 min baseline interval. Infusion of AR α 2C antagonist was then initiated. In steady state (32 min after the start of the experiment), femoral flow (% difference) was determined relative to initial flow.

The compound of example 8 showed a dose-dependent increase in femoral flow in diabetic ZDF fa/fa animals at doses of 0.1, 0.3 and 1 μ g/kg. In Wistar rats, no increase in femoral flow was observed up to a dose of 1 μ g/kg/min. At the same time, no changes in blood pressure and heart rate were measured. Placebo: 10% ethanol/40% PEG 400/50% NaCl. The data (average) are shown in table 2:

table 2:

b-2d) determination of perfusion-enhancing substances (hemodynamics)

To reduce perfusion, the right external iliac artery in anesthetized (e.g., isoflurane, enflurane by inhalation) rats (e.g., ZDF/Crl-Lepr fa/fa) was ligated under sterile conditions. Depending on the degree of collateral differentiation of the animal, the femoral artery must additionally be ligated to reduce perfusion. After said operation or prophylactically, the test animal is treated with the test substance orally, intragastrically (via a gastric tube or by food or drinking water intake), intraperitoneally, intravenously, intraarterially, intramuscularly, inhalatively or subcutaneously. The test substance is administered enterally or parenterally, one or more times per day, up to 50 weeks, or continuously via a subcutaneously implanted osmotic minipump (e.g., an Alzet pump). During the experiment, the lower limb micro-perfusion and temperature were recorded. Here, under anesthesia, a temperature sensitive laser doppler probe (Periflux) was adhered to the paw, thereby measuring the micro-perfusion and skin temperature. According to the test protocol, samples such as blood (intermediate diagnosis) 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 were euthanized painlessly.

B-2e) determination of perfusion-enhancing substances (microcirculation)

In both diabetic (ZDDFfa/fa) and healthy rats (Wistar), laser Doppler probes were mounted under anesthetic conditions (isoflurane anesthetic) on the sole of the foot for measuring the microcirculation of the skin. Test animals were treated once orally with the test substance. During the experiment, the lower limb micro-perfusion and temperature were continuously recorded. Here, a temperature sensitive laser doppler probe (periflex, O2C) was attached to the paw, thereby measuring the micro-perfusion and skin temperature. Microcirculation measurements were measured on both paws 30min after oral administration of the test substance. From these data, mean values were calculated and compared to placebo treated animals. It is shown that the test substance shows the Minimum Effective Dose (MED) at which the microcirculation is significantly improved compared to placebo (vehicle = 10% EtOH + 30% PEG400 +60% water for injection; 1 ml/kg) and the fold increase in the microcirculation compared to placebo at this dose. The med (ttest) with a significant increase in skin temperature is also given.

The adrenergic receptor α of the compound of example 8 is shown in Table 3_2CMicrocirculation data for receptor antagonist and comparative substance ORM12741 (AR α 2c receptor antagonist from Orion):

table 3:

b-2f) perfusion-enhancing substances (motion)Function of) Determination in running wheel tests

To determine motor function, the running behavior of mice (e.g., eNOS knockout mice, wild-type mice C-57 Bl6, or ApoE knockout mice) was examined on running wheels. In order to habituate the mice to the use of running wheels automatically, the animals were individually placed in cages with running wheels and trained 4-5 weeks before the start of the experiment. The movement of the mice on the running wheel was recorded by the photocell with the aid of the computer 2 weeks before the start of the experiment, and various running parameters such as the distance run per day, the various distances involved, and their time distribution during the day were determined. Animals were randomly grouped (8-12 animals) according to their natural running behavior (control, sham and one to more substance groups). After a 2 week priming period, to reduce perfusion in the hind legs, the femoral arteries on both sides were ligated under anesthesia under sterile conditions (e.g., anesthesia by inhalation of isoflurane). After said operation or otherwise prophylactically, the test animal is treated with the test substance orally, intragastrically (through a gastric tube or by food or drinking water intake), intraperitoneally, intravenously, intraarterially, intramuscularly, inhalatively or subcutaneously. The test substance is administered enterally or parenterally, one or more times per day, for up to 5 weeks, or continuously via a subcutaneously implanted osmotic minipump. The running behaviour of the animals was observed and recorded over a period of weeks after the operation. At the end of the experiment, the animals were euthanized painlessly. According to the protocol, samples such as blood and other body fluids or organs are removed for further in vitro examinations (S. Vogelsberger New blue tissue simulation clinical assessment International (Cubeha.), publisher: VVB Laufersweeler Verlag (3.2006), ISBN-10: 383595007X, ISBN-13: 978-.

B-2g) determination of the perfusion-enhancing substance (occlusion pressure measurement)

To reduce perfusion, the right external iliac artery in anesthetized (e.g., anesthetized by isoflurane inhalation) rats (e.g., ZDF rats) was ligated under sterile conditions. Depending on the degree of collateral differentiation of the animal, the femoral artery must additionally be ligated to reduce perfusion. After said operation or prophylactically, the test animal is treated with the test substance orally, intragastrically (via a gastric tube or by food or drinking water intake), intraperitoneally, intravenously, intraarterially, intramuscularly, inhalatively or subcutaneously. The test substance is administered enterally or parenterally, one or more times per day, for up to 5 weeks, or continuously via a subcutaneously implanted osmotic minipump (e.g., an Alzet pump). The animals were measured for occlusion pressure after the procedure (followed by randomization) and once a week for a period up to 2 months after the procedure. Here, under anesthesia, an inflatable band was placed around the hind legs of the rat and a temperature adjustable laser doppler probe (periflex) was bonded to the paw. The band is inflated until the laser doppler probe no longer measures blood flow. The pressure of the band was then continuously and gradually reduced, and the pressure at which blood flow was again detected was measured. According to the test protocol, samples such as blood (intermediate diagnosis) and other body fluids or organs are removed for further in vitro examination. At the end of the experiment, the animals were euthanized (S. Vogelsberger New energy particle fur dielndization Claudiotitio Intermitens, Cubever: VVB Laufersweeler Verlag (3.2006), ISBN-10: 383595007X, ISBN-13: 978-.

B-2h) examination of substances affecting wound healing (ulcer model)

To induce superficial trauma, diabetic mice (db/db, i.e., BKS. Cg-m Dock7m +/+ Leprdb/J mice) were anesthetized with isoflurane. A coherent lesion (10 mm x 10 mm) was created on the left rib depilated skin area. Animals were then randomly assigned to different experimental groups. In all groups, the wounds were covered with a dressing (Systagenix Wound Management, UK). Animals were treated daily (from day 1 after wound inflicting) by gavage (200 μ l, vehicle = 10% EtOH + 30% PEG400 +60% water for injection) with the doses of material given. 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 fig. 1 as the size of the wound remaining over the course of the experiment. For this purpose, all individual values are expressed as a percentage relative to the individual animals on the day of trauma. Shown are mean +/-SEM.

B-2i) examination of substances affecting renal function

In animals with acute or disease-caused kidney injury (e.g., STZ rats, ZDF rats with DOCA implants, UUO kidney injury models, glomerulonephritis models, diabetes, atherosclerosis), diuresis is performed periodically before or during continuous treatment with the test substance. The test animals are treated orally, intragastrically (through gastric tubes or by food or drinking water intake), intraperitoneally, intravenously, intraarterially, intramuscularly, inhalationally or subcutaneously with the test substances. The test substance is administered enterally or parenterally, once or more times per day, or continuously via a subcutaneously implanted osmotic minipump (e.g., an Alzet pump). Plasma and urine parameters were determined throughout the duration of the experiment.

B-2j) hemodynamics in anesthetized dogs

Healthy or heart failure Mongrel using a weight of 25-35 kg for both sexes^®Dogs (Marshall BioResources, Marshall farm Inc; Clyde NY; USA). By slow intravenous administration of 25 mg/kg thiopental sodium (Trapanal)^®) And 0.15 mg/kg of acalciumchloride (Alloferin)^®) To begin anesthesia and to aid in the course of the experiment with the aid of 0.04 mg/kg Fentanyl (Fentanyl)^®) 0.25 mg/kg of Dihydrobenzperidol (Dihydrobenzperidol)^®) And 15 mug/kg/h acalciumchloride (Alloferin)^®) Is maintained by continuous infusion. After intubation, the animal was ventilated with a ventilator at a constant breathing volume, such that approximately 5% of the tidal end CO was reached₂And (4) concentration. Ventilation was performed with room air enriched with about 30% oxygen (normoxia). For measuring hemodynamic parameters, a fluid-filled catheter is implanted into the femoral artery for measuring blood pressure. Swan-Ganz with two cavities^®The catheter is passed into the pulmonary artery via the jugular vein (the distal lumen is used to measure pulmonary artery pressure and the proximal lumen is used to measure central venous pressure). Continuous Cardiac Output (CCO) is determined by means of a temperature sensor at the tip of the catheter. Blood flow is measured at different vascular beds, such as the coronary, carotid or femoral arteries, by placing flow probes (Transonic flowprobes) at the respective vessels. Micro-tip catheter (Millar) in carotid artery^®Instruments) into the left ventricle, the pressure in the left ventricle is measured and dP/dt is derived therefrom as a measure of contractile force. The substance is administered intravenously or intraduodenally via the femoral vein as a cumulative dose/activity profile (bolus or continuous infusion). Recording hemodynamic signals with the aid of pressure receiver/amplifier and PONEMAH^®(as data acquisition software) records and evaluates.

In order to induce heart failure,the pacemaker was implanted in dogs under sterile conditions. In the presence of sodium pentobarbital (15-30mg kg)^-1Intravenous) induction of anesthesia, followed by intubation and subsequent ventilation (room air; Sulla 808, Dr ä ger^®Germany), by continuous infusion of pentobarbital (1-5 mg kg)^-1h^-1) And fentanyl (10-40 mug kg)^-1h^-1) Anesthesia is maintained. Pacemaker cable (Setrox S60)^®Biotronik, germany) was implanted through an incision in the left jugular vein and placed in the right ventricle. Connecting the cable to a pacemaker (logo)^®Biotronik, germany), the pacemaker was located in a small subcutaneous pocket between the scapulae. Ventricular pacing was initiated 7 days after the surgical intervention to obtain heart failure at a frequency of 220 beats/min over a period of 10-28 days.

B-2k) determination of antidepressant effects in forced swim tests in rats

Rats forced to swim in confined rooms where they cannot escape are accommodated after the initial phase of increased activity by adopting a characteristic rigid posture and only also performing the absolutely required movements to keep the head above the water surface. A number of clinically active antidepressants can reduce this immobility (e.g., Cryan JF, Markou A, Lucki I. Assessingding therapeutic activity in rodents: receptors preferences and future patients. trends Pharmacol. Sci. 2002; 23: 238-. The methods used here are based on the protocols of Porsolt et al (Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural deputy in rates: a new model sensitive to anti-reflective tables. Eur. J. Pharmacol. 1978; 47379-91; and Porsolt RD, Brossard G, Hautois C. Roux S. Rodent models of compressed form samples and tail subset of compressed form samples tables. Curce. Curr. protocol Neurosis. 8: 8.10A, 1-10; Chapter 8: 8.10A, 1-10) and De Vry et al (Deholy J, Maurel S, Schreiber R, Beunz R, Jentz KR.; European Vrelease map of strain 1999: Eur. 10). During two intervals of 24h (training and testing), the rats were forced to swim in a narrow cylinder filled with water that could not escape. Training treatments (duration 15 min) were performed prior to treatment with the substance, and no behaviour was recorded, in order to familiarize the rats with the test treatment for 5 minutes after 24 h. During both treatments, the rats were individually placed in water-filled cylinders, which were visually separated from each other. After the treatment, the rats were removed from the water and dried. Rats were treated with test substance or vehicle solution about 24, 5 and 1h prior to test treatment; the first administration is performed immediately after the training treatment. The 3 substance administrations prior to the test treatment resulted in more stable pharmacological results compared to a single administration. The trial treatments were electronically recorded using a video surveillance camera and, after storage, analyzed off-line using a computer. For each animal, behavior was analyzed by 3-4 independent observers who scored the total time to immobility in seconds over the 5 minute treatment period of the trial.

Passive behavior or immobility was defined as rats: it floats in the water in an upright position and only makes small movements to keep the head above the water surface or to maintain its body in a stable position of equilibrium. Active behavior, in contrast, is characterized by active swimming movements, such as vigorous movements of the front or rear legs and/or the 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 duration of immobility between the groups were statistically examined by ANOVA or appropriate non-parametric tests with p <0.05 as significance level.

B-2l) radio telemetry measurement of blood pressure and Heart Rate in conscious rats

A commercially available telemetry system from Data Sciences International DSI, USA was used for measurements on awake rats as described below. The system consists of 3 main components: (1) implantable transmitters (Physiotel telemetry transmitters), (2) receivers (Physiotel receivers) via a multiplexer (DSI Data Exchange Matrix) (3) Data acquisition computer. The telemetry device is capable of continuously recording the blood pressure, heart rate and body movements of conscious animals in their habit habitat.

The study was performed on adult female Wistar rats with a body weight >200 g. After the emitters were implanted, the experimental animals were individually housed in type III Makrolon ® cages. They are free to access standard feed and water. By alternating the illumination of the rooms, the day/night rhythm in the laboratory is set.

Emitter implantation:

at least 14 days prior to the initial trial, the telemetry transmitter (PA-C40, DSI) used was surgically implanted into experimental animals under sterile conditions.

For implantation, fasted animals were anesthetized with isoflurane (IsoFlo @, Abbott, 5% start, 2% maintenance) and shaved and disinfected over a wide area of the abdomen. After opening the abdominal cavity along the white line, the fluid-filled measuring catheter of the system is inserted into the descending aorta cranially above the bifurcation point and fixed with tissue adhesive (VetBonD TM, 3M). The transmitter housings were fixed intraperitoneally to the abdominal wall musculature and the wounds were closed layer by layer. After surgery, antibiotics (Ursiloclin 10%, 60 mg/kg subcutaneous, 0.06 ml/100 g body weight, Serumwerk Bernburg AG, Germany) were applied to prevent infection and analgesics (Rimadyl @, 4 mg/kg subcutaneous, Pfizer, Germany).

Materials and solutions:

unless otherwise stated, the test substances were administered orally in each case to a group of animals (n = 6). The test substances are dissolved in a suitable solvent mixture in an amount corresponding to 2 ml/kg body weight. Solvent treated animal group (placebo/vehicle = diethylene glycol monoethyl ether, Transcutol)^®2 ml/kg oral) was used as a control.

Experimental procedure:

the telemetry set was constructed for 24 animals.

Rats with instrumentation living in the apparatus were each assigned a proprietary receiving antenna (RPC-1Receiver, DSI). The implanted transmitter can be activated externally by means of a magnetic switch fitted and switched to transmit during the pre-run of the experiment. The transmitted signal may be collected online by a data collection system (data request A.R.T. for Windows, DSI) and processed accordingly.

In standard operation, the following items each measure a 10 second period: (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 were measured within 24 hours after administration.

The acquisition of the measurements was repeated at 5 minute intervals under computer control. The source data obtained as absolute values are corrected in the figure with the latest measured atmospheric Pressure (APR-1, DSI).

Evaluation:

after the experiment was completed, each data obtained was classified by Analysis software (database. A.R.T.4.1 Analysis). The mean (4 absolute values) of the pre-runs (i.e. before application of the substance) was taken as the blank value and compared to the measured absolute value, whereby the deviation in percent was obtained. By determining the mean (15 minute mean), the data was smoothed over a pre-set period of time.

The literature:

K. witte, K.Hu, J.Swiatek, C.Mussig, G.Ertl and B.Lemmer, Experimental heart failure in rates: efficiencies on myocardial circular devices and annual beta-acquisition signaling, Cardiovasc. Res. 47 (2): 203-.

As a result:

the compound of example 8 with Orion's adrenergic receptor α_2CThe results of a comparison of the receptor antagonist (ORM-12741), which has been used in assays for treating Alzheimer's disease and Raynaud's syndrome, are shown in FIGS. 2-5.

Example 8 shows no hemodynamic effect (hypertension, heart rate) up to an oral dose of 1 mg/kg, a slight transient increase in heart rate observed with 3 and 10 mg/kg, in contrast to the comparative substance ORM-12741, Orion's adrenergic receptor α_2CReceptor antagonists, showing an additional blood pressure reduction at 10 mg/kg.

Description of the drawings:

FIG. 1:b-2h) testing substances affecting wound healing (ulcer model). The remaining wound area in% relative to placebo-treated animals in dbdb mice. Mean ± SEM (n = 10).

FIG. 2:b-2l) deviation of the heart rate in% versus time [ h ] after administration of the substance]Drawing; example 8

FIG. 3:b-2l) deviation in% of mean arterial blood pressure versus time [ h ] after administration of the substance]Drawing; example 8

FIG. 4:b-2l) deviation of the heart rate in% versus time [ h ] after administration of the substance]Drawing; comparative example ORM12741

FIG. 5:b-2l) deviation in% of mean arterial blood pressure versus time [ h ] after administration of the substance]Drawing; comparative example ORM12741

C) Working examples of pharmaceutical compositions

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

and (3) tablet preparation:

composition (A):

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

Tablet weight 212 mg. The diameter is 8 mm, and the curvature radius is 12 mm.

Production:

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

Oral suspension:

composition (A):

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

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

Production:

rhodigel was suspended in ethanol and the compound of example 1 was added to the suspension. Water was added with stirring. The mixture was stirred for about 6h until the swelling of the Rhodigel was complete.

Intravenously administrable solutions:

composition (A):

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 bottle is closed with an infusion plug and a crimped cap.

Claims

1. Compounds of formula (I) and salts thereof, solvates thereof and solvates of salts thereof,

wherein

R¹Represents C₁-C₆-alkyl or C₃-C₅-a cycloalkyl group,

wherein alkyl is substituted with 1-2 substituents independently selected from hydroxy、C₁-C₄-alkoxy and haloalkoxy groups,

and

R²represents hydrogen or C₁-C₄-an alkyl group,

or

R³represents hydrogen, fluorine, methoxy or ethoxy,

and

R⁴represents hydrogen, fluorine, methoxy or ethoxy.

2. A compound of formula (I) and salts thereof, solvates thereof and solvates of salts thereof according to claim 1, wherein

R¹Represents C₁-C₆-alkyl or C₃-C₅-a cycloalkyl group,

wherein alkyl is substituted with 1-2 substituents independently selected from hydroxy and C₁-C₄-an alkoxy group,

and

R²represents hydrogen or C₁-C₄-an alkyl group,

or

R¹And R²And their placeThe attached nitrogen atoms together form a 4-7 membered N-heterocyclic ring,

or

R³represents hydrogen, fluorine, methoxy or ethoxy,

and

R⁴represents hydrogen, fluorine, methoxy or ethoxy.

3. A compound of formula (I) and salts thereof, solvates thereof and solvates of salts thereof according to claim 1, wherein

R¹Represents C₂-C₆-an alkyl group,

and

R²represents hydrogen, and is selected from the group consisting of,

or

wherein azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxothiomorpholine and 1, 1-dioxothiomorpholine may be substituted with 1-2 substituents independently of one another selected from hydroxy, trifluoromethyl, hydroxycarbonyl, C₁-C₃-alkyl, methoxy anda methoxy group and a methyl group, and the like,

or

R³represents hydrogen

And

R⁴represents hydrogen, fluorine or methoxy,

or

R³Represents hydrogen, fluorine or methoxy,

and

R⁴represents hydrogen.

4. A compound of formula (I) and salts thereof, solvates thereof and solvates of salts thereof according to claim 1 or 3, wherein

R¹Represents C₂-C₄-an alkyl group,

and

R²represents hydrogen, and is selected from the group consisting of,

or

R¹And R²Together with the nitrogen atom to which they are attachedThe formation of the azetidine is carried out,

R³represents hydrogen, fluorine or methoxy,

and

R⁴represents hydrogen, and is selected from the group consisting of,

or

R³Represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen, fluorine or methoxy.

5. A compound of formula (I) and salts thereof, solvates thereof and solvates of salts thereof according to any of claims 1 to 4, wherein

R¹Represents C₂-C₄-an alkyl group,

and

R²represents hydrogen, and is selected from the group consisting of,

or

R³represents hydrogen, fluorine or methoxy,

and

R⁴representsThe presence of hydrogen in the presence of hydrogen,

or

R³Represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen, fluorine or methoxy.

6. A compound of formula (I) and salts thereof, solvates thereof and solvates of salts thereof according to any of claims 1 to 5, wherein

wherein the azetidine has two substituents which together with the carbon atom of the azetidine to which they are commonly attached form an oxetane,

R³represents hydrogen, and is selected from the group consisting of,

and

R⁴represents hydrogen.

7. A process for the preparation of a compound of formula (I) or a salt thereof, a solvate thereof or a solvate of a salt thereof according to claim 1, wherein

[A] Reacting a compound of formula (II) in the presence of a reducing agent

With compounds of the formula (III)

Wherein R is³And R⁴Having the meaning given in claim 1,

to obtain the compound of the formula (IV),

wherein R is³And R⁴Having the claimsThe meaning given in1 is that of the compound,

or

[B] Reacting a compound of formula (IV) in the presence of an acid,

wherein R is³And R⁴Having the meaning given in claim 1,

to obtain the compound of the formula (V),

wherein R is³And R⁴Having the meaning given in claim 1,

or

[C] Reacting a compound of formula (VI) in the presence of a base

Wherein

R⁵represents C₁-C₄-an alkyl group, preferably a methyl or ethyl group,

with a compound of the formula (VII),

wherein R is¹And R²Having the meaning given in claim 1,

to obtain the compound of the formula (VIII),

wherein R is¹And R²Has the meaning given in claim 1, and R⁵As defined above, the above-mentioned,

or

[D] Reacting a compound of formula (IX) in the presence of a dehydrating agent

Wherein R is¹And R²Having the meaning given in claim 1,

with compounds of the formula (V)

Wherein R is³And R⁴Having the meaning given in claim 1,

to obtain the compound of formula (I).

8. A compound of formula (VIII) or (IX) and salts thereof, solvates thereof and solvates of salts thereof,

wherein

and

R⁵represents C₁-C₄-alkyl, preferably methyl or ethyl.

9. A compound of formula (I) as defined in any one of claims 1 to 6 for use in the treatment and/or prevention of a disease.

10. A compound of formula (I) as defined in any one of claims 1 to 6 for use in a method for the treatment and/or prevention of primary and secondary diabetic microangiopathies, diabetic wound healing, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microangiopathy, peripheral and cardiovascular diseases, thromboembolic diseases and ischaemia, peripheral circulatory disorders, raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathy.

11. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 6 in combination with one or more inert, non-toxic, pharmaceutically suitable adjuvants.

12. Medicament comprising a compound of formula (I) as defined in any one of claims 1 to 6 in combination with one or more further active substances selected from the group consisting of active substances which alter lipid metabolism, antidiabetics, hypotensives, agents which reduce sympathetic tone, perfusion enhancers and/or agents acting antithrombotic as well as antioxidants, aldosterone-and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, organic nitrate and NO donors, IP receptor agonists, inotropic compounds, calcium sensitizers, ACE inhibitors, compounds which modulate cGMP and cAMP, natriuretic peptides, NO-dependent guanylate cyclase stimulators, NO-independent guanylate cyclase activators, inhibitors of human neutrophil elastase, compounds which inhibit the signal transduction cascade, Compounds that modulate cardiac energy metabolism, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory agents, analgesics, antidepressants and other psychotropic agents.

13. The medicament according to claim 11 or 12 for the treatment and/or prevention of primary and secondary diabetic microangiopathies, diabetic wound healing, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disease, peripheral and cardiovascular diseases, thromboembolic diseases and ischemia, peripheral circulation disorders, raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication, and peripheral and autonomic neuropathies.

14. A method for the treatment and/or prophylaxis of the following diseases in humans and animals: primary and secondary diabetic microangiopathy, diabetic wound healing, diabetic ulcers of the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microangiopathy, 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, by administering an effective amount of at least one compound of formula (I) as defined in any of claims 1 to 6 or a medicament as defined in any of claims 11 to 13.

15. Adrenergic receptor alpha 2C receptor antagonists for use in a method for the treatment and/or prevention of concomitant diseases and/or sequelae of diabetes, diabetic 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 extremities, diabetic foot ulcers, for promoting diabetic wound healing and for promoting wound healing of diabetic foot ulcers.