WO2005028451A1

WO2005028451A1 - Tetrahydroquinoxalines and their use as m2 acetylcholine receptor agonists

Info

Publication number: WO2005028451A1
Application number: PCT/EP2004/009934
Authority: WO
Inventors: Alexander Kuhl; Peter Kolkhof; Leila Telan; Jan-Georg Peters; Klemens Lustig; Raimund Kast; Klaus Münter; Johannes-Peter Stasch; Hanna Tinel
Original assignee: Bayer Healthcare Ag
Priority date: 2003-09-18
Filing date: 2004-09-07
Publication date: 2005-03-31
Also published as: DE10343098A1

Abstract

The invention relates to tetrahydroquinoxalines of formula (I), in which A, X, R<1>, R<2>, R<3>, R<4>, and R are defined as cited in claim 1, to a method for their production and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular diseases.

Description

TETRAHYDROCHINOXALINE AND THEIR USE AS M2 ACETYLCHOLINE RECEPTOR AGONISTS

The invention relates to tetrahydroquinoxalines, a process for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases. Acetylcholine is the carrier of the parasympathetic nervous system. This part of the vegetative nervous system has a decisive influence on fundamental processes of various organ functions, e.g. Lungs, bladder, stomach and intestines, glands, brain, eyes, blood vessels and heart.

Acetylcholine itself is not therapeutically applicable due to the very rapid activation by acetylcholinesterase, but its effect can be reduced by direct parasympathomimetics, e.g. the carbachol, are imitated. Active ingredients that act agonistically like acetylcholine at the muscarinic (M) acetylcholine receptors can, depending on the organ or tissue system, influence and control numerous functions. For example, activation of muscarinic acetylcholine receptors in the brain can affect the memory and processes of learning processes and pain processing.

By using receptor-subtype-specific agonists, for example, the muscarinic M2 acetylcholine receptor, which is particularly strongly expressed in cardiac muscle cells, is able to reduce the heart rate and contractility after beta-adrenergic stimulation (B. Rauch, F. Niroomand, J. Eur. Heart. 1991, 12, 76-82). Both effects reduce myocardial oxygen consumption.

WO 00/39103 describes tetrahydroquinoxalm derivatives for the treatment of diseases which are caused by cell adhesion, such as, for. B. inflammatory diseases or arteriosclerosis.

The object of the present invention is to provide medicaments for the treatment of diseases, in particular cardiovascular diseases.

The present invention relates to compounds of the formula

in which stands for (CC ₆ ) -alkanediyl which is optionally mono- or disubstituted by hydroxy,

X represents CH or N,

R ^{1 represents} phenyl or pyridyl, where phenyl and pyridyl are optionally substituted by 1 to 3 substituents, independently of one another selected from the group consisting of halogen, hydroxy, hydroxycarbonyl, arnino, trifluoromethyl, trifluoromethoxy, nitro, cyano, alkyl, alkoxy, alkylamino , Alkoxycarbonyl, arninocarbonyl and alkyl arninocarbonyl,

R ^{2 represents} cycloalkyl, which is optionally substituted by 1 to 3 substituents, selected independently of one another from the group consisting of halogen, hydroxy, amino, alkyl, alkoxy and alkylamino,

R ^{3 represents} alkyl or cycloalkyl, alkyl and cycloalkyl optionally being substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, alkoxy, alkylamino, hydroxycarbonyl, alkoxycarbonyl, arninocarbonyl and alkylaminocarbonyl, and cycloalkyl can also be substituted by alkyl,

R ^{4 represents} hydrogen or (-CC ₄ ) alkyl,

R ^{5 represents} hydrogen or (CC ₄ ) alkyl

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

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, compounds mentioned below as exemplary embodiment (s) and their Salts, solvates and solvates of the salts, insofar as the compounds mentioned below of formula (I) are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

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

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the invention. However, salts are also included which are not themselves suitable for pharmaceutical applications but 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 mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, maleic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

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

In the context of the present invention, unless otherwise specified, the substituents have the following meaning: Alkyl per se and "alk" and "alkyl" in alkoxy. Alkylamino, alkylaminocarbonyl and alkoxycarbonyl represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents. (-C-C ₃ ) alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical each having 1 to 3 carbon atoms per alkyl substituent, examples and preferably being mentioned: methylamino, ethylamino, n-propylamino, isopropylamino , tert-butylamino, n-pentylamino, n-hexylamino, NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt- Butyl-N-mefhylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents. (-C-C ₃ ) -Alkylaminocarbonyl stands for example for a monoalkylaminocarbonyl radical with 1 to 3 carbon atoms or for a dialkylamino-carbonyl radical with 1 to 3 carbon atoms per alkyl substituent. The following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methyl -Methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl.

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

Alkanediyl stands for a straight-chain or branched saturated alkanediyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkanediyl radical having 1 to 4 carbon atoms is preferred. Examples include and are preferably methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1 , 4-diyl, butane-l, 3-diyl, butane-2,4-diyl, pentane-l, 5-diyl, pentane-2,4-diyl, 2-methylpentane-2,4-diyl. Cycloalkyl stands for a cycloalkyl group with generally 3 to 8, preferably 3 to 6 carbon atoms, by way of example and preferably for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl stands for a mono- or tricyclic aromatic, carbocyclic radical with generally 6 to 14 carbon atoms, for example and preferably for phenyl, naphthyl and phenanthrenyl.

Halogen stands for fluorine, chlorine, bromine and iodine.

If radicals in the compounds according to the invention are substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.

Compounds of the formula (1) are preferred

in which

A represents (CC ₆ ) alkanediyl,

X represents CH or N,

R ^{1 represents} phenyl or pyridyl, where phenyl and pyridyl are optionally substituted by a substituent, independently selected from the group consisting of halogen, hydroxy, amino, alkyl, alkoxy, alkylamino, alkoxycarbonyl, arninocarbonyl and alkylaminocarbonyl,

R ^{2 represents} (C ₃ -C ₆ ) cycloalkyl,

R ^{3 represents} (CC ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, alkyl and cycloalkyl optionally being substituted by 1 to 3 substituents selected independently of one another from the group consisting of hydroxy, trifluoromethyl and (C 1 -C ₄ ) alkoxy,

R ^{4 represents} hydrogen or methyl,

R ^{5 represents} hydrogen or methyl

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

Compounds of the formula (I) are particularly preferred

in which A represents ethane-l, l-diyl or pentane-l, l-diyl,

X represents CH or N,

R ^{1 represents} phenyl or pyridyl, where phenyl and pyridyl are substituted by a methoxy group,

R ^{2 represents} cyclopropyl,

R ^{3 represents} (C ₃ -C ₆ ) alkyl,

R ^{4 represents} hydrogen,

R ^{5 represents} hydrogen or methyl

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

Compounds of the formula (I) in which A represents ethane-l, l-diyl are very particularly preferred.

Also very particularly preferred are compounds of formula (I) in which R ^] -A- for a radical of the formula

^* stands

where * stands for the connection to the nitrogen atom.

Compounds of the formula (I) in which R ^{2 represents} cyclopropyl are also very particularly preferred.

Compounds of the formula (ϊ) in which R ^{3 represents} 1,2-dimethylpropan-1-yl are also very particularly preferred.

Compounds of the formula (I) in which R ⁴ and R ^{5 are} hydrogen are also very particularly preferred.

The radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of another combination, regardless of the respectively specified combinations of the radicals. - ^■

Combinations of two or more of the preferred ranges mentioned above are particularly preferred.

The present invention also relates to a process for the preparation of the compounds of the formula (I), which is characterized in that

either

[A] Compounds of the formula

in which

R, R, R and R have the meaning given above, with compounds of the formula

R ' ^S NH "(m), in which

A and R ^{1 have} the meaning given above, in the presence of conventional condensing agents, if appropriate in the presence of a base or

[B] Compounds of the formula

in which

R, R, R and R have the meaning given above, and

Y ^{1 represents} halogen, preferably bromine or chlorine, with compounds of the formula

, R ° H ₂ N ^' (V), in which

R ^{3 has} the meaning given above, in the presence of a base.

Compounds of formula (II) can be prepared, for example, by using compounds of formula

in which

Y, R, R and R have the meaning given above, first with compounds of formula (V) and then with trifluoroacetic acid or hydrogen chloride in dioxane to cleave the tert-butyl ester.

Compounds of formula (VI) can be prepared, for example, by using compounds of formula

in which

R, R and R have the meaning given above,

with compounds of the formula

in which

Y ^{1 has} the meaning given above,

implements.

Compounds of the formula (VIIa) which correspond to compounds of the formula (VE) in which R ⁴ and R ^{5 are} hydrogen can be prepared, for example, by using compounds of the formula in a three-stage process in the first stage

in which

R has the meaning given above, with compounds of the formula (VIJJ) to compounds of the formula

in which

Y ¹ and R ^{2 have} the meaning given above,

implements,

in the second stage with base in compounds of the formula

in which

R ^{2 has} the meaning given above,

transferred and reacted with borane in the third stage.

Compounds of the formula (VIIIb) which correspond to compounds of the formula (VH) in which R ^{4 is} hydrogen and R ^{5 is} (C 1 -C ₄ ) -alkyl can be prepared, for example, by using a three-stage process in a first Stage compounds of the formula (LX) with compounds of the formula

in which R has the meaning given above,

to compounds of the formula

in which

R ² and R ^{5 have} the meaning given above,

implements,

in a second stage the double bond with sodium cyanoborohydride to give compounds of the formula

in which

R ² and R ^{5 have} the meaning given above,

reduced and implemented in the third stage with borane.

Compounds of formula (Vüc), which correspond to compounds of formula (VH), in which R ^{4 is} (C 1 -C ₄ ) alkyl and R ^{5 is} (C 1 -C ₄ ) alkyl can be prepared, for example, by in a three-stage process in a first stage compounds of the formula (LX) with compounds of the formula

in which

R ⁴ and R ^{5 have} the meaning given above,

to compounds of the formula

in which

R, R and R have the meaning given above,

implements,

in which

R, R and R have the meaning given above,

reduced and implemented in the third stage with borane.

Compounds of the formula (Vπd) which correspond to compounds of the formula (VIT) in which R ^{4 is} (C 1 -C ₄ ) -alkyl and R ^{5 is} hydrogen can be prepared, for example, by using a three-stage process in a first Stage compounds of the formula (LX) with compounds of the formula

in which

R has the meaning given above,

to compounds of the formula

in which

R ² and R ^{4 have} the meaning given above,

implements,

in a second stage to compounds of the formula

in which

R ² and R ^{4 have} the meaning given above,

cyclized and reacted with borane in the third stage.

Compounds of the formula (LX) can be prepared, for example, by using compounds of the formula

in which

R ^{2 has} the meaning given above,

reacted with reducing agents in the presence of a catalyst.

Compounds of formula (XXI) can be prepared, for example, by using the compound of formula

with compounds of the formula

R - NH "(XXIU),

in which

R ^{2 has} the meaning given above,

if appropriate in the presence of a base.

Compounds of the formula (IV) can be prepared, for example, by reacting the corresponding precursor with compounds of the formula (VIU) analogously to process step (VII) + (VITf) -> (VI) (see also synthesis scheme 3).

Compounds of the formulas (in), (V), (VUI), (XU), (XV), (XVUJ), (XXII) and (XXm) are known or can be prepared analogously to known processes.

The amide coupling in process step (II) + (TU) -> (I) is generally carried out in inert solvents, preferably in a temperature range from room temperature to 50 ° C. at normal pressure. Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol ether such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran, dimethylformamide or methylene chloride are preferred.

Typical condensing agents are, for example, carbodiimides such as e.g. N, N'-Diefhyl-, N, N, '- Dipropyl-, N, N'-Diisopropyl-, N, N'-Dicyclohexylcarbodiimid, N- (3-Dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene

(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium- perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium phosphonium , or 0- (benzotriazol-l-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2-

(2-oxo-l- (2H) -pyridyl) -l, l, 3,3-tetramethyluronium tetrafluoroborate (TPTU) or 0- (7-azabenzotriazol-l-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU), or 1 -hydroxybenztriazole (HOBt), or benzotriazol-l-yloxytris (dimethylamino) phosphonium hexafluorophosphate

(BOP), or mixtures of these.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

The combination of N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and diisopropylethylamine in methylene chloride or dimethylformamide is preferred.

Process steps (IV) + (V) -> (I); (LX) + (XVUJ) -> (XLX) and (XXII) + (XXm) -> (XXI) as well as the first substep of (V) + (VT) -> (IT) are generally carried out in inert solvents , optionally in the presence of a base, preferably in a temperature range from 0 ° C to 50 ° C at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-dichloroethane or Trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetonitrile, dimethyl acetate amide, ethyl acetate form , Dimethylacetamide, 1, 2-dimethoxyethane, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, or mixtures of the solvents, preferred are dimethylformamide, tetrahydrofuran, methylene chloride or a mixture of dimethylformamide and methylene chloride.

Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine.

The reaction with an acid in the second process step from (V) + (VI) -> (JJ) generally takes place in inert solvents, preferably in a temperature range from 0 ° C. to 50 ° C. at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, or other solvents such as dimethylformamide, dioxane or tetrahydrofuran, methylene chloride or dioxane is preferred.

Process step (VH) + (Vffl) -> (VI) is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from 0 ° C. to the reflux of the solvent at atmospheric pressure.

Bases are, for example, amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, or mixtures of these bases, preference is given to triethylamine or a mixture of triethylamine and DBU.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, or other solvents dimethylformamide or tetrahydrofuran, methylene chloride is preferred.

Process step (VIU) + (LX) -> (X) takes place in two stages. The first stage is carried out in inert solvents with 2 equivalents of the compounds of the formula (VIU), based on the compounds of the formula (LX), in the presence of 2 equivalents of a base, preferably in a temperature range from 0 ° C. to 50 ° C. normal pressure. The second stage closes without Working up the reaction mixture and is carried out by adding a further base and heating the reaction mixture to reflux of the solvent.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol such as xylene glycol, such as xylene glycol, such as xylene glycol, and diethylene glycol xylene glycol , Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, methylene chloride is preferred.

Bases are, for example, alkali hydroxides such as sodium or potassium hydroxide, or alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferred for the first stage is diisopropylethylamine or triethylamine, preferably for the second stage is DBU.

Deacylation in process step (X) -> (XI) is generally carried out in a solvent, in the presence of a base, preferably in a temperature range from 0 ° C. to 50 ° C. at atmospheric pressure.

Solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane or tetrahydrofuran, or mixtures of the solvents with water, a mixture of dioxane and water being preferred.

Bases are, for example, alkali hydroxides such as lithium, sodium or potassium hydroxide, sodium hydroxide is preferred.

The reaction with borane in process steps (XI) -> (VUa); (XIV) -> (Vllb); (XVII) -> (VIIc) and (XX) -> (VUd) are generally carried out in inert solvents, preferably in a temperature range from 40 ° C. to the reflux of the solvent at normal pressure.

Inert solvents are, for example, ethers such as dioxane or tetrahydrofuran, tetrahydrofuran is preferred.

The reaction with α-keto esters or diketones in the process steps (LX) + (XH) -> (XJΣT) and (LX) + (XV) -> (XVI) is generally carried out in inert solvents, in the presence of acetic acid, preferably in a temperature range from room temperature to 40 ° C at normal pressure. Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane or tetrahydrofuran; methylene chloride is preferred.

The reduction with sodium cyanoborohydride in process steps (Xm) -> (XIV) and (XVI) -> (XVII) is generally carried out in inert solvents, in the presence of acetic acid, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.

Inert solvents are, for example, alcohols such as methanol or ethanol; methanol is preferred.

The cyclization in process step (XLX) -> (XX) is generally carried out in inert solvents, preferably with reflux of the solvent at normal pressure.

Inert solvents are, for example, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone, dimethylformamide is preferred.

The reduction in process step (XXI) -> (LX) takes place in inert solvents, preferably in a temperature range from room temperature to 50 ° C. at normal pressure.

Inert solvents are, for example, alcohols such as methanol, ethanol, propanol, isopropanol or butanol or ethyl acetate or diethyl ether, methanol or ethanol being preferred.

Reducing agent is, for example, hydrogen; Examples of catalysts are tin dichloride, titanium trichloride or palladium on activated carbon. The combination of palladium on activated carbon and hydrogen is preferred.

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes (synthesis schemes 1, 2 and 3).

Science scheme 1:

Science scheme 2:

Science scheme 3:

Pd / C analog: (XXI) -> (XI)

The compounds according to the invention show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action.

They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

They stand out as agonists of the muscarinic M2 acetycholine receptor.

Because of their pharmacological properties, the compounds according to the invention can be used alone or in combination with other active substances for the treatment and / or prophylaxis of cardiovascular diseases, in particular coronary heart disease, angina pectoris, myocardial infarction, stroke, atherosclerosis, essential, pulmonary and malignant hypertension, heart failure, heart failure, cardiac arrhythmias or thromboembolic disorders.

They are also suitable for the treatment and / or prophylaxis of diseases of the eye (glaucoma), stomach and intestines (atonias), the brain (e.g. Parkinson's disease, Alzheimer's disease, chronic pain sensation), kidney failure or erectile or renal dysfunction.

The present invention furthermore relates to the use of the compounds according to the invention for the treatment and or prophylaxis of diseases, in particular the aforementioned diseases.

The present invention furthermore relates to the use of the compounds according to the invention for the production of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an atherosclerotically effective amount of the compounds according to the invention.

The present invention furthermore relates to medicaments containing at least one compound according to the invention and at least one or more further active compounds, in particular for the treatment and / or prophylaxis of the aforementioned diseases.

The compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration, the state-of-the-art is suitable for rapid and or modified application forms which release the compounds according to the invention and which contain the compounds according to the invention in crystalline and or amorphized and / or dissolved form, such as Tablets (non-coated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings which control the release of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be done by bypassing an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbal) or by switching on absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other application routes, e.g. Inhalation medication forms (including powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films / wafers or capsules to be applied lingually, sublingually or buccally, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as plasters), Milk, pastes, foams, scattering powder, implants or stents.

The compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These auxiliaries include Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (for example antioxidants such as ascorbic acid), dyes (for example inorganic pigments such as iron oxides) and taste and / or odor corrections.

The present invention furthermore relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non- contain toxic, pharmaceutically suitable auxiliaries, and their use for the aforementioned purposes.

In general, it has proven to be advantageous to administer amounts of approximately 0.0001 to 10 mg / kg, preferably approximately 0.001 to 1 mg / kg body weight in the case of parenteral administration in order to achieve effective results. In the case of oral administration, the amount is approximately 0.1 to 10 mg / kg, preferably approximately 0.5 to 5 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses over the day.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume.

A. Examples

Abbreviations:

aq. watery

Boc tert-butoxycarbonyl

CDCI3 Deuterochloroform

DIEA diisopropylethylamine

DMAP dimethylaminopyridine

DMSO dimethyl sulfoxide

DMF dimethylformamide d. Th. Of theory

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

ESI electrospray ionization (for MS)

Mp melting point sat. saturated

HATU 0- (7-azabenzotriazol-1-yl) -NN, N'N'-tetramethyluronium hexafluorophosphate

HBTU <- (benzotriazol-1-yl) -NNN ', N'-tetramethyluronium hexafluorophosphate

HOBt 1 -hydroxy-1H-benzotriazole x H ₂ 0 h hour

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectroscopy

MS mass spectroscopy

MeOH methanol

NMR nuclear magnetic resonance spectroscopy

Pd / C palladium / coal percent percent

R _f retention index (at DC)

RT room temperature

R. retention time (with HPLC)

TFA trifluoroacetic acid

THF tetrahydrofuran HPLC and LC-MS methods:

Method 1 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent A: 5 ml of HCl water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.

Method 2 (LCMS): Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A - 0.2 min 100% A -> 2.9 min 30% A - 3.1 min 10% A - »4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Method 3 (LCMS): Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50 mm x 4.6mm; Eluent A: water + 500 μl 50% formic acid / 1; Eluent B: acetonitrile + 500 μl 50% formic acid / 1; Gradient: 0.0 min 10% B ^ 3.0 min 95% B-> 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min- 3.0 min 3.0 ml / min- 4.0 min 3.0 ml / min; UV detection: 210 nm.

Method 4 (LCMS): Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A -> 3.0 min 5% A -» 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 5 (LCMS): Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A - 0.2 min 100% A ^■ 2.9 min 30% A - 3.1 min 10% A - »4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 6 (LCMS): Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm; Eluent A: water + 500 μl 50% formic acid / 1, eluent B: acetonitrile + 500 μl 50% formic acid / 1; Gradient: 0.0 min 0% B - »2.9 min 70% B - 3.1 min 90% B -> 4.5 min 90% B; Oven: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 7 (LCMS): Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A ^■ »2.5 min 30% A -» 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 8 (preparative HPLC): stationary phase: RP18; Eluents: 0.025% aqueous trifluoroacetic acid, acetonitrile.

Output connections:

Example 1A

4-fluoro-3-nitrobenzoic acid tert-butyl ester

21.5 g (116.15 mmol) of 4-fluoro-3-nitrobenzoic acid and 30.5 g (139.4 mmol) of tert-butyl trichloroacetimidate are placed in 250 ml of diethyl ether under an argon atmosphere. 0.64 g (4.52 mmol) of boron trifluoride-diethyl ether complex are added dropwise and the mixture is stirred for 16 hours at room temperature. 6 g of solid sodium hydrogen carbonate are added to the reaction mixture and the mixture is concentrated in vacuo. The residue obtained is purified chromatographically on silica gel (mobile phase gradient cyclohexane → cyclohexane-ethyl acetate 1: 1). 17.8 g (64% of theory) of product are obtained.

'H NMR (300 MHz, DMSO-d ₆ ): δ = 1.57 (s, 9H), 7.2 (dd, 1H), 8.25-8.3 (m, 1H), 8.52 (dd, 1H). MS (ESIpos): m / z = 242 (M + H) ⁺ HPLC (method 1): R _t = 5.07 min

Example 2A

4- (cyclopropylamine) -3-nitrobenzoic acid tert-butyl ester

7.8 g (32.3 mmol) of the compound from Example 1A are placed in 150 ml of tetrahydrofuran. A solution of 3.88 g (67.9 mmol) of cyclopropylamine in 50 ml of tetrahydrofuran is added at 0 ° C. The mixture is stirred at 0 ° C. for 30 minutes, then at room temperature for 16 hours. The reaction mixture is concentrated in vacuo. The residue is taken up in 500 ml of ethyl acetate and washed three times with 100 ml of water and once with 100 ml of saturated sodium chloride solution. It is dried over sodium sulfate and concentrated in vacuo. 8.95 g (99% of theory) of product are obtained.

Η NMR (300MHz, DMSO-d ₆ ): δ = 0.64-0.69 (m, 2H), 0.87-0.93 (m, 2H), 1.54 (s, 9H), 2.67-2.71 (m, 1H), 7.44 ( d, 1H), 8.01 (dd, 1H), 8.33 (br. s, 1H), 8.54 (d, 1H). MS (DCI): m / z = 296 (M + NH ₄ ) ⁺ HPLC (method 1): R _t = 5.47 min

Alternative synthesis to example 2A:

1 g (3.88 mmol) of the compound from Example 21 A are placed in tetrahydrofuran (15 ml). 0.44 g (7.76 mmol) of cyclopropylamine are added at room temperature. The solution is stirred at 55 ° C for 2 hours. The mixture is then poured onto ice water (50 ml). The solid which precipitates is filtered off and dried. 0.65 g (58% of theory) of product is obtained.

Example 3A

3-amino-4- (cyclopropylamine) benzoic acid tert-butyl ester

8.85 g (31.8 mmol) of the compound from Example 2A are placed in 400 ml of methanol under an argon atmosphere, and 0.30 g (1.33 mmol) of palladium on activated carbon (10% Pd) are added. The mixture is stirred under a hydrogen atmosphere at normal pressure overnight. The mixture is filtered through Celite and the filtrate is concentrated in vacuo. It is dried for 2 hours under high vacuum and the product obtained (8.20 g, 94% of theory) is reacted further without delay.

Η NMR (200 MHz, DMSO-d ₆ ): δ = 0.37-0.47 (m, 2H), 0.68-0.80 (m, 2H), 1.48 (s, 9H), 2.35-2.45 (m, 1H), 4.67 ( br. s, 2H), 5.64 (br. s, 1H), 6.75 (d, 1H), 7.08 (d, 1H), 7.15 (dd, 1H). MS (ESIpos): mz = 249 (M + H) ⁺ HPLC (method 1): R _t = 4.18 min

Example 4A

4- (chloroacetyl) -l-cyclopropyl-2-oxo-l, 2,3,4-tetrahydro-6-quinoxalinecarboxylic acid tert-butyl ester

7.90 g (31.8 mmol) of the compound from Example 3A are placed in 200 ml of dichloromethane, and 8.98 g (79.5 mmol) of chloroacetic acid chloride are added at 0 ° C. The mixture is stirred at room temperature for 30 minutes. At 0 ° C 11.2 ml (79.5 mmol) of triethylamine are added. The mixture is stirred for 4 hours at room temperature. Then 7.12 ml (7.26 g, 47.7 mmol) of 1,8-diazabicyclo (5.4.0) undec-7-ene are added and the mixture is heated to reflux. After 16 hours, the reaction mixture is cooled and concentrated in vacuo. The residue is purified chromatographically on silica gel (mobile phase gradient cyclohexane → cyclohexane-ethyl acetate 1: 1). 4.69 g (62% of theory) of product are obtained as an amorphous solid.

Η-NMR (400MHz, CDC1 ₃ ): δ = 0.68-0.72 (m, 2H), 1.16-1.21 (m, 2H), 1.60 (s, 9H), 2.78-2.82 (m, 1H), 4.21 (s, 2H), 4.51 (br. S, 2H), 7.46 (d, 1H), 7.98 (m, 2H). MS (DCr>: m / z = 382 (M + NH ₄ ) ⁺ HPLC (method 1): R, = 4.72 min

Example 5A

l-Cyclopropyl-2-oxo-l, 2,3,4-tetrahydro-6-quinoxalinecarboxylic acid tert-butyl ester

0.614 g (1.68 mmol) of the compound from Example 4A are dissolved in 10 ml of dioxane, 2 ml of 45% sodium hydroxide solution are added and the mixture is stirred at RT for 1 hour. The reaction mixture is concentrated in vacuo. The residue is mixed with 10 ml of water and extracted three times with ethyl acetate. The organic phase is washed with 10 ml of 10% citric acid solution, water and saturated sodium chloride solution. The organic phase is over sodium sulfate dried and concentrated in vacuo. The product obtained is reacted directly without further purification.

LCMS (method 4): R _t = 2.33 min MS (ESIpos): m / z = 289 (M + H) ⁺

Example 6A

1-Cyclopropyl-1, 2,3, 4-tetrahydro-6-quinoxalinecarboxylic acid tert-butyl ester

0.800 g (2.77 mmol) of the compound from Example 5A are dissolved in 15 ml of tetrahydrofuran, 6.0 ml (6.0 mmol) of a 1 molar solution of borane in tetrahydrofuran are added and the reaction is stirred under reflux for 2 h. The reaction mixture is concentrated in vacuo and is chromatographically purified on silica gel [mobile phase gradient cyclohexane-ethyl acetate 10: 1 → cyclohexane-ethyl acetate 5: 1 (v / v)]. 0.446 g (59% of theory) of product is obtained.

^! H-NMR (300MHz, DMSO-d ₆ ): δ = 0.48-0.56 (m, 2H), 0.78-0.87 (m, 2H), 1.49 (s, 9H), 2.32 (m, 1H), 3.24 (s, 4H), 6.90 (d, 1H), 6.95 (d, 1H), 7.08 (d, 1H). LCMS (method 1): R _t = 4.07 min MS (ESIpos): m / z = 275 (M + H) ⁺

Example 7A

4- (chloroacetyl) -l-cyclopropyl-l, 2,3,4-tetrahydro-6-quinoxalinecarboxylic acid tert-butyl ester

0.144 g (0.53 mmol) of the compound from Example 6A are dissolved in 10 ml of dichloromethane, cooled to 0 ° C., mixed with 0.057 ml (0.7 mmol) of chloroacetyl chloride and 0.11 ml (0.7 mmol) of triethylamine and stirred at RT for 3 h. The reaction mixture is concentrated in vacuo. The residue is taken up in 20 ml of ethyl acetate and washed with 5 ml of 1 molar hydrochloric acid solution and 10 ml of water. The organic phase is dried over sodium sulfate and concentrated in vacuo. The reaction mixture is purified chromatographically on silica gel [mobile phase cyclohexane-ethyl acetate 2: 1 (v / v)]. 0.130 g (70% of theory) of product is obtained.

Η NMR (300MHz, DMSO-d ₆ ): δ = 0.60-0.68 (m, 2H), 0.83-0.94 (m, 2H), 1.52 (s, 9H), 2.59 (m, 1H), 3.75 (m, 2H), 4.27 (s, 4H), 7.15 (d, 1H), 7.62 (dd, 1H), 7.94 (, 1H). LCMS (method 6): R _t = 3.50 min MS (ESIpos): m / z = 351 (M + H) ⁺

The compounds listed in Table 1 are prepared analogously to the compound from Example 7A from the corresponding starting materials and purified on silica gel (mobile phase cyclohexane / ethyl acetate).

Table 1

Example 11A

1-Cyclopropyl-4- {N - [(1 S) -l, 2-dimethylpropyl] glycyl} -1, 2,3, 4-tetrahydroquinoxaline-6-carboxylic acid tert-butyl ester

0.332 g (0.95 mmol) of the compound from Example 7A are dissolved in a mixture of 13 ml of dichloromethane and 1 ml of dimethylformamide, and 0.330 g (3.78 mmol) of (S) -3-methyl-2-butylamine are added and the mixture is stirred at RT for 18 h , The reaction mixture is concentrated in vacuo and reacted further without purification.

LCMS (method 3): R, = 1.85 min MS (ESIpos): mz = 402 (M + H) ⁺

The compounds listed in Table 2 are prepared analogously to the compound from Example HA and reacted further without purification. Table 2

Example 15A

1-Cyclopropyl-4- {N - [(1 S) - 1, 2-dimethylpropyl] glycyl} - 1, 2,3, 4-tetrahydro-quinoxaline-6-carboxylic acid hydrochloride

0.490 g (1.22 mmol) of the compound from Example 11A are mixed with 10 ml of a 4 molar solution of hydrogen chloride in dioxane and stirred at RT for 18 h. The reaction mixture is concentrated in vacuo and the product is directly reacted further.

LCMS (method 6): R _t = 1.96 min MS (ESIpos): mz = 346 (M + H) ⁺

The compounds listed in Table 3 are prepared analogously to the compound from Example 15A and reacted further without purification.

Table 3

Example 19A

4-chloro-3-tert-butyl ester nitrobezoesäure

10 g (45.45 mmol) of 4-chloro-3-nitrobenzoic acid chloride are dissolved in DMF (100 ml). 5.10 g of potassium tert-butoxide are added in portions at room temperature. The solution is stirred for one hour at room temperature. The mixture is then poured into ice water (500 ml) in portions. The solid which precipitates is filtered off and dried. 7.1 g (60% of theory) of product are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.59 (s, 9H), 7.9 (dd, 1H), 8.18 (m, 1H), 8.49 (dd, 1H). MS (ESIpos): mz = 258 (M + H) ⁺ HPLC (method 1): R _t = 5.10 min Example 20A

3 - [(2-Bromproρanoyl) amino] -4- (cyclopropylamino) benzoic acid tert-butyl ester

1.45 g (5.84 mmol) of the compound from Example 3A are dissolved in 20 ml of dichloromethane and cooled to 0 ° C. 0.62 ml (6.1 mmol) of 2-bromopropionyl chloride are added and 0.86 ml (6.1 mmol) of triethylamine are slowly added dropwise. The reaction mixture is stirred at 0 ° C for 1 h. For working up, it is poured onto 50 ml of water, the organic phase is washed twice with 0.5 molar hydrochloric acid, then with water and saturated sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. The cleaning is done on silica gel. 0.63 g (22% of theory) of the product is obtained.

^] H NMR (200 MHz, DMSO-d ₆ ): δ = 0.38-0.52 (m, 2H), 0.74-0.88 (m, 2H), 1.45-1.68 (s, 9H), 1.69-

1.83 (d, 3H), 2.46 (m, 1H), 4.71 (quartet, 1H), 6.00-6.14 (m, 1H), 7.02 (d, 1H), 7.67 (m, 2H), 9.43

(s, 1H).

MS (ESIpos): mz = 383 (M + H) ⁺

HPLC (method 1): R _t = 4.83 min

Example 21A

l-Cyclopropyl-2-methyl-3-oxo-l, 2,3,4-tetrahydroquinoxaline-6-carboxylic acid tert-butyl ester

0.625 g (1.63 mmol) of the compound from Example 20A are dissolved in 1 ml of DMF and stirred at 80 ° C. for 18 h. The solvent is removed in vacuo. The purification is carried out on silica gel (cyclohexane / ethyl acetate 5: 1 → cyclohexane / ethyl acetate 3: 1). 0.113 g (23% of theory) of the product are obtained.

Η-NMR (200MHz, DMSO-d ₆ ): δ = 0.31-0.49 (m, IH), 0.57-0.90 (m, 2H), 0.96-1.08 (m, IH), 1.13 (m, 3H), 1.52 ( s, 9H), 3.92 (quartet, IH), 7.08 (d, IH), 7.38 (d, IH), 7.52 (dd, IH). MS (ESIpos): mz = 303 (M + H) ⁺ HPLC (method 1): R _t = 3.06 min

Example 22A

l-Cyclopropyl-2-methyl-l, 2,3,4-tetrahydroquinoxaline-6-carboxylic acid tert-butyl ester

0.110 g (0.36 mmol) of the compound from Example 21A are mixed with 1 ml of a 1 molar solution of borane in THF and stirred at 65 ° C. for 4 h. The reaction mixture is concentrated in vacuo, 1 ml of methanol is added and the solvent is removed in vacuo. The mixture is dried under high vacuum for 0.5 h, purified on silica gel (eluent: cyclohexane / ethyl acetate 1: 6) and the product is reacted further without delay.

'H-NMR (400MHz, DMSO-d ₆ ): δ = 0.39-0.48 (m, IH), 0.49-0.59 (m, IH), 0.68-0.78 (m, IH), 0.89-0.98 (m, IH) , 1.09 (m, 3H), 1.49 (s, 9H), 2.33 (m, IH), 3.02 (dd, IH), 3.24 (dd, IH), 3.56 (m, IH), 5.77 (br s, IH) , 6.87 (d, IH), 6.98 (d, IH), 7.09. (dd, IH). MS (ESIpos): m / z = 289 (M + H) ⁺ HPLC (method 1): R _t = 4.34 min

Example 23A

4- (Chloroacetyl) -l-cyclopropyl-2-methyl-l, 2,3,4-tetrahydroquinoxaline-6-carboxylic acid tert-butyl ester

0.065 g (0.23 mmol) of the compound from Example 22A are reacted according to the instructions from Example 7A. 85 mg (94% of theory) of the product are obtained.

Η-NMR (400MHz, DMSO-d ₆ ): δ = 0.44-0.55 (m, IH), 0.73-0.92 (m, 2H), 0.95-1.07 (m, IH), 1.13 (d, 3H), 1.50 ( s, 9H), 2.54 (m, IH), 3.53 (dd, IH), 3.75 (m, IH), 3.85 (m, IH), 4.52 (m, 2H), 7.15 (d, IH), 7.62 (dd , IH), 7.98. (m, IH). MS (ESIpos): m / z = 365 (M + H) ⁺ HPLC (method 1): R, = 5.17 min

Example 24A

1-Cyclopropyl-4- {N - [(1 S) - 1, 2-dimethylpropyl] glycyl} -2-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid tert-butyl ester

0.082 g (0.23 mmol) of the compound from Example 23A are dissolved in a mixture of acetonitrile and DMF and 59 mg (0.68 mmol) of (S) -3-methyl-2-butylamine are added. The reaction mixture is stirred at 80 ° C. for 18 h, then concentrated in vacuo and dried in a high vacuum for 3 h. The product will continue to be implemented immediately. MS (ESIpos): m / z = 416 (M + H) ⁺ LCMS (method 6): R _t = 2.33 min

Example 25A

1-Cyclopropyl-4- {N - [(1 S) - 1,2-dimethylpropyl] glycyl} -2-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid

CH,

0.094 g (0.23 mmol) of the compound from Example 24A are reacted according to the procedure from Example 15A. The product obtained is immediately implemented without delay.

MS (ESIpos): mz = 360 (M + H) ⁺ LCMS (method 2): R _t = 1.91 min

Example 26A

1-Cyclopropyl-3-isopropyl-2-oxo-1, 2-dihydroquinoxaline-6-carboxylic acid tert-butyl ester

0.550 g (1.88 mmol) of the compound from Example 3A are dissolved in 10 ml of dichloromethane, with 0.814 g (5.65 mmol) of 3-methyl-2-oxobutanoic acid and 22 mg (0.38 mmol) of acetic acid added and stirred at RT for 60 h. The reaction mixture is concentrated in vacuo and reacted further without delay.

MS (ESIpos): m / z = 329 (M + H) ⁺ LCMS (method 2): R _t = 3.55 min

The compounds listed in Table 4 are prepared analogously to the compound from Example 26A from the corresponding starting materials and reacted further without purification.

Table 4

Example 29A

l-cyclopropyl-3-isopropyl-2-oxo-l, 2,3,4-tetrahydroquinoxaline-6-carboxylic acid tert-butyl ester

0.617 g (1.88 mmol) of the compound from Example 26A are dissolved in a mixture of 10 ml of THF and 10 ml of methanol, 1.42 g (22.6 mmol) of sodium cyanoborohydride and 22 mg (0.38 mmol) of acetic acid are added, 16 h at RT and 2 h stirred under reflux. The reaction mixture is concentrated in vacuo and purified on silica gel using cyclohexane / ethyl acetate 10: 1 → cyclohexane / ethyl acetate 5: 1. 0.525 g (62% of theory) of the product are obtained.

MS (ESIpos): mz = 331 (M + H) ⁺ HPLC (method 1): R _t = 4.96 min

The compounds listed in Table 5 are prepared analogously to the compound from Example 29A from the corresponding starting materials and reacted further without purification.

Table 5

Example 32A

l-cyclopropyl-3-isopropyl-l, 2,3,4-tetrahydroquinoxaline-6-carboxylic acid tert-butyl ester

0.513 g (1.10 mmol) of the compound from Example 29A are dissolved in 8 ml of THF, mixed with 6.0 ml of a 1 molar solution of borane in THF and stirred under reflux for 5 h. The reaction mixture is concentrated in vacuo and purified on silica gel with cyclohexane / ethyl acetate 3: 1. 0.274 g (64% of theory) of the product are obtained. MS (ESIpos): m / z = 317 (M + H) ⁺ LCMS (method 3): R _t = 2.97 min

The compounds listed in Table 6 are prepared analogously to the compound from Example 32A from the corresponding starting materials and reacted further without purification.

Table 6

Example 35A

6-chloro-5-nitronicotinoyl chloride

0.900 g (4.89 mmol) of 6-hydroxy-5-nitronicotinic acid are dissolved in 26 ml of phosphoryl chloride and stirred under reflux overnight. The product is freed from the solvent in vacuo. The product obtained is implemented without delay. MS (ESIpos): m / z = 221 (M + H) ⁺ HPLC (method 1): R _t = 3.72 min

Example 36A

6-chloro-N - [(1 S) - 1 - (4-methoxyphenyl) ethyl] -5-nitronicotinamide

0.900 g (4.1 mmol) of the compound from Example 35A are dissolved in 40 ml of dichloromethane and 1.14 ml (8.1 mmol) of triethylamine are added at 0 ° C. Then 0.68 g of (S) -4-methoxyphenylethylamine are slowly added dropwise and the mixture is stirred at RT for 1 h. For working up, the solvent is removed in vacuo, the residue is dissolved in ethyl acetate, washed three times with water and dried over sodium sulfate. After removal of the solvent in vacuo, 1.1 g (79% of theory) of the product are obtained.

MS (ESI-neg): m / z = 334 (MH) ⁺ HPLC (method 1): R _t = 4.42 min

Example 37A

6- (Cyclopropylamino) -N - [(IS) -I - (4-methoxyphenyl) ethyl] -5-nitronicotinamide

1.1 g (3.24 mmol) of the compound from Example 36A are dissolved in 25 ml of THF, 1.13 ml (16 mmol) of cyclopropylamine are added and the mixture is stirred at RT for 3 h. For working up, the solvent is removed in vacuo, the residue is dissolved in ethyl acetate and washed three times with water and dried over sodium sulfate. After concentration in vacuo, a precipitate precipitates, which is filtered off. 1.02 g (85% of theory) of the product are obtained.

MS (ESIpos): m / z = 357 (M + H) ⁺ HPLC (method 1): R _t = 4.35 min

Example 38A

5-amino-6- (cyclopropylamino) -N - [(lS) -l- (4-methoxyphenyl) ethyl] -nicotinamide

0.75 g (2.1 mmol) of the compound from Example 37A are dissolved in 10 ml of methanol, 75 mg of Pd / C (10%) are added and the mixture is hydrogenated at RT and atmospheric pressure for 6 h. For working up, the mixture is filtered through diatomaceous earth and the solvent is removed in vacuo. 0.65 g (90% of theory) of the product is obtained.

MS (ESIpos): m / z = 327 (M + H) ⁺ HPLC (method 1): R _t = 3.72 min

Example 39A

4-Cyclopropyl-N - [(IS) -l- (4-methoxyphenyl) ethyl] -3-oxo-l, 2,3,4-tetrahydropyrido- [2,3-b] pyrazine-7-carboxamide

248 mg (0.76 mmol) of the compound from Example 38A are dissolved in dichloromethane, 155 mg (1.52 mmol) of ethyl glyoxylate and 22 μl (0.38 mmol) of acetic acid are added, and the mixture is stirred at RT for 48 h. 143 mg (2.3 mmol) of sodium cyanoborohydride and a further 22 μl (0.38 mmol) of acetic acid are then added and the mixture is stirred at RT for 18 h. For working up, the solvent is removed in vacuo. The cleaning takes place by means of preparative HPLC (method 8). 111 mg (40% of theory) of the product are obtained.

MS (ESIpos): m / z = 367 (M + H) ⁺ LCMS (method 6): R _t = 2.29 min

Example 40A

4-Cyclopropyl-N - [(IS) -l- (4-methoxyphenyl) ethyl] -l, 2,3,4-tetrahydropyrido [2,3-b] pyrazine-7-carboxamide

111 mg (0.26 mmol) of the compound from Example 39A are dissolved in dichloromethane, 46 mg (1.2 mmol) of lithium aluminum hydride are added and the mixture is heated under reflux for 5 h. For working up, sodium hydroxide solution (10% w / w) is slowly metered in and stirred until a granular precipitate has formed. This is washed three times with THF and the combined filtrates are concentrated in vacuo. 72 mg (30% of theory) of the product are obtained, which is used without delay in the next reaction.

MS (ESIpos): m / z = 353 (M + H) ⁺ LCMS (method 7): R _t = 1.35 min

Example 41A

1 - (Chloroacetyl) -4-cyclopropyl-N - [(IS) - 1 - (4-methoxyphenyl) ethyl] - 1, 2,3, 4-tetrahydropyrido [2,3-b] pyrazine-7-carboxamide

64 mg (0.082 mmol) of the compound from Example 40A are dissolved in 63 ml of dichloromethane, 13 μl (0.16 mmol) of chloroacetyl chloride and 17 μl (0.12 mmol) of triethylamine are added at 0 ° C. and the mixture is stirred for 2 hours, the reaction mixture being brought to RT can be heated. For working up, the reaction mixture is washed once with 1 normal hydrochloric acid and three times with water, dried over sodium sulfate and concentrated in vacuo. The substance is purified on silica gel (mobile phase: cyclohexane / ethyl acetate 5/1). 26 mg (63% of theory) of the product are obtained, which is used without delay in the next reaction.

MS (ESIpos): mz = 429 (M + H) ⁺ LCMS (method 2): R _t = 2.38 min

From examples;

example 1

l-Cyclopropyl-4- {N - [(lS) -l, 2-dimethylpropyl] glycyl} -N - [(lS) -l- (4-methoxy-ρhenyl) ethyl] -2-methyl-l, 2, 3,4-tetrahydroquinoxaline-6-carboxamide

89 mg (0.23 mmol) of the compound from Example 25A are introduced under argon in 5 ml of DMF and at room temperature with 51 mg (0.34 mmol) of (S) - (-) - (4-methoxyphenyl) ethylamine, 50 mg (0.26 mmol) EDC, 17 mg (0.12 mmol) HOBt, 5 mg (0.04 mmol) DMAP and finally 0.084 ml (0.77 mmol) 4-methyl-morpholine were added and the mixture was stirred at room temperature for 16 h. The reaction mixture is concentrated in vacuo and by means of preparative HPLC (column: Phenomenex Luna C18 5 μm, 250 mm × 20 mm, eluent: 54.8% water, 45% acetonitrile, 0.2% trifluoroacetic acid; oven: RT; flow: 25 ml / min; UV detection: 210 nm) separately. 14.3 mg (13% of theory) of the product are obtained.

^] H NMR (400 MHz, DMSO-d ₆ ): δ = 0.39-0.52 (m, IH), 0.68-1.16 (m, 14H), 1.42 (d, 3H), 1.48-1.88 (m, 2H), 2.24 -2.42 (m, IH), 3.29 (s, 2H), 3.37-4.12 (m, 8H), 5.09 (m, IH), 6.86 (d, 2H), 7.10

(m, IH), 7.26 (m, 2H), 7.54-7.99 (m, 2H), 8.34 (d, IH). MS (ESIpos): m / z = 493 (M + H) ⁺ LCMS (method 3): R _t = 1.83 min

Example 2

l-Cyclopropyl-4- {N - [(lS) -l, 2-dimethylpropyl] glycyl} -N- [l- (6-methoxypyridin-3-yl) ethyl] - l, 2,3,4-tetrahydroquinoxaline- 6-carboxamide

The preparation is carried out using the compound from Example 15A and [1- (6-methoxypyridin-3-yl) ethyl] amine by the method described for Example 1. The cleaning takes place by means of preparative HPLC (method 8).

Η NMR (400MHz, DMSO-d ₆ ): δ = 0.52-0.68 (m, 2H), 0.75-1.28 (m, 12H), 1.48 (d, 3H), 1.86-2.21 (m, IH), 2.58 ( m, IH), 3.10 (m, 2H), 3.44 (m, 2H), 3.82 (s, 3H), 4.23 (m, 2H), 5.13 (m, IH), 6.78 (d, IH), 7.16 (d , IH), 7.72 (m, 2H), 8.14 (d, IH), 8.44 (br s, IH), 8.75 (br s, IH) MS (ESIpos): m / z = 480 (M + H) ⁺ LCMS (Method 3): R _t = 1.59 min Example 3 l-Cyclopropyl-4- {N - [(lS) -l, 2-dimethylpropyl] glycyl} -N - [(lS) -l- (4-methoxyphenyl ) pentyl] - 1, 2,3, 4-tetrahydroquinoxaline-6-carboxamide

The preparation is carried out using the compound from Example 15A and [(IS) -1- (4-methoxyphenyl) pentyl] amine by the method described for Example 1. The cleaning is carried out by means of preparative HPLC (method 8). Η NMR (300MHz, CDC1 ₃ ): 0.63-0.66 (m, 2H), 0.86-0.95 (m, 14H), 1.25-1.68 (m, 4H), 1.67-1.89 (m, 2H), 2.00-1.91 ( m, 2H), 2.54-2.50 (m, 2H), 3.42 (m, 2H), 3.51-3.57 (d, IH), 3.66-3.75 (d, IH), 3.79 (s, 3H), 3.90-3.86 ( , IH), 5.05-5.12 (m, IH), 6.24 (s, br, IH), 6.86 (d, 2H), 7.13 (d, IH), 7.27-7.31 (m, 3H), 7.59 (d, IH ), 7.65 (s, br, IH). MS (ESIpos): m / z = 521 (M + H) ⁺ LCMS (method 2): R _t = 2.50 min

Example 4

1-cyclopropyl-4- {N - [(1 S) - 1, 2-dimethylpropyl] glycyl} -3 -isopropyl-N - [(1 S) - 1 - (4-methoxyphenyl) ethyl] -1, 2,3,4-tetrahydroquinoxaline-6-carboxamide

The preparation is carried out using the compound from Example 16A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1. The cleaning takes place by means of preparative HPLC (method 8).

Η NMR (200 MHz, DMSO-d ₆ ): δ = 0.40-0.50 (m, IH), 0.63-0.98 (m, 17H), 1.09 (m, IH), 1.29

(m, IH), 1.44 (d, 3H), 1.53 (, IH), 1.75 (m, IH), 2.32 (m, IH), 2.57 (m, IH), 3.10-3.28 (m, 3H),

3.40-3.51 (m, 2H), 3.73 (s, 3H), 5.62 (m, IH), 6.86 (m, 2H), 7.11 (d, IH), 7.29 (d, 2H), 7.59-7.95

(m, 3H), 8.32 (d, IH).

MS (ESIpos): m / z = 521 (M + H) ⁺

HPLC (method 1): R _t = 4.68 min Example 5

1-cyclopropyl-4- {N - [(IS) -l, 2-dimethylpropyl] glycyl} -N - [(IS) -l - (4-methoxyphenyl) ethyl] - l, 2,3, 4-tetrahydroquinoxaline-6-carboxamide

The preparation is carried out using the compound from Example 15A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1. The cleaning takes place by means of preparative HPLC (method 8).

Η NMR (200 MHz, DMSO-d ₆ ): δ = 0.53-0.63 (m, 2H), 0.63-0.98 (m, 10H), 1.43 (d, 3H), 1.56 (m, IH), 1.75 (m , IH), 2.36 (m, IH), 2.55 (m, IH), 3.35-3.82 (m, 10H), 5.60 (m, IH), 6.86 (m, 2H), 7.11 (d, IH), 7.29 ( d, 2H), 7.59-8.05 (m, 2H), 8.35 (d, IH). MS (ESIpos): m / z = 479 (M + H) ⁺ HPLC (method 1): R _t = 4.36 min

Example 6

l-Cyclopropyl-4- {N - [(lS) -l, 2-dimethylpropyl] glycyl} -N - [(lS) -l- (4-methoxy-ρhenyl) ethyl] -3-methyl-l, 2, 3,4-tetrahydroquinoxaline-6-carboxamide

The preparation is carried out using the compound from Example 17A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1. The cleaning takes place by means of preparative HPLC (method 8).

'H NMR (200 MHz, DMSO-d ₆ ): δ = 0.46-0.59 (m, IH), 0.59-0.71 (m, IH), 0.72-1.26 (m, 13H), 1.39-1.48 (m, 3H ), 2.08 (m, IH), 2.60 (m, IH), 3.02-3.49 (m, 7H), 3.71 (s, 3H), 4.40 (m, IH), 5.62 (m, IH), 6.86 (m, 2H), 7.15 (d, IH), 7.29 (dd, 2H), 7.73 (m, IH), 8.35 (m, IH), 8.72 (m, IH). MS (ESIpos): m / z = 493 (M + H) ⁺ LCMS (method 3): R _t = 1.77 min

Example 7

1-Cyclopropyl-4- {N - [(1 S) - 1, 2-dimethylpropyl] glycyl} -N- [1 - (6-methoxy-pyridin-3-yl) ethyl] -3-methyl-1,2 , 3,4-tetrahydroquinoxaline-6-carboxamide

The preparation is carried out using the compound from Example 17A and [1- (6-methoxypyridin-3-yl) ethyl] amine by the method described for Example 1. The cleaning takes place by means of preparative HPLC (method 8). MS (ESIpos): m / z = 494 (M + H) ⁺ HPLC (method 1): R _t = 3.92 min

Example 8

4-Cyclopropyl-l- {N - [(IS) -l, 2-dimethylpropyl] glycyl} -N - [(IS) -l- (4-methoxyphenyl) ethyl] - 1, 2,3, 4- tetrahydropyrido [2,3-b] pyrazin-7-carboxamide

The preparation takes place with the compound from Example 41 A and (S) -3-methyl-2-butylamine according to the method described for Example HA. The cleaning takes place by means of preparative HPLC (method 8).

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.61-0.71 (m, 2H), 0.83-0.98 (m, 8H), 1.07-1.28 (m, 4H), 1.44 (d, 3H), 2.10 (m, IH), 2.88 (m, IH), 3.11 (m, IH), 3.52 (m, 2H), 3.74 (s, 3H), 3.75-4.40 (m, 4H), 5.11 (quintet, IH), 6.86 (d, 2H), 7.29 (d, 2H), 8.31-8.62 (m, 2H), 8.76 (m, IH). MS (ESIpos): m / z = 480 (M + H) ⁺ LCMS (method 2): R, = 1.91 min

Example 9

l-Cyclopropyl-4- {N - [(lS) -l, 2-dimethylpropyl] glycyl} -3-ethyl-N - [(lS) -l- (4-methoxyphenyl) ethyl] -l, 2, 3,4-tetrahydroquinoxaline-6-carboxamide

The preparation is carried out using the compound from Example 18A and (S) - (-) - (4-methoxyphenyl) ethylamine by the method described for Example 1. The cleaning takes place by means of preparative HPLC (method 8).

Η NMR (200 MHz, DMSO-d ₆ ): δ = 0.46-0.59 (m, IH), 0.60-1.19 (m, IH), 0.72-1.26 (m, 16H), 1.27-1.65 (m, 5H) , 1.90 (m, IH), 2.33 (m, IH), 2.56 (m, IH), 3.18-3.66 (m, 3H), 3.71 (s, 3H), 4.70 (m, IH), 5.12 (m, IH ), 6.86 (m, 2H), 7.11 (d, IH), 7.29 (dd, 2H), 7.61-8.05 (m, 2H), 8.37 (d, IH). MS (ESIpos): m / z = 507 (M + H) ⁺ LCMS (method 2): R _t = 2.32 min

Assessment of physiological effectiveness

Abbreviations:

DMEM Dulbecco's Modified Eagle Medium

FCS Fetal Calf Serum

HEPES 4- (2-hydroxyethyl) -l-iperiperazineethanesulfonic acid

1. in v tro tests to determine M2 activity and selectivity

a) Cellular, functional in vitro test

The identification of agonists of the human M2 acetylcholine receptor (M2AChR) and the quantification of the effectiveness of the substances described here was carried out using a recombinant cell line. The cell is originally derived from an ovary epithelial cell of the hamster (Chinese Hamster Ovary, CHO Kl, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell line constitutively expresses a modified form of the calcium-sensitive photoprotein aequorin, which after reconstitution with the co-factor coelenterazine emits light when the free calcium concentration in the inner mitochondrial compartment increases (Rizzuto R, Simpson AW, Brini M, Pozzan T .; Nature 358 (1992) 325-327). In addition, the cell is stably transfected with the human M2AChR (Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon, DJ, EMBO Journal 6 (1987) 3923-3929) and the gene that is responsible for the promiscuous G _π ₆ coded protein (Amatruda TT, Steele DA, Slepak VZ, Simon MI, Proceedings in the National Academy of Science USA 88 (1991), 5587-5591). The resulting M2AChR test cell responds to stimulation of the recombinant M2ACh receptor with an intracellular release of calcium ions, which can be quantified by the resulting aequorin luminescence with a suitable luminometer (Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17 (1996) 235-237).

To determine the in vzYro selectivity with regard to the muscarinic acetylcholine receptor subtypes Ml to M5, corresponding CHO Kl cells are used, which likewise have the gene of the calcium-sensitive photoprotein aequorin and the gene of the Ml, M3 or M5 receptor subtype or in the case of M4 receptor subtypes are additionally stably transfected with the gene of the promiscuous G _α ι ₆ protein.

Test procedure: The cells are placed in culture medium (DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES; Gibco Cat. # 21331-020; belongs to: Invitrogen GmbH, 76131 the day before the test Karlsruhe) plated in 384 (or 1536) well microtiter plates and kept in a cell incubator (96% humidity, 5% v / v C0 ₂ , 37 ° C). On the test day, the culture medium is replaced by a Tyrode solution (in mM: 140 NaCl, 5 KC1, 1 MgCl ₂ , 2 CaCl ₂ , 20 glucose, 20 HEPES), which also contains the co-factor coelenterazine (50 μM), and the microtiter plate then incubated for another 3-4 hours. Immediately after transfer of the test substances into the holes in the microtiter plate, the resulting light signal is measured in the luminometer. The results are shown in Table A:

Table A

b) Binding studies on human muscarinic acetylcholine receptors

Stably transfected CHO Kl cells which express the human muscarinic M2 receptor are, after reaching 80% confluency, in 10 ml binding buffer (20 mM 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid, 5 mM magnesium chloride, pH 7.4) per 175 cm ² cell culture bottle suspended and homogenized using an Ultra-Turrax device. The homogenates are centrifuged at 1000 g and 4 ° C for 10 minutes. The supernatant is removed and centrifuged at 20,000 g and 4 ° C. for 30 minutes. The membrane sediment with the M2 receptors is taken up in 10 ml of binding buffer and stored at -70 ° C.

For the binding experiment, 2 nM ³ H-oxotremorin M (3200 GBq / mmol, PerkinElmer) are incubated for 60 minutes with 100-1000 μg / ml M2 membranes per batch (0.2 ml) in the presence of the test substances at room temperature. The incubation is stopped by centrifugation at 10 000 g for 10 minutes and then washing with 0.1% bovine serum albumin in binding buffer at 4 ° C. It is centrifuged for another 10 minutes at 10000 xg and 4 ° C. The sediment is resuspended in 0.1 ml of 1N sodium hydroxide solution and transferred to scintillation tubes. After adding 4 ml of Ultima Gold scintillator, the radioactivity bound to the membranes is quantified using an LS6000 IC scintillation counter from BeckmanCoulter. ed. The non-specific binding is defined as radioactivity in the presence of 10 μM oxotremorine M and is usually less than 5% of the total radioactivity bound. The binding data (IC ₅₀ and dissociation constant Ki) are determined using the GraphPad Prism Version 3.02 program.

2. in vivo test for the detection of cardiovascular effects

a) Langendorff heart of the guinea pig

After the chest is opened, anesthetized guinea pigs are removed from the heart and inserted into a conventional Langendorff apparatus. The coronary arteries are perfused at a constant volume (10 ml / min) and the resulting perfusion pressure is registered by a corresponding pressure transducer. A decrease in perfusion pressure in this arrangement corresponds to a relaxation of the coronary arteries. At the same time, the pressure that is developed by the heart during each contraction is measured via a balloon inserted into the left ventricle and another pressure sensor. The frequency of the isolated beating heart is calculated from the number of contractions per unit of time.

b) Blood pressure measurements on anesthetized rats

Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheotomy, a catheter for measuring blood pressure is inserted into the femoral artery. The substances to be tested are administered orally in Transcutol, Cremophor EL, H ₂ 0 (10% / 20% / 70%) in a volume of 1 ml / kg.

c) Effect on the mean blood pressure of awake, spontaneously hypertensive rats

Continuous blood pressure measurements over 24 hours are carried out on spontaneously hypertensive 200-250g free-moving female rats (MOL: SPRD). For this purpose, the animals are chronically implanted with pressure transducers (Data Sciences Inc., St. Paul, MN, USA) in the descending abdominal aorta below the renal artery and the associated transmitter is fixed in the abdominal cavity. The animals are kept individually in type m cages, which are positioned on the individual receiving stations, and are adapted to a 12-hour light / dark rhythm. Water and feed are freely available. For data collection, the blood pressure of each rat is recorded every 5 minutes for 10 seconds. The measuring points are combined for a period of 15 minutes and the average value is calculated from these values. The test compounds are dissolved in a mixture of Transcutol (10%), Cremophor (20%), H ₂ 0 (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight. The test doses are between 0.3-30 mg / kg body weight. d) Blood pressure and heart rate measurements on anesthetized dogs

The experiments are carried out in dogs (Mongrel) of both sexes with a body weight between 20 and 30 kg. Anesthesia is slow i.v. Injection of 25 mg / kg thiopental (Trapanal®) was initiated and continued during the experiment with a continuous infusion of 0.08 mg / kg / h fentanyl (Fentanyl®) and 0.25 mg / kg / h droperidol (Dehydrobenzperidol®). Alloferin (0.02 mg / kg / h) is added as a muscle relaxant. The dogs are artificially ventilated with 1 part laughing gas and 3 parts oxygen. The test substances are administered intravenously via the femoral vein.

A MillarTip catheter for recording left ventricular pressure or calculating contractility is inserted into the left ventricle via the carotid artery. A hollow catheter is inserted into the aorta through the femoral artery and connected to a pressure transducer to measure peripheral blood pressure. After a left thoracotomy, the circumflex ramus (LCX) or the interventricular ramus (LAD) of the left coronary artery is dissected and an electromagnetic flow head is applied to measure the coronary flow. The EKG is recorded via an extremity lead and an EKG amplifier, the heart rate and EKG parameters are determined via the measured ECG. Oxygen saturation at the coronary sinus is determined using a Swan-Gantz oximetry TD catheter.

B. Embodiments of pharmaceutical compositions

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

Tablet:

Composition:

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

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

production:

The mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are dried with the magnesium stearate for 5 min. mixed. This mixture is compressed with a conventional tablet press (tablet format see above). A pressing force of 15 kN is used as a guideline for the pressing.

Oral suspension:

Composition:

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

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

production:

The Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The mixture is stirred for about 6 hours until the swelling of the Rhodigel is complete.

Claims

claims

Compound of formula

in which

A represents (CC ₆ ) alkanediyl which is optionally mono- or disubstituted by hydroxy,

X represents CH or N,

R ^{1 represents} phenyl or pyridyl, phenyl and pyridyl optionally being substituted by 1 to 3 substituents, independently of one another selected from the group consisting of halogen, hydroxy, hydroxycarbonyl, amino, trifluoromethyl, trifluoromefhoxy, nitro, cyano, alkyl, alkoxy, alkylamino , Alkoxycarbonyl, arninocarbonyl and alkylaminocarbonyl,

R ^{4 represents} hydrogen or (CC ₄ ) alkyl,

R ^{s represents} hydrogen or (CC ₄ ) alkyl and their salts, their solvates and the solvates of their salts.

2. A compound according to claim 1, in which

A represents (CC _δ ) alkanediyl,

X represents CH or N, R ^{1 represents} phenyl or pyridyl, where phenyl and pyridyl are optionally substituted by a substituent, independently selected from the group consisting of halogen, hydroxy, amino, alkyl, alkoxy, alkylamino, alkoxycarbonyl, arninocarbonyl and alkylaminocarbonyl,

R ^{2 represents} (C ₃ -C ₆ ) cycloalkyl, R ^{3 represents} (dC ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, alkyl and cycloalkyl optionally being substituted by 1 to 3 substituents independently of one another from the group consisting of hydroxy, trifluoromethyl and (C _r C) alkoxy,

R ^{4 represents} hydrogen or methyl, R ^{5 represents} hydrogen or methyl, and their salts, their solvates and the solvates of their salts.

3. Connection according to one of claims 1 or 2, in which

A represents ethane-1, 1-diyl or pentane-1, 1-diyl, X represents CH or N,

R ^{2 represents} cyclopropyl,

R ^{3 represents} (C ₃ -C ₆ ) alkyl, R ^{4 represents} hydrogen, R represents hydrogen or methyl, and their salts, their solvates and the solvates of their salts.

4. A process for the preparation of a compound of formula (I) as defined in claim 1, characterized in that either

[A] a compound of the formula

in which

R, R, R and R have the meaning given in claim 1, with a compound of the formula

R ^ NH "(HT), in which

A and R ^{1 have} the meaning given in claim 1, or

[B] a compound of the formula

in which

R ¹ , R ² , R ⁴ and R ^{5 have} the meaning given in claim 1 and

Y ^{1 represents} halogen, with a compound of the formula

, R ° H ₂ N ^' (V), in which

R ^{3 has} the meaning given in claim 1.

5. A compound of formula (I) as defined in any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

6. Medicament containing a compound of formula (I), as defined in one of claims 1 to 3, in combination with a pharmacologically acceptable auxiliary or carrier.

7. Medicament containing a compound of formula (I), as defined in one of claims 1 to 3, and at least one further active ingredient.

8. Use of a compound of formula (I) as defined in any one of claims 1 to 3 for the manufacture of a medicament.

9. Use of a compound of formula (I), as defined in one of claims 1 to 3, for the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular diseases.

10. A method for controlling cardiovascular diseases in humans and animals> by administering an effective amount of a compound of the formula (I) as defined in one of claims 1 to 3.