GB2404658A - Quinoxalinone derivatives and their use in the treatment of diseases - Google Patents

Abstract

The invention relates to compounds of formula I, and its salts, solvates, and solvates of salts; <EMI ID=1.1 HE=31 WI=68 LX=627 LY=809 TI=CF> <PC>Wherein A is C1-C6-alkanediyl which is optionally substituted 1-2 times by hydroxide or 1-3 times by halogen; R1 is 1,3-benzodioxole or optionally substituted aryl; R2 is optionally substituted cycloalkyl; and R3 is optionally substituted alkyl or cycloalkyl. A process for the preparation of the compounds is disclosed as well as their use in the treatment or prophylaxis of diseases, especially cardiovascular diseases.

Description

Quinoxalinones and their use The invention relates to quinoxalinones, to a process for their preparation and to their use for producing medicaments for the treatment and/or prophylaxis of diseases, especially of cardiovascular disorders. Acetylcholine is the transmitter of the parasympathetic nervous system. This part of the autonomic nervous system has a crucial influence on fundamental processes of a wide variety of organ functions, such as, for example, lung, bladder, stomach and intestine, glands, brain, eye, blood vessels and heart. Acetylcholine itself cannot be used therapeutically because it is very rapidly inactivated by acetylcholin esterase, but its effect can be imitated by direct parasympathomimetic agents such as, for example, carbachol. Active substances which have an agonistic effect like acetylcholine on the muscarinic (M) acetylcholine receptors may thus influence and control numerous functions depending on the organ or tissue system. For example, activation of muscarinic acetylcholine receptors in the brain may influence the memory and learning processes and pain processing. It is possible, for example, by using receptor subtype-specific agonists to reduce via the muscarinic M2 acetylcholine receptor, which is expressed particularly strongly in myocardial cells, the heart rate and the contractility after beta-adrenergic stimulation (B. Rauch, F. Niroomand, J. Eur. Heart. 1991, 12, 76-82). Both effects reduce the myocardial oxygen consumption. Substances of similar structure to the compounds ofthe invention are known in other indications and for other mechanisms of action. Thus, for example, WO 00/00478, EP-A 0 728 481 and EP-A 0 509 398 describe quinoxalinone derivatives for the treatment of HIV infections, DE 4341663 describes quinoxalinone derivatives as endothelin receptor antagonists, WO 98/09987 describes quinoxalinone derivatives as thrombin inhibitors, WO 94/11355 describes 3,4-dlhydro-1-phenyl-2(1H)- quinoxalinone derivatives for the treatment of cardiovascular disorders and US 3,654,275 describes quinoxaline carboxamides as compounds having antiinflammatory activity. It is an object of the present invention to provide medicaments for the treatment of disorders, especially cardiovascular disorders. The present invention relates to compounds of the formula

in which A is C1-C6-alkanediyl which is optionally substituted once or twice by hydroxyl or once, twice or three times by halogen, R is 1,3-benzodioxole or aryl, where aryl is optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxyl, hydroxycarbonyl, ammo, trifluoromethyl, trifluoromethoxy, nitro, cyano, optionally hydroxyl-substituted alkyl, optionally cycloalkyl-substituted alkoxy, phenoxy, alkylamino, optionally phenyl-substituted alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aminosulphonyl, alkylsulphonyl, alkylsulphonylamino, trifluoromethylsulphonylamino and morpholinyl, R is cycloalkyl which is optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of halogen,hydroxyl, amino, alkyl, alkoxy and alkylamino, R is alkyl or cycloalkyl, where alkyl and cycloalkyl are optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxyl, amino, trifluoromethyl, alkoxy, alkylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl, and cycloalkyl may optionally also be substituted by alkyl which in turn may be substituted by hydroxyl, and their salts, their solvates and the solvates of their salts. Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, compounds mentioned hereinafter as exemplary embodiment(s) and their salts, solvates and solvates of the salt where the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts. The compounds of the invention may exist, depending on their structure, in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers. The invention also relates, depending on the structure of the compounds, to tautomers of the compounds. Salts which are preferred for the purposes of the invention are physiologically acceptable salts of the compounds of the invention. Physiologically acceptable salts of the compounds (I) of the invention comprise acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds (I) of the invention also comprise salts of conventional bases such as, for example and advantageously, 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 with 1 to 16 C atoms, such as, for example and preferably, ethyl amine. diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine. Solvates refer for the purposes of the invention to those forms of the compounds of the invention which form a complex in the solid or liquid state through coordination with solvent molecules. Hydrates are a specific type of solvates in which the coordination takes place with water. For the purposes of the present invention, unless otherwise specified, the substituents have the following meaning: Alkyl per se and talk' and `alkyl' in alkoxy, alkylamino, alkylaminocarbonyl, alkoxycarbonyl, alkylsulphonyl and alkylsulphonylamino stand for a linear or branched alkyl radical with, usually, 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 by way of example and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Alkylamino is an alkylamino radical with one or two alkyl substituents (chosen independently of one another), by way of example and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylarnino, n-hcxylamino, N,N dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-

N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino. Alkylaminocarbonyl is an alkylaminocarbonyl radical with one or two alkyl substituents (chosen independently of one another), by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, //.AT-dimethylaminocarbonyl, N,N diethylaminocarbanyl, N-

n-propylaminocarbonyl, N-t-butyl-N-methylam.inocarbonyl, N-ethyl-N-npcntylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl. Alkoxycarbonyl is by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl. Alkylsulphonyl is by way of example and preferably methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, tert-butylsulphonyl, n-pentylsulphonyl and n-hexylsulphonyl. Alkylsulphonylamino is by way of example and preferably methylsulphonylamino, ethylsulphonylamino, n-propylsulphonylamino, isapropylsulphonylamino, tertbutylsulphonylamino, n-pentylsulphonylamino and n-hexylsulphonylamino. Alkyldiyl is a straight-chain or branched saturated alkanediyl radical with 1 to 6 carbon atoms. A straight-chain or branched alkanediyl radical with 1 to 4 carbon atoms is preferred. Mention may be made by way of example and preferably of methylene, ethane-l,2-diyl, ethane-l,l-diyl, propane-1,3-diyl, propane-l,2-diyl, propane-2,2-diyl, butane-l,4-diyl, butane- 1,3-diyl, butane-2,4-diyl, pentane-1,5-diyl, pentane-2,4-diyl, 2-methylpentane-2,4-diyl. Cycloalkyl is a cycloalkyl group with, usually, 3 to 8, preferably 3 to 6, carbon atoms, by way of example and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Aryl is a mono-, bi- or tricyclic aromatic, carbocyclic radical with, usually, 6 to 14 carbon atoms, by way of example and preferably phenyl, naphthyl and phenanthrenyl. Halogen is fluorine, chlorine, bromine and iodine. If radicals in the compounds of the invention are substituted, the radicals may, unless otherwise specified, be substituted one or more times identically or differently. Substitution with up to three identical or different substituents is preferred. Substitution with one substituent is very particularly preferred. Preference is given to compounds of the formula (I) in which A is (C1)-C6)-alkanediyl which is optionally substituted once by hydroxyl or three times by fluorine, R is 1,3-benzodioxole or phenyl, where phenyl is optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxyl, hydroxycarbonyl, amino, trifluoromethyl, trifluoromethoxy, optionally hydroxyl-substituted (C1-C6)-alkyl, optionally cyclopropyl-substituted (C1-C4)-alkoxy, phenoxy, (C1-C4)-alkylarnino, optionally phenyl-substituted (C1C4)-alkoxycarbonyL aminosulphonyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkylsulphonylamino, trifluoromethylsulphonylamino and morpholinyl, R is (C3-C6)-cycloalkyl, R is (CI-C6)-alkyl or (C3-C6)-cycloalkyl,where alkyl and cycloalkyl are optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of hydroxyl, trifluoromethyl and (CI-C4)alkoxy, and cycloalkyl may optionally also be substituted by (C1-C6)-alkyl which may in turn be substituted by hydroxyl, and their salts, their solvates and the solvates of their salts. Compounds of the formula (I) in which A is pentane-l,l-diyl or 2-hydroxyethane1,1-diyl are particularly preferred. Compounds of the formula (I) in which R -A- is a radical of the formula

where * is the point of attachment to the nitrogen atom are likewise particularly preferredCompounds of the formula (I) in which R' is phenyl are likewise particularly preferred. Compounds of the formula (I) in which R is cyclopropyl or cyclobutyl are likewise particularly preferred. Compounds of the formula (I) in which R is cyclohexyl or cyclopentyl which are optionally substituted by 1 or 2 substituents selected independently of one another from the group consisting of methyl and ethyl are likewise particularly preferred. Very particular preference is given to compounds of the formula (I) in which A is pentane-1,1-diyl or 2-hydroxyethane-1,1-diyl, R is phenyl which is optionally substituted by 1 or 2 substituents selected independently of one another from the group consisting of methyl, ethyl, methoxy and ethoxy, R is cyclopropyl or cyclobutyl, R is cyclohexyl or cyclopentyl, which are optionally substituted by 1 or 2 substituents selected independently of one another from the group consisting of methyl, ethyl, methoxy and ethoxy, and their salts, their solvates and the solvates of their salts. The definitions of radicals indicated specifically in the respective combinations or preferred combinations of radicals are replaced irrespective of the particular combinations indicated for the radicals as desired also by definitions of radicals of another combination. Combinations of two or more of the abovementioned preferred ranges are very particularly preferred. The invention further relates to a process for preparing the compounds of the formula (I), characterized in that compounds of the formula

in which R and R have the meaning indicated above, are reacted with compounds of the formula

in which A and R have the meaning indicated above, in the presence of conventional condensing agents, where appropriate in the presence of a base. The reaction takes place where appropriate in inert solvents, preferably in a temperature range from room temperature to 50[deg]C under atmospheric pressure. Examples of inert solvents are halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2dichloroethane or trichloroethylene, 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, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulphoxide, acetonitrile or pyridine, with preference for tetrahydrofuran, dimethylformamide or methylene chloride. Examples of conventional condensing agents are carbodiimides such as, for example, N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide,

carbonyl compounds such as carbonyidiimidazole, or 1,2-oxazolium compounds such as 2-elhyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-lethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride or

(HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), or mixtures thereof. Examples of bases are alkali metal carbonates such as, for example, sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines, e.g. triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and diisopropylethyl.amine in methylene chloride is preferred. Compounds of the formula (III) are known or can be prepared in analogy to known processes. The compounds of the formula (II) are prepared by reacting compounds of the formula

in which R has the meaning indicated above, and X is halogen, preferably bromine or chlorine, initially with compounds of the formula

in which R has the meaning indicated above, and subsequently with trifluoroacetic acid to cleave the tert-butyl ester. The reaction in the first stage takes place where appropriate in inert solvents, where appropriate in the presence of a base, preferably in a temperature range from 0[deg]C to 50.C under atmospheric pressure. Examples of inert solvents are halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethanc, 1,2- dichloroethane or trichloroethylene, 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, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethyl sulphoxide, acetonitrile or pyridine, with preference for tetrahydrofuran or methylene chloride. Examples of bases are alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium or potassium carbonate, or amides such as lithiumdiisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine. The reaction in the second stage takes place in inert solvents, preferably in a temperature range from 0[deg]C to 50[deg]C under atmospheric pressure. Examples of inert solvents are halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2dichloroethane or trichloroethylene, or other solvents dimethylformamide or tetrahydrofuran, with preference for methylene chloride. Compounds of the formula (V) are known or can be prepared in analogy to known processes. Compounds of the formula (IV) are prepared by reacting compounds of the formula

in which R has the meaning indicated above, with compounds of the formula

in which X has the meaning indicated above, and X is halogen, preferably bromine or chlorine. The reaction takes place in two stages. The reaction in the first stage takes place in inert solvents with 2 equivalents of the compounds of the formula (VII) based on the compounds of the formula (VI), in the presence of 2 equivalents of a base, preferably in a temperature range from 0[deg]C to 50[deg]C under atmospheric pressure. The second stage follows without working up the reaction mixture and takes place by adding another base. Examples of inert solvents are halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2dichloroethane or trichloroethylene, 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, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethyl sulphoxide, acetonitrile or pyridine, with preference for methylene chloride. Examples of bases are alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium or potassium carbonate, or amides such as lithiumdiisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferably diisopropylcthylamine or triethylamine for the first stage, and preferably DBU for the second stage. Compounds of the formula (VII) are known or can be prepared in analogy to known processes. Compounds of the formula (VI) are prepared by reacting compounds of the formula

in which R has the meaning indicated above, with reducing agents in the presence of a catalyst. The reaction takes place in inert solvents, preferably in a temperature range from room temperature to 50[deg]C under atmospheric pressure. Examples of inert solvents are alcohols such as methanol, ethanol, propanol, isopropanol or butanol or ethyl acetate or diethyl ether, with preference for methanol or ethanol. The 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. Compounds of the formula (VIII) are prepared by reacting the compound of the formula

with compounds of the formula R -NH2 (X), in which R has the meaning indicated above, where appropriate in the presence of a base. The reaction takes place in inert solvents, preferably in a temperature range from room temperature to 50[deg]C under atmospheric pressure. Examples of inert solvents are halohydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2dichloroethane or trichloroethylene, 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, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, 2-butanone, dimethyl sulphoxide, acetonitrile or pyridine, with preference for tetrahydrofuran or methylene chloride. Examples of bases are alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium or potassium carbonate, or amides such as lithiumdiisopropylarnide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine. Compounds of the formula (IX) and (X) are known or can be prepared in analogy to known processes. The preparation of the compounds of the invention can be illustrated by the following synthesis scheme. Synthesis scheme:

≈F. Zaragoza, H. Stephensen, J. Org. Chem., 1999, 64, 2555-2557 describe the solid-phase synthesis of analogous carboxylic acid derivatives @ Review of coupling methods: Y.S. Klausner, M. Bodansky, Synthesis 1972, 453-463. The compounds of the invention show a valuable range of pharmacological and pharmacokinetic effects which could not have been predicted. They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals. They are distinguished as agonists of the muscarinic M2 acetycholine receptor. The compounds of the invention can by reason of their pharmacological properties by employed alone or in combination with other active ingredients for the treatment and/or prophylaxis of cardiovascular diseases, especially of coronary heart disease, angina pectoris, myocardial infarction, stroke, ateriosclerosis, essential, pulmonary and malignant hypertension, heart failure, heart failure, cardiac arrythniias or thromboembolic disorders. They are additionally suitable for the treatment and/or prophylaxis of disorders of the eye (glaucoma), stomach and intestines (atonias), of the brain (e.g. Parkinson's disease, Alzheimer's disease, chronic sensation of pain), kidney failure or erectile or renal dysfunctions. The present invention further relates to medicaments which comprise a compound of the invention, preferably together with one or more pharmacologically acceptable excipients or carriers, and to the use thereof for the aforementioned purposes. The active ingredient may have systemic and/or local effects. It can for this purpose be administered in a suitable way such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival or otic route or as implant. The active ingredient can be administered for these routes of administration in suitable administration forms. Administration forms suitable for oral administration are known ones which deliver the active ingredient rapidly and/or in a modified manner, such as, for example, tablets (uncoated and coated tablets, e.g. with tablets provided with enteric coatings or film-coated tablets), capsules, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, solutions and aerosols. Parenteral administration can take place with avoidance of an absorption step (intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders. Examples suitable for the other routes of administration are pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops/solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, preparations for the ears and eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, milk, pastes, dusting powders or implants, for example stents. The active ingredients can be converted in a manner known per se into the stated administration forms. This takes place with use of inert, non-toxic, pharmaceutically suitable excipients. These include, inter alia, carriers (for example microcrystalline cellulose), solvents (for example liquid polyethylene glycols), emulsifiers (for example sodium dodecyl sulphate), dispersants (for example polyvinylpyrrolidone), synthetic and natural biopolymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colours (for example inorganic pigments such as iron oxides) or masking flavours and/or odours. It has generally proved advantageous to administer on parenteral administration amounts of about 0.0001 to 10 mg/kg, preferably about 0.001 to 1 mg/kg, of body weight to achieve effective results. The amount on oral administration is about 0.1 to 10 mg/kg, preferably about 0.5 to 5 mg/kg, of body weight. It may nevertheless be necessary where appropriate to deviate from the amount mentioned, in particular as a function of the body weight, route of administration, individual response to the active ingredient, nature of the preparation and time or interval level in which administration takes place. Thus, it may be sufficient in some cases to make do with less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. It may in the event of administration of larger amounts be advisable to divide these into a plurality of individual doses over the day. The percentage data in the following tests and examples are, unless otherwise indicated, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data on liquid/liquid solutions are in each case based on volume. A. Examples Abbreviations: aq. aqueous Boc tert-butoxycarbonyl CDC13 deuterochloroform DIEA diisopropylethylamine DMSO dimethyl sulphoxide DMF dimethylformarnide

eq. equivalent ESI electrospray ionization (in MS)

HOBt 1-hydioxy-1H-benzotriazole x h2O h hour HPLC high pressure, high performance liquid chromatography LC-MS coupled liquid chromatography and mass spectroscopy MS mass spectroscopy MeOH methanol M.p. melting point NMR nuclear magnetic resonance spectroscopy Pd/C palladium/carbon Rf retention index (in TLC) RT room temperature Rt retention time (in HPLC) sat. saturated HPLC and LC-MS methods: Method 1: Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 600 mm x 2 mm, 3.5 Microm; eluent A: 5 ml HClO4/l water, eluent B: acetonitrile; gradient: 0 min 2%B, 0.5 min 2[deg]/aB, 4.5 min 90%B, 6.5 min 90%B; flow rate: 0.75 ml/min, temp.: 30[deg]C, UV detection: 210 nm. Method 2: Instrument: Micromass Platform LCZ, HP1100; column: Symmetry C18, 50 mm x 2.1 mm, 3.5 Microm; eluent B: water + 0.1 % formic acid, eluent A: acetonitrile + 0.1 % formic acid; gradient: 0.0 min 10%A 4.0 min 90%A 6.0 min 90%A; oven: 40[deg]C, flow rate: 0.5 ml/min, UV detection: 208-400 nm. Method 3: Column: Agilent Eclise XDB-8, 150 mm x 4.6 mm, 5Microm; eluent A: water, eluent B: acetonitrile; gadient: 1 min 90%A 4 min 10`%A 5.5 min 10%A; oven: 40[deg]C, flow rate: 2.0 ml/min, UV detection: 210/254 nm. Method 4: Instrument: Micromass Quattro LCZ, HP1100; column: Symmetry C18, 50 mm x 2.1 mm, 3.5 Microm; eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1 % formic acid; gradient: 0.0 min 10%A - 4.0 min 90%A 6.0 min 90%A; oven: 40[deg]C, flow rate: 0.5 ml/min, UV detection: 208-400 nm. Method 5: MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance 2790; column: Symmetry C 18, 50 mm x 2.1mm, 3.5 Microm; eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; gradient: 0.0 min 5%B -> 4.5 min 90%B -> 5.5 min 90%B; oven: 50[deg]C, flow rate: 1.0 ml/, UV detection: 210 nm. Method 6: Instrument: Micromass Platform LCZ, HP1100; column: Symmetry C18, 50 mm x 2.1 mm, 3.5 Microm; eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; gradient: 0.0 min 90%A 4.0 min 10%A 6.0 min 10%A; oven: 40[deg]C, flow rate: 0.5 ml/min, UV detection: 208-400 nm. Method 7: Instrument: Micromass Quattro LCZ. HP 1100; column: Symmetry C18, 50 mm x 2.1 mm, 3.5 Microm; eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; gradient: 0.0 min 90%A 4.0 min 10%A 6.0 min 10% A; oven: 40[deg]C, flow rate 0.5 ml/min, UV detection: 208-400 run. Method 8: Instrument: MS Micromass ZQ; HPLC: Waters Alliance 2790; column: Symmetry C 18, 50 mm x 2.1 mm, 3.5 Microm; eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; gradient: 0.0 min 10%B 3.5 min 90%B 5.5 min 90%B; oven: 50[deg]C, flow rate: 0.8 ml/min, UV detection: 210 nm. Method 9: MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 Microm; eluent A: water + 500 Microl of 50% formic acid; eluent B: acetonitrile + 500 Microl of 50% formic acid/I; gradient: 0.0 min 5%B 2.0 min 40%B 4.5 min 90%B 5.5 min 90%B; oven: 45[deg]C, flow rate: 0.0 min 0.75 ml/min 4.5 min 0.75 ml 5.5 min 5.5 min 1.25 ml; UV detection: 210 nm. Method 10: Instrument: Micromass Quattro LCZ with HPLC Agilent Serie 1100; column: UPTISPHERE HDO, 50 mm x 2.0 mm, 3 Microm; eluent A: 1 1 of water + 1 ml of 50% formic acid, eluent B: 1 1 of acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 min 100%A 0.2 min 100%A 2.9 min 30%A - 3.1 min 10%A 4.5 min 10%A; oven: 55[deg]C, flow rate: 0.8 ml/min, UV detection: 208-400 nm. Method 11: Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm x 2 mm, 3.5 Microm; eluent A: 5 ml HCO4/l water, eluent B: acetonitrile; gradient: 0 min 2%B, 0.5 min 2%B, 4.5 min 90%B, 9 min 90%B; flow rate: 0.75 ml/min, temp.: 30[deg]C, UV detection: 210 nm. Method 12: Instrument: Micromass Quattro LCZ, with HPLC Agilent Serie 1100; column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 Microm; eluent A: 11 water + 1 ml of 50% formic acid, eluent B: 1 acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 min 100%A 0.2 min 100%A 2.9 min 30%A 3.1 min 10%A 4.5 min 10%A; oven: 55[deg]C, flow rate: 0.8 ml/min, UV detection: 208-400 nm. Method 13: Instrument: Micromass Quattro LCZ, with HPLC Agilent Serie 1100; column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 Microm; eluent A: 1 1 water + 1 ml of 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml of 50% formic acid; gradient: 0.0 min 100%A 0.2 min 100%A 2.9 min 30%A -> 3.1 min 10%A 4.5 min 10%A; oven: 55[deg]C, flow rate: 0.8 ml/min, UV detection: 208-400 nm. Method 14: MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance 2790; column: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 Microm; eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; gradient: 0.0 min 5%B 2.0 min 40%B - 4.5 min 90%B 5.5 min 90%B; oven: 45[deg]C; flow rate: 0.0 min 0.75 ml/min 4.5 min 0.75 ml/min 5.5 min 1.25 ml/min; UV detection: 210 nm. Starting compounds:

Example I tert-Butyl 4-fluoro-3-nitrobenzoate

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

Example II H NMR (300 MHz, DMSO-d6): 8 = 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): Rt = 5.07 min tert-Butyl 4-(cyclopropylamine)-3-nitrobenzoate

7.8 g (32.3 mmol) of the compound from Example I are introduced into 150 ml of tetrahydrofuran. At 0[deg]C, a solution of 3.88 g (67.9 mmol) of cyclopropylamine in 50 ml of tetrahydrofuran is added. The mixture is stirred at OOC for 30 minutes and 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. The solution is dried over sodium sulphate and concentrated in vacuo. 8.95 g (99% of theory) of product are obtained. 'H NMR (300 MHz, DMSO-d6): = 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+NH4)+ HPLC (method 1): Rt = 5.47 min Alternative synthesis to Example II: 1 g (3.88 mmol) of the compound from Example XXI is introduced into tetrahydrofuran (15 ml). 0.44 g (7.76 mmol) of cyclopropylamine is added at room temperature. The solution is stirred at 55[deg]C for 2 hours. The mixture is then poured into ice-water (50 ml). The precipitated solid is filtered off with suction and dried. 0.65 g (58% of theory) of product is obtained. The compounds are listed in Table 1 are prepared in analogy to the compound from Example II from the appropriate starting compounds.

Example V Table 1

8.85 g (31.8 mmol) of the compound from Example II are introduced into 400 ml of methanol under an argon atmosphere, and 0.30 g (1.33 mmol) of palladium on activated carbon (10% Pd) is added. The mixture is stirred under a hydrogen atmosphere at atmospheric pressure overnight. The mixture is filtered through Celite, and the filtrate is concentrated in vacuo. The product resulting after drying under high vacuum for 2 hours (8.20 g, 94% of theory) is reacted further without delay. H NMR (200 MHz, DMSO-d6): 8 = 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, IH) MS (ESIpos): m/z = 249 (M+H) HPLC (method 1): Rt = 4.18 min The compounds listed in Table 2 are prepared in analogy to the compound from Example V from the appropriate starting compounds. Ethanol is used as solvent. The resulting products are where possible reacted further without delay.

Example VIII Table 2

carboxylate

7.90 g (31.8 mmol) of the compound from Example V are introduced into 200 ml of dichloromethane and, at 0[deg]C, 8.98 g (79.5 mmol) of chloroacetyl chloride are added. The mixture is stirred at room temperature for 30 minutes. At 0[deg]C, 11.2 ml (79.5 mmol) of triethylamine are added. The mixture is stirred at room temperature for 4 hours. Then 7.12 ml (7.26 g, 47.7 mmol) of l,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 by chromatography 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.

Example IX H NMR (400 MHz, CDC13): = 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 (DC1): m/z = 382 (M+NH4)+ HPLC (method 1): Rt = 4.72 min

carboxylate

Preparation takes place in analogy to Example VIII from the appropriate starting compounds. The mixture is worked up by washing three times with 100 ml of water and once with 100ml of saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated in vacuo. The residue is purified by chromatography on silica get (mobile phase gradient cyclohexane cyclohexane/ethyl acetate 2:1).

Example X H NMR (300 MHz, DMSO-d6); 8 = 1.45 (d, 6H), 1.54 (s, 9H), 4.37 (s, 2H), 4.51 (br. s, 2H), 4.61 (quintet, 1H), 7.49 (d, 1 H), 7.81 (dd, 1H), 8.12 (d, 1H) MS (DCI): m/z = 384 (M+NH4)+ HPLC (method 1): Rt = 4.71 min

carboxylate

Preparation takes place in analogy to Example VIII from the appropriate starting compounds. The mixture is worked up by washing three times with 100 ml of water and once with 100 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated in vacuo. 5.42 g (82% of theory) of dark brown foam are obtained, The product is reacted further without further purification.

Example XI Rf= 0.53 (cyclohexane/ethyl acetate 2:1)

quinoxalinecarboxylate

0.10 g (0.27 mmol) of the compound from Example VIII and 0.07 g (0.82 mmol) of cyclopentylamine are dissolved in 10 ml of tetrahydrofuran, and the mixture is stirred at 40[deg]C for 6 hours. It is left to stand at room temperature for 12 hours. The reaction mixture is concentrated in vacuo. The residue is taken up in 20 ml of ethyl acetate and washed twice with 10 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated in vacuo. The resulting product is reacted further immediately without further purification.

Example XII LCMS (method 2): Rt = 2.85 min MS (ESIpos): m/z = 414 (M+H)+

quinoxalinecarboxylate

4.5 g (12.33 mmol) of the compound from Example VIII and 4.24 ml (3.67 g, 37.0 mmol) of cyclohexylamine are dissolved in 175 rnl of tetrahydrofuran, and the mixture is left to stand at room temperature for 72 h. The reaction mixture is concentrated in vacuo. The residue is taken up in 400 ml of ethyl acetate and washed with water (3 x 100 ml) and once with saturated sodium chloride solution (100 ml). The solution is dried over sodium sulphate and concentrated in vacuo. It is purified by chromatography on silica gel [mobile phase gradient dichloromethane dichloromethane/methanol 7.5% (v/v)]. 5.30 g (92% of theory) of product are obtained.

Example XIII 'HNMR (300 MHz, DMSO-d6): 8 =0.50-0.57 (m, 2H), 0.85-1.90 (m, 12H, 1.54 (s, 9H), 2.22-2.37 (m, 1H), 2.78-2.85 (m, 1H), 3.49 (br. s, 2H), 4.42 (s, 2H), 7.52 (d, 1H), 7.83 (dd, 1H), 8.06 (s, 1H) MS (ESIpos): m/z = 428 (M+H) HPLC (method 1): Rt = 4.42 min

quinoxalinecarboxylate

300 mg (0.82 mmol) of the compound from Example IX and 243 mg (2.45 mmol) of cyclohexylamine are stirred in 10 ml of tetrahydrofuran at room temperature for 16 hours. The reaction mixture is worked up by concentration in vacuo. The residue is purified by chromatography on silica gel [mobile phase gradient: dichloromethane dichloromethane/methanol 7.5% (v/v)].

Example XIV LCMS (method 2): Rt = 3.27 min MS (ESIpos): m/z = 430 (M+H)" tert-Butyl 4-(N-cyclopentylglycyl)-l-isopropyl'2-oxo-l,2,3,4-tetrahydro-6quinoxalinecarboxylate

The compound is prepared in analogy to Example XIII from the appropriate starting compounds.

Example XV LCMS (method 7): Rt = 3.16 min MS (ESIpos): m/z = 416 (M+H)+

quinoxalinecarboxylate

The compound is prepared in analogy to Example XII from the appropriate starting compounds. The resulting crude product is purified by chromatography on silica gel with a mobile phase gradient [dichloromethane dichloromethane/methanol 5% (v/v)]. 701 mg (21% of theory) of product are obtained. H NMR (400 MHz, DMSO-d6): 8 = 0.90-1.24 (m, 6H), 1.54 (s, 9H), 1.45-1.82 (m, 8H), 2.00-2.18 (mn, 2H), 2.22-2.40 (m, 2H), 3.56 (br. s, 2H), 4.37 (br. s, 2H), 4.45 (quintet, 1H), 7.14 (d, 1H), 7.76 (d, 1H), 8.07 (br. s, 1H).

Example XVI

carboxylic acid

0.11 g (0.27 mmol) of the compound from Example XI is mixed with 2 ml of a mixture of trifluoroacetic acid and dichloromethane in the ratio 1:1. The mixture is stirred at room temperature for 30 minutes. The solution is concentrated in vacuo and dried under high vacuum. The residue is taken up in 10 ml of a 1:1 dichloromethane/methanol mixture and stirred with 1 g of solid sodium bicarbonate for 60 minutes. The mixture is diluted with 20 ml of dichloromethane and filtered with suction, and the filtrate is concentrated. The resulting product is reacted further without further purification.

Example XVII LCMS (method 3): Rt = 0.84 min MS (ESIpos): m/z = 358 (M+H)+

carboxylic acid

0.11 g (0.27 mmol) of the compound from Example XII is mixed with 2 ml of a mixture of trifluoroacetic acid and dichloromethane in the ratio 1:1. The mixture is stirred at room temperature for 30 minutes. The solution is concentrated in vacuo and dried under high vacuum. The residue is taken up in 10 ml of a 1:1 dichloromethane/methanol mixture and stirred with 1 g of solid sodium bicarbonate for 60 minutes. The mixture is diluted with 20 ml of dichloromethane and filtered with suction, and the filtrate is concentrated. The resulting product is reacted further without further purification. LCMS (method 4): Rt = 2.64 min MS (ESIpos): m/z = 374 (M+H)+ The compounds listed in Table 3 are prepared in analogy to Example XVI from the appropriate starting compounds and either immediately reacted further or purified by preparative HPLC (column material: GROM-SIL 120 OSD4 HE, 10 m; mobile phase gradient acetonitrile:water 10:90 95:5).

Example XXI Table 3

tert-Butyl 4-chloro-3-nitrobezoate

10 g (45.45 mmol) of 4-chloro-3-nitrobenzoyl 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 at room temperature for one hour. The mixture is then poured in portions into ice-water (500 ml). The precipitated solid is filtered off with suction and dried. 7.1 g (60% of theory) of product are obtained. H NMR (300 MHz, DMSO-d6): = 1.59 (s, 9H), 7.9 (dd, 1H), 8.18 (m, 1H), 8.49 (dd, 1H). MS (ESIpos): m/z = 258 (M+H)+ HPLC (method 1): Rt = 5.10 min The compounds listed in Table 4 are prepared in analogy to Example XI (introduction of the amine) or XVI (tert-butyl ester cleavage) from the appropriate starting compounds. Table 4

Exemplary embodiments:

Example 1

(1:1 diastereomer mixture)

500 mg (0.66 mmol) of the compound from Example XXXVII are introduced under argon into 6 ml of DMF and, at room temperature, 109 mg of D-phenylglycinol (0.80 mmol), 153 mg of EDC (0.80 mmol), 99 mg of HOBt (0.73 mmol), 8 mg of DMAP (0.07 mmol) and finally 0.40 ml of 4-methylmorpholine (3.65 mmol) are added, and the mixture is stirred at room temperature for 12 h. 5 ml of dichloromethane and 1 ml of methanol are added to the reaction mixture which is then filtered through a silica gel cartridge. After elution with 15 ml of a mixture of dichloromethane and methanol (9/1; v/v), the filtrate is concentrated and purified by preparative HPLC. 150 mg (43% of theory) of product are obtained.

Example 2 MS (ESIpos): m/z = 535 (M+H)+ HPLC (method 14): Rt = 2.63 min

tetrahydro-6-quinoxalinecarboxylamide

166 mg (34 mmol) of the compound from Example XVIII are dissolved in 5 ml of dichloromethane. 45 mg (34 mmol) of HOBt and 64 mg (34 mmol) of EDC are added to this solution, and the reaction mixture is stirred for 20 minutes. Then 43 mg (34 mmol) of DIEA and 41 mg (34 mmol) of (1S)-1-phenylethylamine are added, and the reaction mixture is stirred at RT for 16 h. For working up, the solvent is removed in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane + 5% methanol). 110 mg (69% of theory) of the product are obtained.

Example 3 'H NMR (300 MHz, DMSO-d6).- = 0.52 (s, 2H), 0.93 (br s, 2H), 1.02-1.20 (m, 6H), 1.48 (d, 3H), 1.55-1.72 (m, 4H), 2.27 (br. s, 1H), 2.82 (septet, 1H), 352 (s, 2H), 4.42 (s, 2H), 5.18 (quintet, 1H), 7.22 (t, 1H), 7.32 (t, 2H), 7.38 (d, 2H), 7.50 (d, 1H), 7.87 (d, 1H), 8.07 (s, 1H), 8.73 (d, 1H) MS (ESIpos): m/z = 475.1 (M+H)+ HPLC (method 1); Rt = 4.19 min [a] = +26.6[deg] (ethanol) Rf= 0.57 (DCM/methanol 10:1)

tetrahydroquinoxaline-6-carboxamide

The preparation takes place in analogy to the preparation of the compound from Example 2 from the appropriate precursors.

s, 1H), 3.51 (s, 2H), 4.67 (s, 2H), 4.61 (quintet, 1 H), 5.18 (quintet, 1 H), 7.21 (t, 1 H), 7.28-7.41 (m, 5H), 7.45 (d, 1H), 7.84 (d, 1H), 8.09 (s, 1H), 8.76 (d, 1H) MS (ESIpos): m/z = 463.1 (M+H)+ HPLC (method 1): Rt = 4.09 min.

Example 4

The preparation takes place in analogy to the preparation of the compound from Example 1 from the appropriate precursors. 'H NMR (200 MHz, CDC13): = 0.63-0.76 (m, 2H), 1.12-1.32 (m, 6H), 1.49-2.14 (m, 6H), 2.76-3.11 (m, 4H), 3.91 (s; br, 2H), 4.22 (s; br, 2H), 4.46 (s; br, 1H), 4.94 (m, 1H), 5.21-5.39 (m, 1H), 6.98-7.03 (m, 2H), 7.32-7.34 (m, 2H), 7.47 (d, 1H), 7.62 (s, 1H), 7.85 (d, 1H), 8.14 (s, 1H). MS (ESIpos): m/z = 509 (M+H) HPLC (method 1): Rt = 3.80 min.

Example 5

tetrahydroquinoxaline-6-carboxamide

The preparation takes place in analogy to the preparation of the compound from Example 2 from the appropriate precursors. 'H NMR (500 MHz, DMSO-d6): m 0.85-1.30 (m, 4H), 1.42-1.53 (m, 9H), 1.541.74 (m, 4H), 1.79-1.88 (m, 2H), 2.27 (br s, 1H), 3.53 (br s, 2H), 4.38 (br s, 2H), 4.60 (quintet, 1H), 5.17 (quintet, 1H), 7.19-7.29 (m, 1H), 7.31 (q, 2H), 7.39 (t, 3H), 7.46 (d, 1H), 7.83 (s, 1H), 8.10 (s, 1H), 8.82 (d, 1H) MS (ESIpos): m/z = 476.9 (M+H)+ HPLC (method 1): Rt = 4.25 min.

Example 6

The preparation takes place in analogy to the preparation of the compound from Example 1 from the appropriate precursors. H NMR (300 MHz, DMSO-d6): = 0.40-1.19 (m, 13H), 1.64 (br s, 1H), 2.55 (m, 1H), 2.82 (m, 1H), 3.58-3.83 (m, 4H), 4.34-4.57 (m, 2H), 4.85-5.00 (m, 1H), 5.005.14 (m, 1H), 7.16-7.60 (m, 6H), 7.90 (d, 1H), 8.13 (s, 1H), 8.64 (d, 1H) MS (ESIpos): m/z = 479.2 (M+H)+ HPLC (method 1): Rt = 3.74 min.

Example 7

The preparation takes place in analogy to the preparation of the compound from Example 1 from the appropriate precursors. H NMR (300 MHz, CDC13): = 0.52-0.92 (m, 7H), 0.92-1.08 (t, 6H), 1.08-1.43 (m, 9H), 1.70 (m, 1H), 2.82 (m, IH), 2.95 (m, 1H), 3.74 (s, 3H), 3.75 (m, 2H), 4.38 (m, 2H), 4.64 (m, 2H), 5.09 (quartet, IH), 6.76-6.91 (m, 3H), 7.34 (d, 2H), 7.49 (d, IH), 7.64 (m, 1H), 8.05 (d, 1H), 8.17 (s, 1H) MS (ESIpos): m/z = 535.3 (M+H)+ HPLC (method 1); Rt = 4.50 min.

Example 8

1,2,3,4-tetrahydroquinoxalin.e-6-carboxamide

The preparation takes place in analogy to the preparation of the compound from Example 2 from the appropriate precursors. 'HNMR (300 MHz, DMSO-d6): = 0.52 (t, 2H), 0.82-0.99 (m, 2H), 1.01-1.15 (m, 5H), 1.45-1.55 (m, 4H), 1.55-1.71 (m, 4H), 1.74-1.92 (m, 1H), 2.19-2.33 (m, 1H), 2.77-2.90 (quintet, 1H), 3.50 (s, 2H), 4.42 (s, 2H), 5.13 (quintet, 1H), 7.34 (d, 2H), 7.51 (d, 3H), 7.85 (d, 1H), 8.05 (s, 1H), 8.75 (d, 1H) MS (ESIpos): m/z = 553.0 (M+H)+ HPLC (method 1): Rt = 4.31 min.

Example 9 [alpha ] = +25[deg] (ethanol) Rf = 0.45 (DCM/methanol 10;1)

tetrahydroquinoxaline-6-carboxamide

The preparation takes place in analogy to the preparation of the compound from Example 2 from the appropriate precursors. 'H NMR (300 MHz, DMSO-d6): = 0.52 (s, 2H), 0.82-1.31 (m, 8H), 1.42-1-73 (m, 7H), 2.27 (br s, 1H), 2.82 (septet, 1H), 3.51 (s, 2H), 4.42 (s, 2H), 5.17 (quintet, 1H), 7.13 (t, 2H), 7.37-7.47 (m, 3H), 7.50 (d, 1H), 7.86 (d, 1H), 8.05 (s, 1H), 8.73 (d, 1H) MS (ESIpos): m/z = 493.1 (M+H)+ HPLC (method 1): Rt = 4.13 min.

Example 10 Rf = 0.50 (DCM/methanol 10:1)

The preparation takes place in analogy to the preparation of the compound from Example 1 from the appropriate precursors. 'H NMR (300 MHz, DMSO-d6): = 0.40-1.19 (m, 13H), 1.52 (br s, 1H), 1.81 (m, 1H), 2.32 (br s, 1H), 2.82 (m, 1H), 3.36-3.77 (m, 4H), 4.44 (s, 1H), 4.87-5.10 (m, 2H), 5.97 (d, 2H), 6.84 (s, 2H), 6.98 (s, 1H), 7.51 (d, 1H), 7.87 (d, 1H), 8.08 (s, 1H), 8.58 (d, 1H) MS (ESIpos): m/z = 523.3 (M+H)+ HPLC (method 1): Rt = 3.77 min. The compounds listed in Table 5 are prepared in analogy to Example 1 from the appropriate starting compounds.

B. Assessment of the physiological activity Abbreviations: DMEM Dulbecco's modified Eagle medium FCS fetal calf serum HEPES 4-(2-hydroxyethyl)-l-piperazineethanesulphonic acid 1. in vitro Tests to determine the M2 activity and selectivity a) Cellular functional in vitro test A recombinant cell line was used to identify agonists of the human M2 acetylcholine receptor (M2AChR) and to quantify the activity of the substances described herein. The cell is originally derived from a hamster ovary epithelial cell (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 calciumsensitive photoprotein aequorin which after reconstitution with the cofactor coelenterazine emits light when the free calcium concentration in the inner mitochondrial compartment is increased (Rizzuto R, Simpson AW, Brini M, Pozzan T.; Nature 358 (1992) 325-327).The cell is additionally stably transfected with the human M2AChR (Peralta EG, Ashkenazi A, WinslowJW, Smith DH, Ramachandran J, Capon, DJ, EMBO Journal 6 (1987) 3923-3929) and with the gene which codes for the promiscuous Galpha 16 protein (Amatruda TT, Steele DA, Slepak VZ, Simon MI, Proceedings in the National Academy of Science USA 88 (1991), 55875591). The resulting M2AChR test cell responds to stimulation of the recombinant M2ACh receptor with an intracellular release of calcium ions, which can be quantified through the resulting aequorin luminescence with a suitable luminometer (Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17 (1996) 235-237). The in vitro selectivity for the muscarinergic acetylcholine receptor subtypes Ml to M5 is determined by using appropriate CHO Kl cells which are stably transfected likewise with the gene of the calcium-sensitive photoprotein aequorin and the gene of the Ml, M3 or MS receptor subtypes or, in the case of the M4 receptor subtypes, additionally with the gene of the promiscuous Gate protein. Test procedure: The cells are plated out on the day before the test in culture medium (DMEM, 10% FCS, 2 mM Glutamine, 10 mM HEPES; Gibco Cat.# 21331-020; now belongs to: Invitrogen GmbH, 76131 Karlsmhe) in 384 (or 1536) well microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO2, 37[deg]C). On the day of the test, the culture medium is replaced by a Tyrode solution (in mM: 140 NaCl, 5 KC1, 1 MgCl2, 2 CaCl2, 20 glucose, 20 HEPES) which additionally contains the cofactor coelenterazine (50 MicroM), and the microtiter plate is then incubated for a further 3-4 hours. Immediately after the test substances have been transferred into the wells of 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 muscarinergic acetylcholine receptors Stably transfected CHOK1 cells which express the human muscarinergic M2 receptor are, after 80% confluence is reached, suspended in 10 ml of binding buffer (20 mM 40(2-hydroxyethyl)-1-piperazineethanesulphonic acid, 5 mM in magnesium chloride, pH 7.4) per 175 cm cell culture bottle and homogenised using an UltraTurrax apparatus. The homogenates are centrifuged at 1000 g and 4[deg]C for 10 minutes. The supernatant is removed and centrifuged at 20 000 g and 4[deg]C for 30 min. The membrane sediment with the M2 receptors is taken up in 10 ml of binding buffer and stored at -70[deg]C. For the binding test, 2 nM H-oxotremorine M (3200 GBq/mmol, Perkin Elmer) are incubated with 100-1000 Microg/ml M2 membranes per mixture (0.2 ml) in the presence of the test substances at room temperature for 60 minutes. The incubation is stopped by centrifugation at 10 000 g for 10 minutes and subsequent washing wit 0.1 % bovine serum albumin in binding buffer at 4[deg]C. Centrifugation is again carried out at 10 000 x g and 4[deg]C for 10 minutes. The sediment is resuspended in 0.1 ml of 1 N sodium hydroxide solution and transferred into scintillation vials. After addition of 4 ml of Ultima Gold scintillator, the radioactivity bound to the membranes is quantified using a BeckmanCoulter LS6000 IC scintillation counter. The nonspecific binding is denned as radioactivity in the presence of 10 MicroM oxotremorine M and is usually less than 5% of the bound total radioactivity.The binding data (IC50 and dissociation constant Ki) are determined using the graph pad prism version 3.02 programme. 2. in vivo Test to detect the cardiovascular effect a) Langendorff guinea pig heart The heart is removed from anaesthetised guinea pigs after opening the thoracic cavity and introduced into a conventional Langendorff apparatus. The coronary arteries are perfused at constant volume (lOml/min) and the profusion pressure arising during this is recorded via an appropriate pressure transducer. A decrease in the profusion pressure in this arrangement corresponds to a relaxation of the coronary arteries. At the same time, the pressure developed by the heart during each contraction is measured via a balloon inserted into the left ventricle and a further pressure transducer. The rate of the heart beating in isolation is found by calculation from the number of contractions per unit time. b) Blood pressure measurements on anaesthetised rats Male Wistar rats with a body weight of 300-350 g are anaesthetised with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is introduced into the femoral artery to measure the blood pressure. The substances to be tested are administered orally in Transcutol, Cremophor EL, H2O (10%/20%/70%) in a volume of 1 ml/kg. c) Effect on the mean blood pressure of conscious spontaneously hypertensive rats Continuous blood pressure measurements over 24 hours are carried out on spontaneously hypertensive female rats (MOL:SPRD) weighing 200-250 g and moving freely. For this purpose, pressure transducers (Data Sciences Inc., St. Paul, MN, USA) are implanted chronically in the descending abdominal aorta below the renal artery of the animals, and the transmitter connected thereto is fixed in the abdominal cavity. The animals are kept singly in type III 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 acquisition, the blood pressure of each rat is recorded for 10 seconds every 5 minutes. The measurements are combined in each case for a period of 15 minutes and the mean is calculated from these values.The test compounds are dissolved in Transcutol (10%), Cremophor (20%), H20 (70%) mixture and administered orally by gavage in a volume of 2 mi/kg of body weight. The test doses are between 0.3-30 mg/kg of body weight. d) Blood pressure and heart rate measurements on anaesthetised dogs The experiments are carried out on dogs (mongrel) of both sexes with a body weight between 20 and 30 kg. Anaesthesia is induced by a slow i.v. injection of 25 mg/kg thiopental (Trapanal and continued during the experiment by continuous infusion of 0.08 mg/kg/h fentanyl (Fentanyl ) and 0-25mg/kg/h droperidol (Dehydrobenzperidol ). Alloferin (0.02 mglkglh) is added as muscle relaxant. The dogs are artificially ventillated with 1 part of nitrous oxide and 3 parts of oxygen. The test substances are administered intravenously via the femoral vein. A MillarTip catheter is passed via the carotid artery into the left ventricle to pick up the left ventricular pressure and calculate the contractility. A hollow catheter is introduced via the femoral artery into the aorta and connected to a pressure transducer to measure the peripheral blood pressure. After a left-sided thoracotomy, the left circumflex (LCX) or the left anterior descending (LAD) coronary artery is exposed and an electromagnetic flow head is sited to measure the coronary flow. The ECG is recorded via an extremity lead and an ECG amplifier, and the heart rate and ECG parameters are found from the recorded ECG. The oxygen saturation at the coronary sinus is determined via a Swan-Gantz oximetry TD catheter. C. Exemplary embodiments of pharmaceutical compositions The compounds of the invention can be converted into pharmaceutical preparations in the following ways: Tablet: Composition: 100 mg of the compound of Example I, 50 mg of lactose (monohydrate), 50 mg of maize 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% strength solution (m/m) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 min. This mixture is compressed using a conventional tablet press (see above for format of the tablet). A compressive force of 15 kN is used as guideline for the compression. Suspension which can be administered orally: Composition: 1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water. 10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention. Production: The Rhodigel is suspended in ethanol, and the active ingredient is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

Claims (10)

Patent claims

1. Compound of the formula

in which A is C1-C6-alkanediyl which is optionally substituted once or twice by hydroxyl or once, twice or three times by halogen, R is 1,3-benzodioxole or aryl, where aryl is optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxyl, hydroxycarbonyl, ammo, trifluoromethyl, trifluoromethoxy, nitro, cyano, optionally hydroxylsubstituted alkyl, optionally cycloalkyl-substituted alkoxy, phenoxy, alkylamino, optionally phenyl-substituted alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aminosulphonyl, alkylsulphonyl, alkylsulphonylamino, trifluoromethylsulphonylamino and morpholinyl, R is cycloalkyl which is optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxyl, amino, alkyl, alkoxy and alkylamino, R is alkyl or cycloalkyl, where alkyl and cycloalkyl are optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxyl, amino, trifluoromethyl, alkoxy, alkylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl, and cycloalkyl may optionally also be substituted by alkyl which in turn may be substituted by hydroxyl, and its salts, its solvates and the solvates of its salts.

2. Compound according to Claim 1, in which A is (C1-C6)-alkanediyl which is optionally substituted once by hydroxyl or three times by fluorine, R is 1,3-benzodioxole or phenyl, where phenyl is optionally substituted by 1 to

3 substituents selected independently of one another from the group consisting of halogen, hydroxyl, hydroxycarbonyl, amino, trifluoromethyl, trifluoromethoxy, optionally hydroxyl-substituted (C1-C6)-alkyl, optionally cyclopropyl-substituted (Ci-C4)-alkoxy, phenoxy, (C1-C4)-alkylamino, optionally phenyl-substituted (C1-C4)alkoxycarbonyl, aminosulphonyl, (Ci-C4)-alkylsulphonyl, (C1-C4)alkylsulphonylamino, trifluoromethylsulphonylamino and morpholinyl, R is (C3-C6)-cycloalkyl, R is (Ci-C6)-alkyl or (C3-C6)-cycloalkyl, where alkyl and cycloalkyl are optionally substituted by 1 to 3 substituents selected independently of one another from the group consisting of hydroxyl, trifluoromethyl and (C1-C4)-alkoxy, and cycloalkyl may optionally also be substituted by (Ci-C6)-alkyl which may in turn be substituted by hydroxyl, and its salts, its solvates and the solvates of its salts. 3. Compound according to either of Claims 1 or 2, in which A is pentane- 1, 1 -diyl or 2-hydroxyethane-l,l-diyl, R' is phenyl which is optionally substituted by 1 or 2 substituents selected independently of one another from the group consisting of methyl, ethyl, methoxy and ethoxy, R is cyclopropyl or cyclobutyl, R is cyclohexyl or cyclopentyl, which are optionally substituted by 1 or 2 substituents selected independently of one another from the group consisting of methyl, ethyl, methoxy and ethoxy, and its salts, its solvates and the solvates of its salts.

4. Process for preparing a compound of the formula (I) according to Claim 1, characterized in that a compound of the formula

in which R and R have the meaning stated in Claim 1, is reacted with a compound of the formula

in which A and R have the meaning stated in Claim 1.

5. Compound as defined in any of Claims 1 to 3 for the treatment and/or prophylaxis of diseases.

6. Medicament comprising a compound as defined in any of Claims I to 3 in combination with a pharmacologically acceptable excipient or carrier.

7. Medicament comprising a compound as defined in any of Claims 1 to 3, and at least one further active ingredient.

8. Use of a compound as defined in any of Claims 1 to 3 for producing a medicament.

9. Use of a compound as defined in any of Claims 1 to 3 for producing a medicament for the treatment and/or prophylaxis of cardiovascular disorders.

10. Method for controlling cardiovascular disorders in humans and animals by administering an effective amount of a compound as defined in any of Claims 1 to 3.