HRP20040573A2 - Substituted imidazolidines, method for the production thereof, use thereof as a drug or for diagnosis, and drug containing substituted imidazolidines - Google Patents

Description

The invention relates to substituted imidazolidines of formula I,

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where

R1 and R2 independently represent CN, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl or (C4-C6)-cycloalkenyl,

wherein all carbon chains and rings are unsubstituted or mutually independently substituted with 1-11 F atoms or with up to two residues selected from the group consisting of OH, NH2, NHCH3, N(CH3)2 and OCH3; or

R1 and R2 together with two carbon atoms, to which they are connected, form a five- to eight-membered saturated or unsaturated carbon ring,

wherein, however, there are no double bonds between the two carbon atoms to which R1 and R2 are attached and

wherein the ring is unsubstituted or substituted with 1-12 F atoms or with up to two residues selected from the group consisting of CH3 and OCH3;

R3 is F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, O-phenyl, CN, NO2 or NH2;

wherein phenyl is unsubstituted or substituted with up to two residues selected from the group consisting of CH3, F, Cl, Br, I, OH and OCH3; and

whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms;

R4 to R6 are mutually independently H, F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, CN, No2, NH2, (C1-C4)-alkylamino or (C1-C4)-di-alkylamino;

whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms;

R7 is H, F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, CN, NO2 or NH2;

whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms; as well as their pharmaceutically acceptable salts, as well as trifluoroacetates.

Preference is given to compounds of formula I, in which:

R1 and R2 independently represent (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl or (C4-C6)-cycloalkenyl,

wherein all carbon chains and rings are unsubstituted or mutually independently substituted with 1-11 F atoms or with up to two residues selected from the group consisting of NHCH3, N(CH3)2 and OCH3; or

R1 and R2 together with two carbon atoms, to which they are connected, form a five- to eight-membered saturated or unsaturated carbon ring,

wherein, however, there are no double bonds between the two carbon atoms to which R1 and R2 are attached and

wherein the ring is unsubstituted or substituted with 1-12 F atoms or with up to two residues selected from the group consisting of CH3 and OCH3;

R3 is F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, O-phenyl, CN, NO2 or NH2;

wherein phenyl is unsubstituted or substituted with up to two residues selected from the group consisting of CH3, F, Cl, Br, OH and OCH3; and

whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms;

R4 to R6 are independently H, F, Cl, Br, CH3, OH, OCH3, CN, NO2, NH2, NHCH3, N(CH3)2;

whereby the methyl groups are not substituted or are substituted with 1-3 F atoms;

R 7 is H, F, Cl, Br, I, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkenyl, (C 3 -C 6 )-cycloalkyl, OH, (C 1 -C 4 )-alkoxy, CN, NO 2 or NH2;

whereby the carbon chains or rings are not substituted or are substituted with 1 - 11 F atoms; as well as their pharmaceutically acceptable salts, as well as trifluoroacetaim.

The following compounds of formula I are particularly advantageous:

trans-(2-chloro-6-trifluoromethyl-phenyl)-(octahydrobenzo-imidazol-2-ylidene)-amine hydrochloride,

(S,S)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate,

cis-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate,

(R,R)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate,

trans-(octahydro-benzoimidazol-2-ylidene)-(2-phenoxy-phenyl)-amine hydrochloride,

trans-(2,6-dichlorophenyl)-(4,5-diisopropyl-imidazolidin-2-ylidene)-amine hydrochloride,

trans-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imid-azolidin-2-ylidene)-amine trifluoroacetate,

cis-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imid-azolidin-2-ylidene)-amine hydrochloride,

trans-(2,6-dichloro-phenyl)-(4,5-diethyl-imidazolidin-2-ylidene)-amine hydrochloride,

(2,6-dichloro-phenyl)-(4,5-dimethyl-imidazolidin-2-ylidene)-amine nitrate,

trans-(2,6-dichloro-phenyl)-(hexahydro-cyclopenta-imidazol-2-ylidene)-amine trifluoroacetate.

The following compounds of formula I have a very outstanding and particular advantage:

(S,S)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate,

cis-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate,

(R,R)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate,

trans-(2,6-dichlorophenyl)-(4,5-diisopropyl-imidazolidin-2-ylidene)-amine hydrochloride,

trans-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imid-azolidin-2-ylidene)-amine trifluoroacetate,

cis-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imidazolidin-2-ylidene)-amine hydrochloride,

trans-(2,6-dichloro-phenyl)-(4,5-diethyl-imidazolidin-2-ylidene)-amine hydrochloride,

(2,6-dichloro-phenyl)-(4,5-dimethyl-imidazolidin-2-ylidene)-amine nitrate,

trans-(2,6-dichloro-phenyl)-(hexahydro-cyclopenta-imidazol-2-ylidene)-amine trifluoroacetate.

In addition, as acid addition salts all pharmacologically tolerable salts come into consideration, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates, adipinates, fumarates, gluconates, glutamates, glycerol phosphates, small and small. These groups also correspond to physiologically tolerable anions; but also trifluoroacetates.

If compounds of formula I have one or more centers of asymmetry, they can have both S and R configurations. The compounds may exist as optical isomers, as diastereomers, as racemates or as mixtures thereof.

Compounds of formula I may also exist as tautomers or as a mixture of tautomeric structures.

This refers primarily to the following tautomers:

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If R1 and R2 are different and have a nitrogen-carbon double bond with sufficient stability of configuration, then two more isomers due to the double bond also come into play:

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Said carbon residues, i.e. partially or fully fluorinated or substituted carbon residues can have a straight chain or can also be branched.

Methods for the production of useful compounds will also be described. Thus, substances represented by formula I can be produced in a manner known to the expert from basic isothiocyanates II and corresponding diamines III.

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The intermediate thiourea derivatives formed here can be cyclized using methyl iodide (Synthesis, 1974, 41-42) or carbodiimide (Synthesis, 1977, 864-865) into the corresponding imidazolidines I. If the isothiocyanates II used in this process cannot be obtained commercially, they can be produced in a manner known from the literature from the corresponding anilines by methods known to the expert, e.g. treatment with thiophosgene (J. Med. Chem., 1975, 18, 90-99) or with thio-carbonyldiimidazole (Justus Liebigs Ann Chem., 1962, 657, 104).

In addition to the isothiocyanates II described above, isocyanates IV with amines of the formula III type can also be successfully converted into compounds of the formula I. In doing so, intermediately formed urea derivatives are cyclized with phosphorus oxychloride into the corresponding imidazolidines of formula I.

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In the case of the proposed invention, it could surprisingly be shown that the described compounds are strong inhibitors of the sodium/hydrogen exchanger (NHE), especially NHE3.

NHE3 inhibitors known so far are derived from compounds of the acylguanidine type (EP-OS 825 178, HOE 96/F226), of the norbornylamine type (DE 199 60 204.2-HMR 99/L 073), of the 2-guanidino-quinazoline type (WO 01 79 186 Al) or benzamidine type (WO 01 21582A1, WO 01 72 742 Al). Also described as an NHE3 inhibitor is squalamine (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144), which does not act directly like the compounds of formula I, but reaches its maximum strength only after one hour.

A compound similar to the compounds described here, clonidine, is known to be a weak NHE inhibitor. In any case, its effect on rat NHE3 with an IC50 °d of 620 μM is remarkably moderate. Instead, it exhibits significant selectivity for NHE2, for which it has an IC50 of 42 μM (J. Orlowski et al. J. Biol. Chem. 268, 25536). This is why it is also labeled as an NHE2 inhibitor. In addition to a weak effect on the NHE, clonidine has a high affinity for the adrenergic alpha2 receptor and the imidazoline II receptor, which is why it causes a strong blood pressure-lowering effect (Ernsberger et al. Eur. J. Pharmacol. 134, 1, 1987).

Compounds of formula I are characterized by increased activity towards NHE3 and reduced activity towards II and alpha2.

In the bodies of different species, NHE3 can be found primarily in the bile, intestines and kidneys (Larry Fliegel et al, Biochem. Cell. Biol. 76: 735-741, 1998), but it can also be found in the brain (E. Ma et al Neuroscience 79; 591-603).

Because of this unexpected property, the compounds of formula I are suitable for the treatment of diseases caused by a lack of oxygen.

Due to their pharmacological properties, these compounds are extremely suitable as anti-arrhythmic drugs with a cardio-protective component for the prophylaxis and treatment of heart attacks, as well as for the treatment of angina pectoris, whereby they also preventively inhibit or greatly alleviate the pathophysiological processes at the onset of ischemic injuries, especially in the occurrence of ischemic heart arrhythmias. Due to their protective effect against pathological hypoxic and ischemic conditions, due to the inhibition of the cellular mechanism of Na+/H+ exchange, the compounds of formula I according to the invention can be used as drugs for the treatment of all acute or chronic injuries caused by ischemia, or diseases that are primarily or secondarily caused by it. This refers to their use as a medicine for surgical procedures, for example in organ transplants, where these compounds can be used both to protect organs in the donor before and during collection, to protect extracted organs, for example during processing or their disposal in baths physiological fluids, as well as when transferring to the recipient's body. These compounds are also valuable drugs with a protective effect during angioplasty operations, for example on the heart, as well as on peripheral blood vessels. In accordance with their protective effect against ischemia-induced injuries, these compounds are also suitable as a drug for the treatment of ischemia of the nervous system, especially of the CNS, where they are suitable, for example, for the treatment of stroke or cerebral edema. Furthermore, the compounds of formula I according to the invention can also be used to treat forms of shock, such as for example allergic, cardiogenic, hypovolemic and bacterial shock.

Furthermore, these compounds cause an improvement in respiratory function and therefore they can be used to treat respiratory conditions in the following clinical conditions and diseases: impaired central respiratory function (e.g. central sleep apnea, sudden infant death, postoperative hypoxia), muscular respiratory disorders, breathing disorders after long-term artificial respiration, breathing disorders during adaptation in high altitude areas, obstructive and mixed form of sleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia.

In addition, these compounds increase the tone of the muscles of the upper respiratory tract, so that snoring is suppressed.

The combination of an NHE inhibitor with a carbonic anhydrase inhibitor (e.g. acetazolamide), whereby the latter contributes to metabolic acidosis and thus already increases the ability to breathe, has been shown to be beneficial due to enhanced effect and reduced use of the active substance.

It has been shown that the compounds used according to the invention have a mild cleaning effect and can therefore be usefully used as cleaning agents or in dangerous intestinal blockages, where it is particularly advantageous to prevent ischemic injuries that occur with blockages in the intestinal area.

Furthermore, there is a possibility of preventing the formation of gallstones.

The compounds of formula I used according to the invention are furthermore characterized by a strong inhibitory effect on cell proliferation, for example on the proliferation of fibroblasts and on the proliferation of smooth muscle cells of blood vessels. Therefore, the compounds of formula I come into consideration as valuable therapeutic agents for diseases in which the primary or secondary cause is cell proliferation, and they can therefore be used as antiatherosclerotics, agents against diabetic late complications, cancer diseases, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or renal fibrosis, organ hypertrophy and hyperplasia, especially hyperplasia or hypertrophy of the prostate.

The compounds used according to the invention are effective inhibitors of cellular sodium-proton antiporters (Na/H-exchangers), which are also elevated in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) and in such cells that are easily accessible for measurements, such as for example in erythrocytes, platelets or in leukocytes. The compounds used according to the invention are therefore suitable as a distinguished and simple scientific tool, for example, for use as a diagnostic to determine and differentiate certain forms of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. Furthermore, the compounds of formula I are suitable for preventive therapy to prevent the genesis of high blood pressure, for example essential hypertension.

In addition, NHE inhibitors have been found to have a beneficial effect on serum lipoproteins. It is generally recognized that an important risk factor for the development of arteriosclerotic changes in blood vessels, especially coronary heart disease, is an excessively high value of fat in the blood, so-called hyperlipoproteinemia. Therefore, for the prophylaxis and regression of atherosclerotic changes, the reduction of elevated lipoproteins in the serum is of extraordinary importance. The compounds used according to the invention can therefore be used for prophylaxis and for the regression of atherosclerotic changes, whereby they exclude the causal risk factor. With this protection of blood vessels from endothelial dysfunction syndrome, the compounds of formula I are a valuable drug for the prevention and treatment of coronary spasms of blood vessels, atherogenesis and atherosclerosis, left atrial hypertrophy and dilated cardiomyopathy, and thrombotic diseases.

For this reason, the mentioned compounds are usefully used for the production of medicine for the prevention and treatment of sleep apnea and breathing disorders caused by muscles; for the production of medicine for the prevention and treatment of snoring; for the production of blood pressure lowering medicine; for the production of a drug with a purgative effect for the prevention and treatment of intestinal blockages; for the production of a drug with a discharge effect for the prevention and treatment of diseases caused by ischemia and reperfusion of central and peripheral organs, such as acute kidney failure, stroke, endogenous shock states, intestinal diseases, etc.; for the production of a drug for the treatment of hypercholesterolemia; for the production of medicine for the prevention of atherogenesis and atherosclerosis; for the production of medicine for the prevention and treatment of diseases caused by an increased amount of cholesterol; for the production of medicine for the prevention and treatment of diseases caused by endothelial dysfunction; for the production of medicine for the treatment of ectoparasite attacks; for the production of a medicine for the treatment of the mentioned complaints in combination with substances that lower blood pressure, primarily with inhibitors of the enzyme that converts angiotensin (e. Angiotensin Converting Enzyme, ACE) and angiotensin receptor antagonists. The combination of NHE inhibitors of formula I with active substances that lower blood pressure, primarily with an HMG-CoA reductase inhibitor (e.g. lovastatin or pravastatin), whereby the latter brings a hypolipidemic effect and thus increases the hypolipidemic properties of NHE inhibitors of formula I, has been shown to be a favorable combination with enhanced action and reduced use of the active substance.

The administration of sodium-proton exchange inhibitors of formula I as new drugs for reducing elevated blood fat is requested, as well as combinations of sodium-proton exchange inhibitors with blood pressure-lowering drugs and/or hypolipidemic drugs.

In this case, drugs containing compound I can be administered orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred application depending on the respective disease presentation. In addition, compounds I can be administered alone or together with galenic excipients, both in veterinary medicine and in human medicine.

Excipients suitable for the desired drug formulation are known to the expert, based on his professional knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other carriers of active substances, for example, antioxidants, dispersing agents, emulsifiers, antifoam agents, flavor correctors, preservatives, to promote dissolution or dyes.

For oral forms of administration, the active compounds are mixed with additional substances that are suitable for this purpose, such as carriers, stabilizers or inert diluents, and are brought into a form that is suitable for application, such as tablets, dragees, capsules, by usual procedures. , aqueous, alcoholic or oily solutions. Gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used as inert carriers. At the same time, the preparation can be made by a dry or also a wet granulation process. Suitable oil carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish liver oil.

Active compounds used for subcutaneous or intravenous administration can be brought into solutions, suspensions or emulsions, if desired, with the usual substances such as solubilizers, emulsifiers or other auxiliary substances. Suitable solvents include, for example: water, physiological solutions of table salt or alcohols, for example ethanol, propanol, glycerin, and in addition also sugar solutions such as glucose or mannitol solutions, or also mixtures of the various mentioned solvents.

Solutions, suspensions or emulsions of the active substance of formula I in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents, are suitable as pharmaceutical formulations for administration in the form of an aerosol or spray.

If necessary, the formulation may also contain other pharmaceutical excipients, such as surfactants, emulsifiers and stabilizers, as well as propellant gas. Such a preparation contains an active substance usually in a concentration of approximately 0.1 to 10, especially from approx. 0.3 to 3 wt. %.

The dosage and frequency of administration of the active substance of formula I, which is intended to be applied, depends on the strength and duration of action of the compound used; in addition, it also depends on the type and severity of the disease to be treated, as well as on the sex, age, weight and individual reaction of the treated mammal.

On average, the daily dose of the compound of formula I for a patient with severe approx. 75 kg is at least 0.001 mg/kg, preferably 0.1 mg/kg, up to a maximum of 30 mg/kg, preferably 1 mg/kg of body weight. In the case of an acute outbreak of the disease, possibly immediately after experiencing a heart attack, even higher and above all more frequent dosages may be necessary, for example up to 4 individual doses per day. Especially with i.v. application, possibly in a patient with a heart attack in intensive care, up to 200 mg per day may be necessary.

Description of experiments and examples

List of abbreviations used

Rt retention time,

TFA trifluoroacetic acid,

LCMS (e. Liguid Chromatografy Mass Spectroscopy), liquid chromatography mass spectroscopy,

MS (e. Mass Spectroscopy), mass spectroscopy,

CI+ chemical ionization, positive,

ES+ electrical connection, positive

In general

The retention times (Rt) listed below refer to LCMS measurements with the following parameters:

Method A:

stationary phase: Merck Purospher 3μ 2 × 55 mm,

mobile phase: 95% H2O (0.05% TFA) → 95% acetonitrile;

4 minutes; 95% acetonitrile; 1.5 min → 5% acetonitrile; 1 minute; 0.5 ml/min.

Method B:

stationary phase: YMC J'sphere ODS 2 × 33 mm,

mobile phase: 95% H2O (0.05% TFA) → 95% acetonitrile;

2.3 minutes; 95% acetonitrile; 1 min —> 5% acetonitrile; 0.1 min; 1 ml/min.

Preparative HPLC was performed under the following conditions:

stationary phase: Merck Purospher RP18 (10 μM) 250 × 25 mm;

mobile phase: 90% H2O (0.05% TFA) → 90% acetonitrile; 40 minutes; 25 ml/min.

If it is an enantiomerically pure compound, then the configuration and/or sign of the optical rotation is indicated. If these data are present, then they are racemates or compounds that are not optically active.

Example 1

(S,S)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate

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2,6-dichlorophenyl isothiocyanate (600 mg) and (1S,2S)-(+)-1,2-diaminocyclohexane (336 mg) were dissolved in toluene (30 ml) and stirred for 3 h at 70°C. After standing overnight, the solvent was removed and the residue was mixed with ether. The resulting thiourea is then sucked off. 840 mg of the desired product is isolated.

A portion of the thus obtained thiourea (420 mg) is then mixed with toluene (15 ml) and heated briefly under reflux. N,N'-dicyclohexylcarbodiimide (226 mg) dissolved in toluene (5 ml) was then added dropwise and the mixture was stirred for 5 h at 70°C. After standing overnight, the resulting precipitate is filtered off and the filtrate is concentrated to dryness. The residue is then purified via preparative HPLC. The pure fractions were combined, the acetonitrile was removed on a rotary evaporator and the aqueous phase was freeze-dried. 70 mg of the desired compound is obtained.

LCMS-Rt: 3.69 min, (A)

MS (ES+, M+H+): 284.2

Example 2

cis-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate

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2,6-dichlorophenyl isothiocyanate (600 mg) and cis-1,2-diaminocyclohexane (336 mg) are reacted and processed as described in Example 1. From the 900 mg of thiourea obtained in the first step, 454 mg are further reacted. 112 mg of the desired compound were obtained.

LCMS-Rt: 3.65 min, (A)

MS (Cl+, M+H+): 284.1

Example 3

(R,R)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)amine trifluoroacetate

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2,6-Dichlorophenyl isothiocyanate (50 mg) and (R,R)-(-)-1,2-diaminocyclohexane (28 mg) were placed in toluene (1.5 ml) and heated under reflux for 15 min. N,N'-dicyclohexylcarbodiimide (76 mg) was then added and refluxed further. After standing overnight, the toluene was extracted and the residue was purified by preparative HPLC. Since only contaminated fractions were obtained with the first cleaning, the chromatography was repeated with a second column (MN Nucleosil 100-5-C18 250×25 mm; flow rate 20 ml/min), but otherwise under the same conditions. The pure fractions were combined, the acetonitrile was removed by rotary evaporation and the aqueous phase was freeze-dried. 10 mg of the desired compound was obtained.

LCMS-Rt: 3.70 min, (A)

MS (Cl+, M+H+): 284.0

Example 4

trans-(octahydro-benzoimidazol-2-ylidene)-(2-phenoxy-phenyl)-amine hydrochloride

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a) 2-phenoxyphenylisothiocyanate

To a solution of 1.85 g (0.01 mol) of 2-phenoxyaniline in 50 ml of THF, 1.96 g (0.011 mol) of thiocarbonyldiimide-azole is added, it is stirred for 4 hours at room temperature, after removing the solvent by distillation, the compound is obtained as a brown amorphous product.

b) N-(trans-2-aminocyclohexyl)-N'-(2-phenoxyphenyl)-thiourea

A solution of 0.8 g of trans-1,2-diaminocyclohexane in 30 ml of THF was mixed with a solution of 1.6 g of 2-phenoxyphenyl isothiocyanate in 10 ml of THF and stirred for approx. 4 hours at room temperature. After evaporation of the solvent and then chromatography on silica gel with a mixture of 10 parts ethyl acetate, 5 parts n-heptane, 5 parts methylene chloride, 5 parts methanol and 1 part concentrated aqueous ammonia, the desired compound is obtained as an amorphous, oily product.

c) trans-(octahydro-benzoimidazol-2-ylidene)-(2-phenoxy-phenyl)-amine hydrochloride

A solution of 1.03 g of N-(trans-2-aminocyclohexyl)-N'-(2-phenoxyphenyl)-thiourea in 30 ml of ethanol was mixed with 3.4 g of methyl iodide and the reaction mixture was kept under reflux for 5 hours. After standing overnight, the solvent is distilled off and the residue is treated with water and then made alkaline with saturated sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate, the organic extraction phase is evaporated and the oily residue is chromatographed on silica gel with a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of methylene chloride, 5 parts of methanol and 1 part of concentrated aqueous ammonia. An oily product is obtained, which is dissolved in acetic ester and acidified with a saturated solution of HCl gas in diethyl ether. The solvent is distilled off, the residue is dissolved in water and freeze-dried. 0.49 g of a solid with a melting point of 110°C is obtained. MS (ES+, M+H+): 308.2

Example 5

trans-(2-chloro-6-trifluoromethyl-phenyl)-(octahydro-benzo-imidazol-2-ylidene)-amine hydrochloride

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a) N-(trans-2-aminocyclohexyl)-N'-(2-chloro-6-trifluoromethylphenyl)-urea

A solution of 1.6 g of 2-chloro-6-trifluoromethylphenylisocyanate in 30 ml of THF was mixed with a solution of 0.46 g of trans-1,2-diaminocyclohexane in 10 ml of THF and stirred for approximately 3 hours at room temperature. After standing overnight, the solvent was distilled off and 0.57 g of the desired compound was obtained as a semi-solid, yellow product.

b) trans-(2-chloro-6-trifluoromethyl-phenyl)-(octahydro-benzo-imidazol-2-ylidene)-amine hydrochloride

0.57 g of N-(trans-2-aminocyclohexyl)-N'-(2-chloro-6-trifluoromethylphenyl)-urea is boiled in 20 ml of phosphorus oxychloride (POCl) for 4-5 hours under reflux. POCl3 is distilled off, the residue is mixed with water and adjusted to pH 7-8 with 2N NaOH. It is then extracted with ethyl acetate, the organic solvent is distilled off and the residue is chromatographed on silica gel with a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The eluent is distilled off and the white solid residue is dissolved in a little ethyl acetate and made acidic with a saturated solution of HCl gas in diethyl ether. The solvent is distilled off and the residue is treated with diisopropyl ether, after which 0.4 g of the desired product is obtained as a solid with a melting point of 160-165°C.

MS (Cl+, M+H+): 318.3

Example 6

trans-(4,5-di-tert-butyl-imidazolidin-2-ylidene)-(2,6-dichloro-phenyl)-amine hydrochloride

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2,6-dichlorophenyl isothiocyanate (150 mg) and trans-2,2,5,5-tetramethyl-hexane-3,4-diamine (127 mg) - analog Synthesis 1999, 2, 228; in the form of a racemic mixture - placed in toluene (1.5 ml) and heated for 15 min under reflux. N,N'-dicyclohexylcarbodiimide (126 mg), dissolved in 2 ml of toluene, was then added and kept under reflux. After standing overnight, the toluene was removed and the residue was purified by preparative HPLC. Pure fractions are combined, acetonitrile is removed by rotary evaporation, the aqueous phase is neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. The combined phases in ethyl acetate are washed with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent is filtered off, the residue is taken up in water, 2 normal hydrochloric acid is added and it is freeze-dried. 111 mg of the desired compound is obtained.

LCMS-Rt: 4.43 min, (A)

MS (Cl+, M+H+): 342.2

Example 7

trans-(2,6-dichlorophenyl)-(4,5-diisopropyl-imidazolidin-2-ylidene)-amine hydrochloride

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trans-2,5-dimethyl-hexane-3,4-diamine (226 mg) analog Synthesis 1999, 2, 228; in racemic form - placed in THF (2.5 ml) and 2,6-dichloro-phenyl isothiocyanate was added in portions at room temperature (150, 80 and 40 mg portions). N,N'-dicyclohexylcarbodiimide (324 mg) was then added and further stirred at room temperature. A little more N,N'-dicyclohexylcarbodiimide is added to complete the reaction. After standing overnight, the resulting precipitate is suctioned off and the filtrate is concentrated. The residue is purified by preparative HPLC. The pure fractions are combined, the acetonitrile is removed by rotary evaporation, the aqueous phase is neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. The phases in the acetic ester are washed with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent is filtered off, the residue is concentrated and taken up in water, 2 normal hydrochloric acid is added and freeze-dried. 220 mg of the desired compound was obtained. LCMS-Rt: 1.93 min, (B) MS (ES+, M+H+) : 314.1

The compounds described in the following table were synthesized in accordance with the respective given example.

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Pharmacological data

Test description

This study determined the correction of intracellular pHs (pHi) after acidification, which is used in functionally capable NHE also under bicarbonate-free conditions. For this purpose, pHi were determined with the fluorescent dye BCECF (Calbiochem, the precursor BCECF-AM is used), which is sensitive to pH. Cells were first stained with BCECF. BCECF fluorescence was determined in a "Ratio Fluorescence Spectrometer" (Foton Technology International, South Brunswick, N.J., USA) at excitation wavelengths of 505 and 440 nm and emission wavelength of 535 nm and was converted to pHi using standard curves. BCECF-stained cells were incubated in NH4Cl buffer (pH 7.4) (NH4Cl buffer: 115 mM NaCl, 20 mM NH4Cl, 5 mM KCl, 1 mM CaCl2, 1 mM MgSO4, 20 mM Hepes, 5 mM glucose, 1 mg/ml BSA; the pH was adjusted to 7.4 with 1M NaOH). Intracellular acidification was induced by the addition of 975 μl buffer without NH4Cl1 (see below) to cells incubated in 25 μl aliquots of NH4Cl buffer. Then, the rate of pH increase was registered at NHE1 after two minutes, at NHE2 after five minutes and at NHE3 after three minutes. To calculate the inhibition strength of the test substances, the cells were first tested in buffers, in which there was no complete or no pH recovery. For complete pH recovery (100%), cells were incubated in Na+-containing buffer (133.8 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl2, 1/25 mM MgCl2, 0.97 mM Na2HPO4, 0, 23 mM NaH2PO4, 5 mM Hepes, 5 mM glucose, pH 7.0 was adjusted with 1M NaOH). To determine the 0% value, cells were incubated in buffer without Na+ (133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl2, 1/25 mM MgCl2, 0.97 mM K2HPO4, 0.23 mM KH2PO4, 5 mM Hepes, 5 mM glucose, pH 7.0 adjusted with 1M NaOH). The test substances were placed in a buffer containing Na. The increase in intracellular pH values at each tested substance concentration was expressed as a percentage of the maximum increase. The IC50 value of the respective substance for individual NHE subtypes was calculated from the percentage values of the pH increase using the Sigma-Plot program.

the results

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Claims (19)

1. Imidazolidine formulas [image] indicated by that R1 and R2 independently represent CN, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl or (C4-C6)-cycloalkenyl, wherein all carbon chains and rings are unsubstituted or mutually independently substituted with 1-11 F atoms or with up to two residues selected from the group consisting of OH, NH2, NHCH3, N(CH3)2 and OCH3; or R1 and R2 together with two carbon atoms, to which they are connected, form a five- to eight-membered saturated or unsaturated carbon ring, wherein, however, there are no double bonds between the two carbon atoms to which R1 and R2 are attached and wherein the ring is unsubstituted or substituted with 1-12 F atoms or with up to two residues selected from the group consisting of CH3 and OCH3; R3 is F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, O-phenyl, CN, NO2 or NH2; wherein phenyl is unsubstituted or substituted with up to two residues selected from the group consisting of CH3, F, Cl, Br, I, OH and OCH3; and whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms; R4 to R6 are mutually independently H, F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, CN, NO2, NH2, (C1-C4)-alkylamino or (C1-C4)-di-alkylamino; whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms; R7 is H, F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, CN, NO2 or NH2; whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms; as well as their pharmaceutically acceptable salts, as well as trifluoroacetates. 2. Compounds of formula I according to claim 1, characterized in that R1 and R2 independently represent (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl or (C4-C6)-cycloalkenyl, wherein all carbon chains and rings are unsubstituted or mutually independently substituted with 1-11 F atoms or with up to two residues selected from the group consisting of NHCH3, N(CH3)2 and OCH3; or R1 and R2 together with two carbon atoms, to which they are connected, form a five- to eight-membered saturated or unsaturated carbon ring, wherein, however, there are no double bonds between the two carbon atoms to which R1 and R2 are attached and wherein the ring is unsubstituted or substituted with 1-12 F atoms or with up to two residues selected from the group consisting of CH3 and OCH3; R3 is F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, O-phenyl, CN, NO2 or NH2; wherein phenyl is unsubstituted or substituted with up to two residues selected from the group consisting of CH3, F, Cl, Br, OH and OCH3; and whereby the carbon chains or rings are not substituted or are substituted with 1-11 F atoms; R4 to R6 are independently H, F, Cl, Br, CH3, OH, OCH3, CN, NO2, NH2, NHCH3, N(CH3)2; whereby the methyl groups are not substituted or are substituted with 1-3 F atoms; R7 is H, F, Cl, Br, I, (C1-C4)-alkyl, (C1-C4)-alkenyl, (C3-C6)-cycloalkyl, OH, (C1-C4)-alkoxy, CN, NO2 or NH2; in black, the carbon chains or rings are not substituted or are substituted with 1-11 F atoms; as well as their pharmaceutically acceptable salts, as well as trifluoroacetates. 3. Compounds of formula I according to one or more claims 1 and 2, characterized in that they are: trans-(2-chloro-6-trifluoromethyl-phenyl)-(octahydrobenzo-imidazol-2-ylidene)-amine hydrochloride, (S,S)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate, cis-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate, (R,R)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate, trans-(octahydro-benzoimidazol-2-ylidene)-(2-phenoxy-phenyl)-amine hydrochloride, trans-(2,6-dichlorophenyl)-(4,5-diisopropyl-imidazolidin-2-ylidene)-amine hydrochloride, trans-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imid-azolidin-2-ylidene)-amine trifluoroacetate, cis-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imid-azolidin-2-ylidene)-amine hydrochloride, trans-(2,6-dichloro-phenyl)-(4,5-diethyl-imidazolidin-2-ylidene)-amine hydrochloride, (2,6-dichloro-phenyl)-(4,5-dimethyl-imidazolidin-2-ylidene)-amine nitrate, trans-(2,6-dichloro-phenyl)-(hexahydro-cyclopenta-imidazol-2-ylidene)-amine trifluoroacetate. 4. Compounds of formula I according to one or more claims 1 and 3, characterized in that they are: (S,S)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate, cis-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate, (R,R)-(2,6-dichlorophenyl)-(octahydro-benzoimidazol-2-ylidene)-amine trifluoroacetate, trans-(2,6-dichlorophenyl)-(4,5-diisopropyl-imidazolidin-2-ylidene)-amine hydrochloride, trans-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imid-azolidin-2-ylidene)-amine trifluoroacetate, cis-(2,6-dichlorophenyl)-(4,5-dicyclopropyl-imidazolidin-2-ylidene)-amine hydrochloride, trans-(2,6-dichloro-phenyl)-(4,5-diethyl-imidazolidin-2-ylidene)-amine hydrochloride, (2,6-dichloro-phenyl)-(4,5-dimethyl-imidazolidin-2-ylidene)-amine nitrate, trans-(2,6-dichloro-phenyl)-(hexahydro-cyclopenta-imidazol-2-ylidene)-amine trifluoroacetate. 5. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of respiratory function disorders. 6. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of breathing disorders, in particular breathing disorders caused by sleep such as sleep apnea. 7. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of snoring. 8. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of acute and chronic kidney diseases, especially acute kidney failure and chronic kidney failure. 9. The use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of bowel function disorders. 10. The use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of disorders of the bile function. 11. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. 12. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs. 13. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment of shock conditions. 14. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine used in surgical operations and organ transplants. 15. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for preservation and disposal of grafts for surgical procedures. 16. The use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment of diseases in which the primary or secondary cause is cell proliferation. 17. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of fat metabolism disorders. 18. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ectoparasite attacks. 19. Medicine, characterized in that it contains an effective amount of compound I according to one or more claims 1 to 3.