DE10015248A1 - Bisamidino compounds as NHE-3 inhibitors - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein X and Y have the meanings given in claim number 1. Said compounds are inhibitors of the sodium/proton exchanger subtype 3 (NHE-3).

Description

The invention relates to the use of compounds of the formula I.

in what mean
X:

n: an integer value between 1 and 6
Y:

and their salts and solvates as NHE inhibitors.

Sodium / proton exchangers or antiporters are transport proteins that are arranged in the plasma membrane and exchange extracellular Na ⁺ for tracellular H ⁺ . These proteins are found in all animals. The Na ⁺ / H ⁺ exchangers form a family with at least six different isoforms (NHE-1 to NHE-6), all of which have now been cloned. While the NHE-1 subtype is ubiquitously distributed throughout the body in all tissues, the remaining NHE subtypes are selectively expressed in specific organs such as in the kidney or in the lumen wall and contraluminal wall of the small intestine. This distribution reflects the specific functions to which the various isoforms serve, namely on the one hand the regulation of the intracellular pH and cell volume by the subtype NHE-1 and on the other hand the Na ⁺ uptake and reuptake in the intestine and kidney by the isoforms NHE-2 or NHE-3. The NHE-4 isoform is mainly found in the stomach. The expression of NHE-5 is limited to brain and neuron tissue. NHE-6 represents the isoform that forms the sodium / proton exchanger in the mitochondria. The NHE-3 isoform is primarily expressed in the apical membrane of the proximal renal tubules. An NHE-3 inhibitor therefore has, among other things, a protective effect on the kidneys.

The therapeutic use of a selective inhibitor for NHE-3 Isoforming is versatile. NHE-3 inhibitors inhibit or reduce Ge weave damage and cell necrosis after pathophysiological hypoxic and ischemic events leading to activation of NHE activity cause like this during renal ischemia or during removal, the transport and reperfusion of a kidney during kidney transplantation the case is.

Inhibitors of the sodium / proton exchanger subtype 3 are an example as described in EP 0 825 178.

The object of the invention is to develop new inhibitors of sodium / proton To provide exchangers.

This problem is solved through the use of connections of the Formula I shown above as NHE inhibitors. The connections show egg ne high NHE-3 activity, combined with a pronounced selectivity versus the NHE-1 and NHE-2 isoforms.  

Bisamidino compounds of the formula are generally known. Representative these classes of substances are described, for example, by O. Dann, H. Char and H. Griesmayer, Liebigs Ann. Chem. 1982, 1836 to 1869, O. Then, H. Char, P. Fleischmann, H. Fricke, Liebigs Ann. Chem. 1986, 438 to 455 and O. Dann, G. Volz, E. Demant, W. Pfeifer, G. Bergen, H. Fick, E. Walkenhorst, Liebigs Ann. Chem. 1973, 1112 to 1140. The Auto others also examined the trypanocid and anti-leukemic properties these substances.

The compounds of formula I have a hypotensive effect and are suitable as active pharmaceutical ingredients for the treatment of hypertension. Still own they are called diuretics.

The compounds of formula I act alone or in combination with NHE Inhibitors of other subtype specificity are anti-ischemic and can be used are used to protect against thrombosis, atherosclerosis, vascular spasms Organs, e.g. B. kidney and liver, before and during operations, as well as chronic or acute kidney failure.

They can also be used to treat stroke, of brain edema, ischemia of the nervous system, various forms the shock as well as to improve the breath drive in, for example following conditions: central sleep apnea, sudden child death, post operative hypoxia and other breathing disorders.

By combining it with a carbonic anhydrase inhibitor, the At management activities can be further improved.

The compounds of formula I have an inhibitory effect on proliferation of cells, for example fibroblast cell proliferation and the Pro liferation of smooth vascular muscle cells and can therefore be used for treatment  of diseases in which cell proliferation is egg is a primary or secondary cause.

The compounds of formula I can be used against diabetes late complications, cancer, fibrotic diseases, endothelial dysfunction, organ hypertrophy and hyperplasia, especially others with prostate hyperplasia or prostate hypertrophy.

They are also suitable as diagnostics for determining and differentiating of certain forms of hypertension, atherosclerosis, diabetes tes and proliferative diseases.

Since the compounds of formula I also the level of serum lipoprotei ne beneficial influence, they can be used to treat an elevated Blood lipid levels alone or in combination with other medicines be set.

The invention relates to the use of compounds of Formula 1 according to claim 1 and its physiologically acceptable salts and / or Solvate for the manufacture of a medicament for the treatment of Thrombosis, ischemic conditions of the heart, peripheral and central nervous system and stroke, ischemic conditions peripheral organs and limbs and for the treatment of shockzu stands.

The invention further relates to the use of compounds of the formula I and its physiologically acceptable salts and / or sol vate for the manufacture of a medicament for the treatment of diseases, in which cell proliferation is a primary or secondary cause provides, for the treatment or prophylaxis of disorders of the fat metabolism or disturbed breathing drive.  

The invention also relates to the use of compounds of the formula I and its physiologically acceptable salts and / or sol vate for the manufacture of a medicament for the treatment of ischemic Kidney, ischemic bowel disease or for prophylaxis of acute or chronic kidney disease.

Methods for identifying substances that cause sodium / proton Inhibitors of subtype 3 inhibit z. B. described in US 5,871,919.

Under hydrates and solvates one understands z. B. the hemi-, mono- or Dihydrates, among solvates e.g. B. alcohol addition compounds such. B. with Methanol or ethanol.

The following compounds have proven to be particularly advantageous in their action as NHE-3 inhibitors:

• a) 2,2-tetramethylene di-1-benzofuran-5-carboxamidine (1);
• b) 2,2-hexamethylenedi-1-benzofuran-5-carboxamidine (2);
• c) 2- [2- (6-Amidinoindol-2-yl) ethyl] -1-benzofuran-5-carboxamidine (3);
• d) trans-1,2-bis (5-amidino-2-benzofuranyl) ethylene (4);

and their salts and solvates.

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions that for the implementations mentioned are known and suitable. You can also of variants Ge known per se, not mentioned here in more detail make use of.  

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.

The compounds of the formula I are preferred according to those of O. Then et al. in the methods described above herge poses.

The amidino group is preferably obtained by converting a cyano group by reaction with e.g. B. hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as. B. Pd / C or Raney nickel. To produce the amidine group, ammonia can also be added to a corresponding nitrile. The addition is preferably carried out in several stages, in a manner known per se

• a) converts the nitrile with H ₂ S into a thioamide, which can be treated with an alkylating agent, e.g. B. CH ₃ I, is converted into the corresponding S-alkyl imidothioester, which in turn reacts with NH ₃ to give the amidine,
• b) the nitrile with an alcohol, e.g. B. ethanol in the presence of HCl converts the corresponding imidoester and this with ammoni ak treated, or
• c) reacting the nitrile with lithium bis (trimethylsilyl) amide and the pro then hydrolyzed.

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation Men in particular sows in question, the physiologically acceptable Sal ze deliver. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid  or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Amei sensic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascor bic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- Toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfur acid. Salts with physiologically unacceptable acids, e.g. B. picrates, can for the isolation and / or purification of the compounds of For mel 1 can be used.

On the other hand, compounds of the formula I with bases (e.g. sodium or potassium hydroxide or carbonate) in the corresponding metal, ins special alkali metal or alkaline earth metal, or in the corresponding Ammonium salts are converted.

Also physiologically acceptable organic bases, such as. B. Ethanola min can be used.

The invention further relates to the use of the compounds of the formula I as NHE-3 inhibitors and / or their physiologically harmless Lichen salts for the production of pharmaceutical preparations, in particular the non-chemical way. Here you can together with min at least a solid, liquid and / or semi-liquid carrier or auxiliary substance and optionally in combination with one or more other Active ingredients are brought into a suitable dosage form.

The invention furthermore relates to pharmaceutical preparations, containing at least one NHE-3 inhibitor of the formula I and / or one its physiologically acceptable salts and solvates.

These preparations can be used as medicinal products in human or veteri used in medicine. Organic or inorganic substances in question that are suitable for enteral (e.g. oral),  parenteral or topical application and with the new compound not react, e.g. water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets, Capsules, powder, granules, syrups, juices or drops, for rectal application application suppositories, for parenteral application solutions, preferred wise oily or aqueous solutions, also suspensions, emulsions or implants, for topical application of ointments, creams or powder, or transdermally in patches.

The compounds can also be lyophilized and the Lyo obtained philisate z. B. can be used for the production of injectables. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, Emulsifiers, salts to influence the osmotic pressure, buffers substances, colors, flavors and / or several other active ingredients included, e.g. B. one or more vitamins.

As a pharmaceutical preparation for administration in the form of aero brines or sprays are suitable e.g. B. solutions, suspensions or emul Sions of the active ingredient of formula I in a pharmaceutically acceptable Chen solvent.

The compounds of formula I and their physiologically acceptable Salts and solvates can be used to treat and / or prevent the above described diseases or disease states can be used.

The substances according to the invention are generally preferred as in dosages between about 0.1 and 100 mg, in particular between between 1 and 10 mg per dosage unit. The daily dose tion is preferably between about 0.001 and 10 mg / kg body weight. However, the specific dose for each patient depends on the different most factors, for example the effectiveness of the used special connection, age, body weight, general health condition, gender, diet, time of administration and  path, the rate of excretion, drug combination and Severity of the respective disease to which the therapy applies. The oral Application is preferred.

The invention is explained in more detail by means of examples.

Synthesis of the active ingredients

According to O., 2,2'-tetramethylenedi-1-benzofuran-5-carboxamidine (1) was Then, H. Char, H. Griesmayer, Liebigs Ann. Chem. 1982, 1836 to 1869 manufactured.

Analogously to this synthesis, 2,2'-hexamethylenedi-1-benzofuran-5- carboxamidine (2).

2- [2- (6-Amidinoindol-2-yl) ethyl] -1-benzofuran-5-carboxamidine (3) according to the regulation in O. Then, H. Char, P. Fleischmann, H. Fricke, Liebigs Ann. Chem. 1986, 438 to 455.

Trans-1,2-bis (5-amidino-2-benzofuranyl) ethylene (4) was prepared according to the above written by O. Dann, G. Volz, E. Demant, W. Pfeifer, G. Bergen, H. Fick, E. Walkenhorst Liebigs Ann. Chem. 1973, 1112 to 1140.

For the pharmacological tests, the dihydrochlorides were ver turns.

Pharmacological tests

The following describes the methodology used to characterize the Compounds of formula I was used as NHE-3 inhibitors.  

The compounds of formula I were characterized in terms of their selectivity against the isoforms NHE-1 to NHE-3. The three isoforms were stably expressed in mouse fibroblast cell lines. The inhibitory effect of the compounds was assessed by determining the EIPA-sensitive ²² Na ⁺ uptake into the cells after intracellular acidosis.

To characterize the Na ⁺ / H ⁺ exchange inhibitors with regard to their isoform selectivity, the compounds were examined for their inhibition of the NHE isoforms NHE-1, -2 and -3, which were stably expressed in a mouse fibroblast cell line (see process part) by determining the EIPA-sensitive ²² Na ⁺ uptake into the cells after intracellular acidosis.

material and methods LAP1 cell lines that express the different NHE isoforms

The LAP1 cell lines expressing the isoforms NHE-1, -2 and -3 (a mouse fibroblast cell line) were obtained from Prof. J. Pouysségur (Nice, Frank Reich). The transfections were carried out according to the method of Fran chi et al. (1986). The cells were cultured in Dulbecco's modified Eagle medium (DMEM) with 10% inactivated fetal calf serum (FCS). For the selection of the NHE-expressing cells, the so-called "acid killing method" by Sardet et al. (1989) used. The cells were first removed in a NH ₄ Cl-containing bicarbonate and sodium-free buffer by washing with a bicarbonate, NH ₄ Cl and sodium-free buffer and incubated with a bicarbonate-free NaCl-containing buffer. Only those cells that functionally express NHE survived in the intracellular acidification to which they were exposed.

Characterization of NHE inhibitors in relation to their isoform selects vity

With the above mouse fibroblast cell lines expressing the isoforms NHE-1, NHE-2 and NHE-3, compounds according to the method described by Counillon et al. (1993) and Scholz et al. (1995) described procedure for selectivity towards the isoforms. The cells were acidified intracellularly using the NH ₄ Cl prepulse method and then by incubation in a bicarbonate-free ²² Na ⁺ -containing buffer. Due to the intracellular acidification, NHE was activated and sodium was absorbed into the cells. The effect of the test compound was expressed as an inhibition of EIPA (ethyl isopropylamiloride) sensitive ²² Na ⁺ uptake.

The cells expressing NHE-1, NHE-2 and NHE-3 were inoculated at a density of 5-7.5 x 10 ⁴ cells / well in microtiter plates with 24 wells and grown to confluence for 24 to 48 hours. The medium was aspirated and the cells were incubated for 60 minutes at 37 ° C. in NH ₄ Cl buffer (50 mM NH ₄ Cl, 70 mM choline chloride, 15 mM MOPS, pH 7.0). The buffer was then removed and the cells were quickly overlaid twice with the choline chloride washing buffer (120 mM choline chloride, 15 mM PIPES / Tris, 0.1 mM ouabain, 1 mM MgCl ₂ , 2 mM CaCl ₂ , pH 7.4); the cells were incubated in this buffer for 6 minutes. After the incubation period had elapsed, the incubation buffer was aspirated. To remove extracellular radioactivity, the cells were quickly washed four times with ice-cold phosphate-buffered saline (PBS). The cells were then solubilized by adding 0.3 ml of 0.1 N NaOH per well. The cell fragment-containing solutions were transferred to scintillation tubes. Each well was washed twice more with 0.3 ml of 0.1 N NaOH and the washing solutions were also added to the corresponding scintillation tubes. The tubes containing the cell lysate were mixed with scintillation cocktail and the radioactivity absorbed into the cells was determined by determining the β radiation.

Inhibition of ²² Na ⁺ uptake in rabbit erythrocytes

Na ⁺ / H ⁺ exchange activity was also determined by observing the uptake of ²² Na ⁺ ions in acidified rabbit erythrocytes. Rabbit erythrocytes have found widespread use in studies of Na ⁺ / H ⁺ exchange activity (Escobales & Fugueroa, 1991; Morgan & Canessa, 1990). The EIPA-sensitive portion of the ²² Na ⁺ uptake in acidified erythrocytes was regarded as Na ⁺ / H ⁺ -dependent ²² Na ⁺ uptake.

Cell preparation

Red blood cell preparation and internal acidification The red blood cells were strongly based on the procedures by Morgan and Canessa (1990).

The blood was obtained from rabbits (e.g. New Zealand White). It was collected in 50 ml Falcon centrifuge tubes containing 5 ml of sodium heparin solution (250 U / ml). The blood and heparin solution were mixed well. The red blood cells were obtained by centrifugation at 2000 × g at 4 ° C; Plasma and white blood cell cuff were removed. The remaining solution was filtered through 200 µm gauze. The filtrate was resuspended with wash buffer to the original volume (140 mM KCl, 0.15 mM MgCl ₂ , 10 mM TRIS / MOPS, pH 7.4). The red blood cells were again obtained by centrifugation (2000 × g, 4 ° C.). The washing process was repeated twice.

Intracellular acidification

For intracellular acidification, 5 ml of the deposited collected red blood cells were again suspended with 45 ml acidification buffer (170 mM KCl, 0.15 mM MgCl ₂ , 0.1 mM ouabain, 10 mM glucose, 10 mM sucrose, 20 mM Tris / Mes, pH 6.2). The red blood cell suspension was incubated for 10 minutes at 37 ° C (with occasional mixing). To fix the internal pH, up to 200 µM and 1 mM DIDS or DIAMOX (acetazolamide) are added. Incubation was continued for 30 minutes at 37 ° C.

The red blood cells were then collected by centrifugation (4 minutes at 2000 × g, 4 ° C); they were again suspended with ice-cold unbuffered washing solution (170 mM KCl, 40 mM sucrose, 0.15 mM MgCl ₂ ) and thus washed four times.

Incubation and measurement of the ²² Na ⁺ uptake

The incubation was carried out in Macrowell tube strips in a format of 8 × 12. The incubation was started by adding 200 .mu.l incubation buffer (160 mM KCl, ²² NaCl (37 MBq / well), 10 mM NaCl, 0.15 mM MgCl ₂ , 0.1 mM ouabain, 10 mM glucose, 40 mM Saccha rose, 10 mM Tris / MOPS, pH 8.0, 0.5 mM Diamox, 1% DMSO) with 20 μl of the (preheated) acidified solution of the red blood cells. The test substances were first dissolved with 100% DMSO and the solution was then diluted to the appropriate concentrations with incubation buffer. The mixture was incubated at 37 ° C. for 5 minutes. (In previous searches, it was shown that under these incubation conditions the ²² Na uptake rate was linear over the 5 minute incubation period).

The incubation was stopped by adding 800 μl of ice-cold stop solution (112 mM MgCl ₂ , 0.1 mM ouabain). The tubes were kept on ice for a short time. The tubes were then covered with parafilm and the red blood cells were obtained by centrifugation at 2000 × g and 4 ° C. for 7 minutes. The supernatant was aspirated with a self-made suction device, with which one could aspirate 4 adjacent tubes at the same time; Spacer rings on the further ends of the tips prevented the tips from penetrating too deeply into the tubes and the pellet of the red blood cells from being aspirated. All ²² Na-containing supernatants and washing solutions were kept and disposed of as radioactive waste.

The red blood cells were three times with 900 ul ice-cold stop solution washed, and that by the Sus oscillation / centrifugation step repeated. After the last wa The pellet of the red blood cells was washed with 200 µl water puts. The tubes were then sonicated 2 × 30 minutes treated. The Macrowell tube strips were then separated and each tube was turned upside down into its own scintile given lation tubes; the shake emptied by gentle shaking Molysed solution of the red blood cells in the scintillation vial.  

Each vial was washed with 3 ml of Aquasafe 300 scintillation fluid PS offset, and the jars were sealed and good mixed.

The radioactivity absorbed into the red blood cells was determined in an egg nem scintillation counter determined by tracking the β decay.

The determination was carried out in triplicate for each substance concentration. The mean of the count was presently subtracted from each value from 10 µM EIPA to include the non-Na ⁺ / H ⁺ -dependent ²² Na ⁺ uptake in the erythrocytes. The mean of the remaining counts in the absence of a substance was used as a 100% control; the mean values in the presence of the test compounds were expressed as a percentage of this control value. The percentages of the recording data were recorded semi-logarithmically; IC50 values were obtained by fitting the values to a nonlinear curve using the equation f (x) = 100 / (1 + (IC50 / x) ** n).

literature

Counillon et al. (1993) Mol. Pharmacol. 44: 1041-1045
Escobales and Figueroa (1991) J. Membrane Biol. 120, 41-49
Franchi et al. (1986) Proc. Natl. Acad. Sci. USA 83: 9388-9392
Morgan and Canessa (1990) J. Membrane Biol. 118, 193-214
Sardet et al. (1989) Cell 56: 271-280
Scholz et al. (1995) Cardiovasc. Res. 29: 260-268.

Test results

IC50 (NHE-1) = 2.2 µM
IC50 (NHE-3) = 1.7 µM

IC50 (NHE-1) = 2.7 µM
IC50 (NHE-3) = 1.9 µM

IC50 (NHE-1) = 4.6 µM
IC50 (NHE-2) = 47.6 µM
IC50 (NHE-3) = 0.98 µM

IC50 (NHE-1) = 0.69 µM
IC50 (NHE-3) = 1.5 µM

Example A Injection glasses

A solution of 100 g of an NHE-3 inhibitor of formula I and 5 g of Dina trium hydrogen phosphate is in 3 l of double distilled water with 2 n Hydrochloric acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection glass contains 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of an NHE-3 inhibitor of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C solution

A solution is prepared from 1 g of an NHE-3 inhibitor of the formula I, 9.38 g of NaH ₂ PO ₄ . 2H ₂ O, 28.48 g Na ₂ HPO ₄ . 12H ₂ O and 0.1 g benzal conium chloride in 940 ml double-distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D ointment

500 mg of an NHE-3 inhibitor of the formula I are mixed with 99.5 g of Vaseli ne under aseptic conditions.

Example E Tablets

A mixture of 1 kg of an NHE-3 inhibitor of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is in Compressed into tablets in the usual way, such that each tablet 10 mg Contains active ingredient.

Example F Dragees

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example G Capsules

2 kg of an NHE-3 inhibitor of the formula I are hard in the usual way filled gelatin capsules so that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of NHE-3 inhibitor of the formula I in 60 l of double distillation filtered water is sterile filtered, filled into ampoules, under sterile loading conditions lyophilized and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims (7)

1. Compounds of formula I.
in which mean
X:
n: an integer value between 1 and 6;
Y:
and their salts and solvates as NHE-3 inhibitors. 2. Compounds according to claim 1:

• a) 2,2'-tetramethylene di-1-benzofuran-5-carboxamidine (1);
• b) 2,2'-hexamethylleridi-1-benzofuran-5-carboxamidine (2);
• c) 2- [2- (6-Amidinoindol-2-yl) ethyl] -1-benzofuran-5-carboxamidine (3);
• d) trans-1,2-bis (5-amidino-2-benzofuranyl) ethylene (4)

and their salts and solvates as NHE-3 inhibitors. 3. Use of compounds of formula I according to claim 1 and ih re physiologically acceptable salts and / or solvates provision of a medicinal product for the treatment of thrombosis, ischemic conditions of the heart, peripheral and central Nervous system and stroke, ischemic conditions pe peripheral organs and limbs and for the treatment of shock states. 4. Use of compounds of formula I according to claim 1 and ih re physiologically acceptable salts and / or solvates Provision of a drug for use in surgical operations organ transplants and for preservation and location grafts for surgical measures. 5. Use of compounds of formula I according to claim 1 and ih re physiologically acceptable salts and / or solvates provision of a medicinal product for the treatment of diseases in which de cell proliferation is a primary or secondary cause provides, for the treatment or prophylaxis of disorders of the fatty substance alternating or disturbed breathing drive. 6. Use of compounds of formula I according to claim 1 and ih re physiologically acceptable salts and / or solvates provision of a medicinal product for the treatment of ischemic kidney, ischemic bowel diseases or for the prophylaxis of acute or chronic kidney disease.   7. Pharmaceutical preparation, characterized by a content at least one NHE-3 inhibitor according to claim 1 and / or one its physiologically acceptable salts and / or solvates.