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Definitions

• Novel substituted 2-aminoimidazoles process for their preparation, their use as medicament or diagnostic agent and medicament containing them
• the invention relates to compounds of the 2-aminoimidazole type which inhibit the sodium proton exchanger, in particular subtype 3 (NHE3), and which are useful in the prevention or treatment of various diseases.
• the compounds can be used, inter alia, in kidney diseases such as acute or chronic kidney failure, disorders of the bile function, respiratory disorders such as snoring or sleep apnea or stroke.
• the invention relates to compounds of the formula I,
• R1 and R2 together with the two carbon atoms to which they are attached denote a carbon ring containing five, six, seven or eight members, one or two double bonds, the ring being unsubstituted or having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 F atoms and / or with one or two radicals from the group OH, NR9R10, alkyl having 1, 2, 3 or 4 C atoms, CN, CF3 or alkoxy is substituted by 1, 2, 3 or 4 C atoms;
• R9 and R10 independently of one another are H or alkyl having 1, 2, 3 or 4 C atoms; or R 1 and R 2 independently of one another are H, alkyl having 1, 2, 3 or 4 C atoms, CN or phenyl where the carbon chains are unsubstituted or independently of 1, 2, 3, 4, 5, 6, 7, 8 or 9 F Atoms are substituted, wherein R1 and R2 are not both simultaneously hydrogen; R 3, R 4, R 5, R 6 and R 7 independently of one another are H, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 C atoms, or alkoxy having 1, 2, 3 or 4 C atoms, where Carbon chains are unsubstituted or independently substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms, wherein R3 and R7 are not both simultaneously hydrogen; R8
• R1 and R2 together with the two carbon atoms to which they are bonded denote a five-, six-, seven- or eight-membered carbon ring containing one or two double bonds, the ring being unsubstituted or having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 F atoms and / or substituted with one or two radicals from the group CH3 or OCH3;
• R3, R4, R5, R6 and R7 independently of one another are H, F, Cl, Br, alkyl having 1, 2, 3 or 4 C atoms or alkoxy having 1, 2, 3 or 4 C atoms, where the carbon chains are unsubstituted or are independently substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms, wherein R3 and R7 are not both simultaneously hydrogen; R8
• R1 and R2 together with the two carbon atoms to which they are attached denote a five, six or seven membered double bond-containing carbon ring, R3 and R7 independently of one another F, Cl, Br or alkyl having 1, 2, 3 or 4 C atoms, wherein the carbon chains are unsubstituted or independently substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms; R4, R5 and R6
• R 1 and R 2 independently of one another are H, alkyl having 1, 2, 3 or 4 C atoms, CN or phenyl, where the carbon chains are unsubstituted or independently of one another with 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms. Atoms are substituted, wherein R1 and R2 are not both simultaneously hydrogen;
• R 3, R 4, R 5, R 6 and R 7 independently of one another are H, F, Cl, Br or alkyl having 1, 2, 3 or 4 C atoms, where the carbon chains are unsubstituted or independently of one another with 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms are substituted, wherein R3 and R7 are not both simultaneously equal to hydrogen;
• R8
• R 1 and R 2 independently of one another denote H or alkyl having 1, 2, 3 or 4 C atoms; wherein R1 and R2 are not both simultaneously hydrogen; R3 and R7 independently of one another are F, Cl, Br or alkyl having 1, 2, 3 or 4 carbon atoms, where the carbon chains are unsubstituted or independently 1, 2, 3, 4, 5, 6, 7, 8 or 9 F Atoms are substituted; R4, R5 and R6
• R1 and R2 together with the two carbon atoms to which they are attached form a five-, six-, seven- or eight-membered carbon ring containing one or two double bonds, where the ring unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 F atoms and / or with one or two radicals from the group CH3 or OCH3; particularly preferred are compounds in which R1 and R2 together with the two carbon atoms to which they are attached form a five-, six- or seven-membered, double bond-containing, unsubstituted carbon ring.
• compounds of the formula I are preferred in which R 1 and R 2 are described independently of one another by H or alkyl having 1, 2, 3 or 4 C atoms.
• NHE sodium / hydrogen exchanger
• R1 and R2 independently of one another, are H, F, Cl, Br, I, CN, Alkyl having 1, 2, 3, 4, 5 or 6 C atoms, alkenyl having 2, 3, 4, 5 or 6 C atoms, alkynyl having 2, 3, 4, 5 or 6 C atoms, cycloalkyl having 3 , 4, 5 or 6 carbon atoms, cycloalkenyl having 4, 5 or 6 carbon atoms or phenyl, wherein phenyl unsubstituted or independently with one or two radicals from the group F, Cl, Br, l, OH, NR9R10, alkyl with 1, 2, 3 or 4 C atoms, CN, CF3 or alkoxy is substituted by 1, 2, 3 or 4 carbon atoms
• R9, R10 independently of one another are H, alkyl having 1, 2, 3 or 4 C atoms; and wherein the carbon chains or rings are unsubstituted or independently with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 F atoms and / or one or two radicals of the Group OH, NR9R10, alkyl having 1, 2, 3 or 4 C atoms, CN, CF3 or alkoxy with 1, 2, 3 or 4
• R9, R10 independently of one another are H, alkyl having 1, 2, 3 or 4 C atoms; preferably R1 and R2 do not simultaneously correspond to phenyl; or R1 and R2 together with the two carbon atoms to which they are attached, a five-, six-, seven- or eight-membered, one or two double bonds containing carbon ring, wherein the ring is unsubstituted or with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 F atoms and / or one or two radicals from the group NR9R10, alkyl having 1, 2, 3 or 4 C atoms, OH, CN, CF3 or alkoxy with 1, 2 , 3 or 4 carbon atoms is substituted with
• R9, R10 independently of one another are H, alkyl having 1, 2, 3 or 4 C atoms; R3, R4, R5, R6 or R7 independently of one another are H, F, Cl, Br, I, alkyl having 1, 2, 3 or 4 C atoms, (C2-4)
• R 1 and R 2 together with the two carbon atoms to which they are attached form a carbon ring containing five, six, seven or eight members containing one or two double bonds, wherein the ring is unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 F atoms and / or by one or two radicals selected from CH3 or OCH3; particularly preferred is the
• R3 and R7 are not described by hydrogen; particularly preferred is the use of compounds in which R3 and R7 are independently described by F, Cl, Br or alkyl having 1, 2, 3 or 4 carbon atoms, wherein the carbon chains unsubstituted or independently with 1, 2, 3 , 4, 5, 6, 7, 8 or 9 F atoms are substituted; very particular preference is given to the use of compounds in which R3 and R7 are described independently of one another by Cl or methyl, in particular Cl.
• R 8 is described by hydrogen or alkyl having 1, 2, 3 or 4 C atoms; particularly preferred is the use of compounds in which R8 is described by hydrogen or methyl.
• R 1, R 2, R 3, R 4, R 5, R 6, R 7 or R 8 contain one or more centers of asymmetry, these can be configured both independently of one another and S.
• the compounds can exist as optical isomers, as diastereomers, as racemates or as mixtures thereof in all ratios.
• the present invention includes all tautomeric forms of the compounds of formula I.
• Carbon chains are any radicals containing straight or branched chain carbon atoms, for example 1, 2, 3, 4, 5 or 6 carbon atoms.
• Examples are alkyl radicals, alkoxy radicals, alkenyl radicals, alkynyl radicals, alkylamino radicals or dialkylamino radicals.
• Carbon rings are all radicals containing carbon atoms which form a ring, for example, from 3, 4, 5 or 6 carbon atoms.
• Examples of carbon rings are cycloalkyl radicals, or cycloalkenyl radicals.
• Carbon chains or rings may be unsaturated in different positions and also polyunsaturated. In carbon chains or rings, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 hydrogen atoms substituted by fluorine atoms. Substituted carbon chains may be substituted in any positions.
• Alkyl radicals can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals.
• Preferred alkyl radicals are methyl, ethyl, isopropyl.
• alkyl radicals one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, hydrogen atoms may be substituted by fluorine atoms.
• fluoroalkyl radicals are trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, heptafluoroisopropyl.
• Substituted alkyl radicals may be substituted in any positions.
• Alkenyl radicals can be straight-chain or branched. This also applies if they carry substituents, for example in Fluoralkenylresten.
• alkenyl radicals are ethenyl, n-prop-1-enyl, n-prop-2-enyl, n-but-1-enyl, n-but-2-enyl, n-pentenyl, n-pentadienyl, isopentenyl, tert-pentenyl , Neopentenyl, n-hexenyl, n-hexadienyl, n-hexatrienyl, 3-methylpentenyl, isohexenyl, neohexenyl.
• alkenyl radicals one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 hydrogen atoms by fluorine atoms be substituted. Substituted alkenyl radicals may be substituted in any positions.
• Alkynyl radicals can be straight-chain or branched. This also applies if they carry substituents, for example in Fluoralkinylresten.
• alkynyl radicals are n-prop-1-ynyl, n-prop-2-ynyl, n-but-1-ynyl, n-but-2-ynyl.
• alkynyl radicals one or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen atoms may be substituted by fluorine atoms.
• Substituted alkynyl radicals may be substituted in any positions.
• cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• cycloalkyl radicals one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 hydrogen atoms may be substituted by fluorate atoms.
• Substituted cycloalkyl radicals may be substituted in any positions.
• the cycloalkenyl radicals may be unsaturated in different positions and also polyunsaturated.
• Examples of cycloalkenyl groups are cyclobut-1-enyl, cyclobut-2-enyl, cyclopentenyl, cyclopentadienyl, 'cyclohexenyl or cyclohexadienyl.
• cycloalkenyl radicals one or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9 hydrogen atoms may be substituted by fluorine atoms.
• Substituted cycloalkenyl radicals may be substituted in any positions.
• Phenyl radicals may be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted, disubstituted or trisubstituted, by identical or different radicals.
• the substituent may be in the 2-position, the 3-position or the 4-position.
• Double substituted phenyl can be used in Be substituted 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position.
• the compounds described by formula I can be prepared under acidic conditions from the underlying guanidines of the formula II or a tautomeric form of the formula II in a manner known to the person skilled in the art,
• radicals R 1 to R 8 are defined in accordance with formula I and E corresponds to an alkyl radical having 1 to 4 carbon atoms, where the two radicals E can also be linked to form a ring.
• the present invention thus further relates to a process for the preparation of ⁇ -
• R11, R12 independently of one another alkyl with 1, 2, 3 or
• R11, R12 independently of one another alkyl with 1, 2, 3 or
• R 1 and R 2 together with the two carbon atoms to which they are attached have a carbon ring containing five to eight membered saturated or double bond, which ring is unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11 or 12 F atoms and / or with one or two radicals from the group NR11 R12, alkyl having 1, 2, 3 or 4 C atoms, CN, CF3 or alkoxy with 1,
• R11, R12 independently of one another alkyl with 1, 2, 3 or
• Alkyl having 1, 2, 3 or 4 C atoms or both radicals E form a cyclic ketal in which E-E is (C 2 -C 4) -alkylene;
• compounds of the formula I can be prepared starting from cyanamides of the formula III and ⁇ -amino ketones of the formula IX in protic solvents such as alcohols, for example ethanol.
• NHE sodium / hydrogen exchanger
• NHE3 is found preferentially in bile, intestine, and kidney in the body of various species (Fliegel et al, Biochem., Cell, Biol., 76: 735-741, 1998), but could also be detected in the brain (E.M. et al., Neuroscience 79: 591-603).
• NHE3 inhibitors are derived, for example, from compounds of the acylguanidine type (EP 825 178), norbornylamine type (DE 199 60 204), 2-guanidinoquinazoline type (WO 01 79 186, WO 02 20496) or benzamidine type (WO 01 21582, WO 01 72 742).
• the squalamine also described as NHE3 inhibitor (M. Donowitz et al Am. J. Physiol 276 (Cell Physiol 45: C136 - C144) does not act directly like the compounds according to formula I, but reaches its maximum potency only after one Hour.
• German patent application DE 10163239 describes imidazolidine-type NHE 3 inhibitors
• German patent application DE 10224892 describes the thiophene type.
• NHE3 inhibitors of the 2-phenylaminobenzimidazole type are described in WO 02 46169 A1. Surprisingly, it has now been found that the imidazole derivatives of the formula I described here likewise represent potent inhibitors of NHE3 and possess advantageous pharmacological properties.
• the clonidine-like clonidine described herein is known as a weak NHE inhibitor. However, its effect on the NHE3 of the rat is with an IC50 of 620 ⁇ M extremely moderate. Instead, it has some selectivity for the NHE2 having an IC50 of 42 ⁇ M (Orlowski, J., et al., J. Biol. Chem.
• NHE2 inhibitor It is therefore more likely to be referred to as NHE2 inhibitor.
• the clonidine has a high affinity for the adrenergic ⁇ 2 receptor and imidazoline H receptor, whereby a strong antihypertensive effect is mediated (Ernsberger et al Eur. J. Pharmacol., 134, 1, 1987).
• Compounds of the formula I are distinguished from clonidine by increased NHE3-inhibiting activity.
• the compounds of formula I are useful in the prevention and treatment of diseases caused by activation or by activated NHE.
• the use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.
• the inhibitors of NHE according to the invention are suitable for the treatment of diseases which are caused by ischemia and / or by reperfusion.
• the compounds described herein are due to their pharmacological properties as antiarrhythmic drugs with cardioprotective component for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris ideally suited, and they also preventively the pathophysiological processes in the development of ischemic induced damage, especially in the induction of ischemic induced cardiac arrhythmias, inhibit or greatly reduce. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds used in the invention
• Formula I due to inhibition of the cellular Na + / H + exchange mechanism can be used as a medicament for the treatment of all acute or chronic ischemia-induced damage or thereby primarily or secondarily induced diseases.
• This relates to their use as drugs for surgical interventions, eg in organ transplants, where the compounds for both the Protection of the organs in the donor before and during removal, for the protection of organs removed, for example, during treatment with or storage in physiological bath fluids, as well as in the transfer to the recipient organism can be used.
• the compounds are also valuable, protective drugs in the conduct of angioplasty surgery, for example, at the heart as well as on peripheral vessels.
• the compounds are also useful as medicaments for the treatment of ischemia of the nervous system, in particular of the CNS, e.g. are suitable for the treatment of stroke or cerebral edema.
• the compounds of formula I used in the invention are also useful in the treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.
• the compounds induce an improvement in respiratory drive and are therefore used for the treatment of respiratory conditions in the following clinical conditions and diseases: impaired central respiratory drive (eg central sleep apnea, sudden infant death, postoperative hypoxia), muscular respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders Adaptation in high mountains, obstructive and mixed form of sleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia.
• impaired central respiratory drive eg central sleep apnea, sudden infant death, postoperative hypoxia
• muscular respiratory disorders eg. central sleep apnea, sudden infant death, postoperative hypoxia
• muscular respiratory disorders eg.g central sleep apnea, sudden infant death, postoperative hypoxia
• respiratory disorders after long-term ventilation e.g., respiratory disorders after long-term ventilation
• respiratory disorders Adaptation in high mountains obstructive and mixed form of sleep apnea
• acute and chronic lung diseases ed.
• a combination of an NHE inhibitor with a carbonic anhydrase inhibitor (eg, acetazolamide), the latter inducing metabolic acidosis and thereby already increasing respiratory activity, proves to be advantageous by enhanced activity and reduced drug usage.
• a carbonic anhydrase inhibitor eg, acetazolamide
• the compounds described herein are useful as medicaments for the therapy and prophylaxis of diseases and disorders caused by Over-excitability of the central nervous system are triggered, in particular for the treatment of epileptic disorders, centrally triggered clonic and tonic spasms, mental depression, anxiety disorders and psychosis.
• the NHE inhibitors described herein can be used alone or in combination with other antiepileptic substances or antipsychotic agents, or Carboanhydratasehemmern, for example with acetazolamide, as well as with other inhibitors of NHE or the sodium-dependent chloride bicarbonate exchanger (NCBE).
• the compounds used according to the invention have a mild laxative effect and can therefore advantageously be used as laxatives or in the event of imminent intestinal blockage.
• the compounds of the invention can be used advantageously for the prevention and treatment of acute and chronic diseases of the intestinal tract, which are triggered by ischemic conditions in the intestinal area and / or by subsequent reperfusion.
• Such complications may be caused, for example, by a lack of intestinal peristalsis, such as e.g. often after surgical procedures, constipation or greatly reduced intestinal activity are observed.
• it is possible to prevent gallstone formation.
• the compounds of the formula I used according to the invention are distinguished by a potent inhibiting action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of vascular smooth muscle cells. Therefore, the compounds of formula I can be used as valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, remedies for diabetic late complications, agents for chronic renal failure, cancers, fibrotic diseases of the heart, as well as pulmonary fibrosis, liver fibrosis or renal fibrosis, organ hypertrophy and hyperplasias, for example, of the heart and the prostate, and thus be used for the prevention and treatment of congestive heart failure or in prostate hyperplasia or prostatic hypertrophy.
• the compounds of the present invention are potent inhibitors of the cellular sodium proton antiporter (Na / H exchanger), which in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) is also increased in those cells which are readily accessible to measurements, such as In erythrocytes, thrombocytes or leukocytes, the compounds used in the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostic agents for the determination and differentiation of certain forms of hypertension, but also atherosclerosis, diabetes and diabetic late complications, proliferative diseases, etc ,
• the compounds of formula I are suitable for preventive therapy for the prevention of the genesis and treatment of hypertension, for example essential hypertension, since they reduce or completely inhibit the reabsorption of NaCl in the tubular kidney system. Accordingly, they are also highly suitable as combination and formulation partners for drugs used for hypertension treatment.
• drugs used for hypertension treatment For example, thiazide-type diuretics, loop diuretics, aldosterone and pseudoaldosterone antagonists such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene can be combined.
• the NHE inhibitors of the present invention may be used in combination with ACE inhibitors such as ramipril, enalapril or captopril. Other favorable combination partners are also ⁇ -blockers.
• the NHE inhibitors described can also be used in the prevention and treatment of thrombotic diseases, since they as NHE inhibitors can both inhibit platelet aggregation itself and, moreover, inhibit or prevent the excessive release of coagulation mediators, in particular von Willebrand factor. Therefore, the NHE Inhibitors of the present invention can be combined with other anticoagulant agents such as acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, fibrinolytic drugs, F ⁇ ktor Vlla antagonists, etc. Combined use of the present NHE inhibitors with NCBE inhibitors is particularly beneficial.
• NHE inhibitors show a favorable effect on the serum lipoproteins. It is generally accepted that high blood lipid levels, so-called hyperlipoproteinemias, are a significant risk factor for the development of atherosclerotic vascular changes, especially coronary heart disease. For the prophylaxis and regression of atherosclerotic changes, therefore, the reduction of elevated serum lipoproteins is of extraordinary importance.
• the compounds used according to the invention can therefore be used for the prophylaxis and regression of atherosclerotic changes by eliminating a causal risk factor.
• the NHE inhibitors of the invention may also be favorably combined with other antiarteriosclerotic agents, such as a class of fibrates, an upregulator of LD2 receptor activity, such as MD-700 and LY295427, or a cholesterol or bile acid resorption inhibitor or an antihypercholesterolemic from the class of statins such as pravastatin, lovastatin, simvastatin.
• antiarteriosclerotic agents such as a class of fibrates, an upregulator of LD2 receptor activity, such as MD-700 and LY295427, or a cholesterol or bile acid resorption inhibitor or an antihypercholesterolemic from the class of statins such as pravastatin, lovastatin, simvastatin.
• compounds of formula I are valuable drugs for the prevention and treatment of coronary vascular spasms, peripheral vascular diseases such as claudicatio intermittens, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic disorders ,
• the compounds mentioned can also be used for the treatment of diseases caused by protozoa and are particularly useful as antimalarials.
• the compounds are useful for controlling sucking parasites such as mosquitoes, ticks, fleas and plant pests. According to their protective effects, the compounds are also useful as medicines for health maintenance and life extension.
• the NHE inhibitors described herein can be conveniently combined with other intracellular pH regulating compounds using inhibitors of the carboanhydrase enzyme group, inhibitors of bicarbonate ion transporting systems such as the sodium bicarbonate cotransporter or the sodium dependent chloride bicarbonate.
• Exchanger as well as other NHE inhibitors, for example, with inhibitory effect on other NHE subtypes, come as a combination partner in question, because they can be enhanced by the pharmacologically relevant pH-regulating effects of the NHE inhibitors described herein.
• the compounds mentioned are therefore advantageously used for the preparation of a medicament for the prevention and treatment of sleep apnea and muscular respiratory disorders; for the manufacture of a medicament for the prevention and treatment of snoring; for the manufacture of a medicament for lowering blood pressure; for the preparation of a medicament having a laxative effect for the prevention and treatment of intestinal blockages; for the manufacture of a medicament for the prevention and treatment of disorders caused by ischemia and reperfusion of central and peripheral organs such as acute renal failure, stroke, endogenous shock states, bowel disease, etc .; for the manufacture of a medicament for the treatment of late-stage diabetic and chronic renal disease, in particular all kidney inflammations (nephritides) associated with increased protein / albumin excretion; for the manufacture of a medicament for the treatment of hypercholesterolemia; for the manufacture of a medicament for the prevention of atherogenesis and atherosclerosis; for the manufacture of a medicament for the prevention and treatment of diseases caused by elevated cholesterol levels; for the manufacture of a medicament for the
• HMG-CoA reductase inhibitor eg lovastatin or pravastatin
• sodium proton exchange inhibitors of formula I as novel drugs for lowering elevated blood lipid levels, and the combination of sodium proton exchange inhibitors with antihypertensive and / or hypolipidemic drugs are claimed.
• the invention also relates to remedies for human, veterinary or phytoprotective use comprising an effective amount of a compound of formula I and / or a pharmaceutically acceptable salt thereof, as well as remedies for human, veterinary or phytoprotective use containing an effective amount of a compound of formula I and / or a pharmaceutically acceptable salt thereof, alone or in combination with one or more other pharmacologically active substances or medicaments.
• Medicaments which comprise a compound of the formula I can be administered, for example, orally, parenterally, intravenously, rectally, topically or by inhalation, the preferred application being dependent on the particular appearance of the disease.
• the compounds of the formula I can be used alone or together with pharmaceutical excipients, both in veterinary medicine and in human medicine and plant protection. Which excipients are suitable for the desired drug formulation is familiar to the person skilled in the art on the basis of his specialist knowledge.
• solvents, gelling agents, suppository bases, tablet excipients, and other drug carriers for example, antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers or dyes can be used.
• the active compounds are mixed with the appropriate additives, such as carriers, stabilizers or inert diluents and brought by the usual methods in the appropriate dosage forms, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions.
• the appropriate additives such as carriers, stabilizers or inert diluents and brought by the usual methods in the appropriate dosage forms, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions.
• inert carrier can z. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch.
• the preparation can be carried out both as a dry and as a wet granules.
• Suitable oily carriers or as solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
• the active compounds used are, if desired, brought into solution, suspension or emulsion with the customary substances such as solubilizers, emulsifiers or other excipients.
• a solvent come z. B. in question: water, physiological saline or alcohols, eg. As ethanol, propanol, glycerol, besides sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.
• a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable, for.
• the formulation may also contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as a propellant gas.
• Such Preparation contains the active ingredient usually in a concentration of about 0.1 to 10, in particular from about 0.3 to 3 wt .-%.
• the dosage of the active ingredient of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; also the type and strength of the disease to be treated as well as the sex, age, weight and individual responsiveness of the mammal to be treated.
• the daily dose of a compound of formula I in a patient weighing about 75 kg is at least 0.001 mg / kg, preferably 0.1 mg / kg to at most 50 mg / kg, preferably 1 mg / kg of body weight.
• a compound of formula I in a patient weighing about 75 kg is at least 0.001 mg / kg, preferably 0.1 mg / kg to at most 50 mg / kg, preferably 1 mg / kg of body weight.
• even higher and above all more frequent dosages may be necessary, for. ß. up to 4 single doses per day.
• up to 200 mg / kg per day may be necessary.
• Pharmaceutically acceptable salts are z. B. from the following acids: from inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or from organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, malonic acid, methanesulfonic acid, fumaric acid.
• inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid
• organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, malonic acid, methanesulfonic acid, fumaric acid.
• Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methyl sulfonates, p-toluene sulfonates, adipinates, fumarates, gluconates, glutamates, glycerol phosphates, maleinates and pamoates (this group also corresponds to the physiologically acceptable anions); but also trifluoroacetates.
• halides in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methyl sulfonates, p-toluene sulfonates, adipinates, fumarates, gluconates, glutamates, glycerol phosphates, maleinates and pamoates (this group also corresponds
• Method D stationary phase: Merck Purospher, 3 ⁇ , 2 x 55 mm mobile phase: 95% H2O (0.1% HCOOH) ⁇ 95% acetonitrile (0.1% HCOOH), 5 min; ⁇ 95% acetonitrile (0.1% HCOOH), 2 min; -> 95% H2O (0.1% HCOOH), 1 min; 0.45 ml / min.
• Phthalimide (3 g) was dissolved in dry tetrahydrofuran (70 ml) and added dropwise at room temperature to a suspension of sodium hydride (539 mg) in tetrahydrofuran (15 ml). The mixture was then heated for one hour at 40 ° C and then added dropwise a solution of chloroacetone (1, 99 g) dissolved in tetrahydrofuran (15 ml). Subsequently, the mixture was kept at reflux temperature for 15 hours. After cooling, it was added to an ice / water mixture and extracted three times with ethyl acetate.
• Diamino-maleic acid dinitrile (500 mg) was dissolved in absolute tetrahydrofuran (7.5 ml) and treated with 2,6-dichlorophenylisothiocyanate. After stirring for 3 hours at room temperature and standing overnight, the solvent was removed and the residue was purified. The product-containing fractions were combined, the acetonitrile removed on a rotary evaporator, the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. After drying over magnesium sulfate, it was brought to dryness. There were 73 mg of the obtained thiourea intermediate.
• 2,6-dichlorophenyl cyanamide (1 g, prepared as described in J. Med. Chem., 1975, 18, 90-99) was dissolved in dry dimethylformamide (25 ml) and powdered potassium carbonate (739 mg) added. After stirring for five minutes at room temperature, methyl iodide (1.52 g) was added dropwise and stirred at room temperature for two hours. After removal of the solvent, the residue was taken up with water and extracted three times with ether. The combined organic phases were dried over magnesium sulfate and filtered. After removal of the solvent, the residue was purified by preparative HPLC.
• BCECF Fluorescent dye BCECF (Calbiochem, using the precursor BCECF-AM) is determined.
• the cells fibroblasts, LAP1 cells
• the BCECF fluorescence was determined in a Ratio Fluorescence Spectrometer (Photon Technology International, South Brunswick, NJ, USA) at excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and converted to the pHj by means of calibration curves.
• NH4Cl buffer pH 7.4
• NH4CI- buffer 115 mM NaCl, 20 mM NH4Cl, 5 mM KCl, 1 mM 'CaCfc, 1 mM MgSO 4, 20 mM Hepes, 5 mM glucose, 1 mg / ml BSA, adjusted to pH 7.4 with 1 M NaOH.
• Intracellular acidification was achieved by addition of 975 ⁇ l NH4Cl-free
• Buffers (see below) to 25 ul aliquots of incubated in NH4CI buffer cells. The subsequent rate of pH recovery was recorded for three minutes. For the calculation of the inhibitory potency of the tested substances, the cells were first examined in buffers in which complete or no pH recovery took place. For complete pH recovery (100%), the cells were incubated in Na + -containing buffer (133.8 mM NaCl, 4.7 mM KCl, 1, 25 mM CaCl 2, 1, 25 mM

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