NO329351B1 - Substituted thiophene, its use and drug for human or veterinary use - Google Patents

Abstract

Substituted thiophene derivatives of formula I are described in which R1 to R8 have the meaning given in the claims. Drugs containing compounds of this type are useful for contraception or therapy of various diseases. Thus, the compounds can be used, inter alia, for the treatment of respiratory disorders and snoring, for the improvement of respiration, for the treatment of acute and chronic diseases, diseases triggered by ischemic and repercussion events as well as in proliferative or fibrotic events, further for therapy or prophylaxis of diseases of the central nervous system , lipid metabolism and diabetes, blood clots and parasitic infections

Description

The present invention relates to compounds of the type substituted thiophene derivatives of formula I. Medicines containing compounds of this type are useful in the prevention or therapy of various diseases. Thus, the compounds can be used, among other things, for the treatment of breathing difficulties and snoring, as well as the improvement of breathing, for the treatment of acute or chronic diseases, diseases that are triggered by ischemic and/or reperfusion events, as well as triggered by proliferative or fibrotic events, for therapy or prophylaxis of diseases of the central nervous system, fat metabolism and diabetes, as well as blood coagulation and parasite infestation.

The present invention relates to compounds of formula I

there

R<1> means H, F, Cl, Br, I, CN or NO 2 ;

R<2> is H, F, Cl, Br, I, CN, NO 2 or C 1 -C 6 alkyl;

n is zero;

q is zero, 1, 2, 3, 4, 5 or 6;

Z is hydrogen;

R<3> means hydrogen, F, Cl, Br, I or CN;

R<4> means hydrogen or -CrH2r-Y;

r is zero, 1, 2, 3 or 4;

Y means hydrogen;

R<5> and R6 are hydrogen or together form a bond;

R and R together mean a butylene chain;

or

R<7> and R<8> together form a residue

where R<5> and R<6> together may form a bond;

R<10> and R<n> are independently hydrogen, fluorine, chlorine, bromine;

R<9> and R<12> are hydrogen or F;

or

one of the substituents R<9> and R<12> is

hydrogen;

and the second is F, Cl, Br, I or -(X)n-CqH2Q-Z;

n is zero or 1;

X is oxygen;

q is zero, 1,2, 3,4, 5 or 6;

and

Z is hydrogen;

as well as their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts.

In one embodiment, the invention relates to compounds of formula I where R<1> is H, F, Cl, Br;

R<2> is F, Cl, Br or CH3;

R<3> is hydrogen, F or Cl;

R<4> is hydrogen or C1-4 alkyl;

R<5> and R6 are hydrogen or a common bond;

R<7> and R8 together form a butylene chain,

or

R<7> and R<8> together form a residue

where R<5> and R<6> together form a bond;

R<10> and R<n>, independently of each other, are hydrogen, fluorine or chlorine;

R<9> and R<12> are hydrogen;

or

one of the substituents R and R is hydrogen;

and the other is F, Cl, Br or -(X)n - CqH2q-Z;

n is zero or 1,

X is oxygen;

q is zero, 1, 2, 3 or 4;

Z is hydrogen;

as well as their pharmaceutically acceptable salt, as well as their trifluoroacetic acid salts.

Preferred are compounds of formula I, where:

R<1> and R<2>, independently of each other, are F, Cl or Br;

R<3> is hydrogen;

R<4> is hydrogen, methyl or ethyl;

R<5> and R6 are hydrogen or together form a bond;

R<7> and R<8> together form a butylene chain,

or

T R

R' and R° together form a residue

where R<5> and R<6> together form a bond;

R<10> and R<n>, independently of each other, are hydrogen or fluorine;

R<9> and R<12> are hydrogen;

or

one of the substituents R9 and R<12> is hydrogen;

and the other is F, Cl, Br or -(X)n - CqH2q-Z;

n is zero or 1,

X is oxygen;

q is zero or 1;

Z is hydrogen;

as well as their pharmaceutically acceptable salt, as well as their trifluoroacetic acid salts.

Particularly preferred are the following compounds of formula I, selected from the group: trans-R,R-2-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4 -methyl-3-thienylamine, trans-R,R-2-bromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine,

2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine,

2-bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine,

2-chloro-3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine, 2-chloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine, 2- chloro-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene, 2-bromo-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene, 2-bromo-3N-(4-fluoro-2 -benzimidazolylamino)-4-methylthiophene, 2-chloro-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene, 2-chloro-3N-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene,

(1H-benzimidazol-2-yl)-(2-chloro-4-methylthiophen-3-yl)-methylarnine, (2-bromo-4-methylthiophen-3-yl)-(5-fluoro-1H-benzimidazol -2-yl)-amine, 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene

and

2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene,

as well as their pharmaceutically acceptable salts. As an example, mention may be made of the hydrochloride or hydrobromide or methanesulfonate of each of the compounds.

The compounds of formula I can be present in the form of their salts. As acid addition salts, salts of all pharmacologically acceptable acids such as halides and especially hydrochlorides, hydrobromides, further lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, benzenesulfonates, p-toluenesulfonates, adipinates, fumarates, gluconates, glutamates, glycerol phosphates, maleates, benzoates, oxalates and pamoates. This group also corresponds to the physiologically acceptable anions; but also trifluoroacetates. If the compounds contain an acid group, they can form salts with bases, such as alkali metal salts and preferably sodium or potassium salts, or as ammonium salts, for example as salts with ammonia or inorganic amines or amino acids. They can also exist as a zwitterion.

If the compounds of formula I contain one or more asymmetric centers, these can independently be configured both S and R. The compounds can also exist as optical isomers, as diastereomers, as racemates or as mixtures of these.

The compounds of formula I can also exist as tautomers, or as a mixture of tautomeric structures. Thereby, one can for example imagine the following tautomeric structures:

The alkyl residues can be straight or branched. This also applies when they carry substituents or act as substituents on other residues, for example in fluoroalkyl residues or carboxylic acid residues. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl (= 1-methylethyl), n-butyl, isobutyl (= 2-methylpropyl), sec-butyl (= 1-methylpropyl), tert-butyl (= 1,1 -dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl or hexyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl.

Methods for producing the compounds of the invention are further described. Thus, the substances described with formula I can be prepared in a manner known per se from the underlying isothiocyanates II and the corresponding diamines III.

The intermediately formed thiourea derivative is cyclized using methyl iodide (Synthesis, 1974, 41-42) or carbodiimide (Synthesis, 1977, 864-865) or with p-toluenesulfonic acid chloride to the corresponding compound with formula I. The isothiocyanates II used here can, to the extent that they are not commercially available, are prepared in a manner known from the literature from the corresponding aminothiophene derivatives by methods known per se, for example by treatment with thiophosgene (J. Med. Chem., 1975, 18, 90-99) or thiocarbonyldiimidazole ( Justus Liebig's Ann. Chem., 1962, 657, 104).

In addition to the isothiocyanates II described above, the isocyanates IV

easily reacted with amines of the type with formula III to compounds with formula I. Hereby, the intermediately formed urea derivative is ring-closed with phosphorus oxychloride to the corresponding compounds with formula I.

With the present invention, it could surprisingly be shown that the described compounds constitute potent inhibitors of the sodium/proton exchanger (NHE), in particular the sodium/proton exchanger of subtype 3 (NHE3).

The hitherto known NHE3 inhibitors are derived from compounds of the type acylguanidine (EP825178), norbornylamine (DE199 60 204), 2-guanidino-quinazoline (WO 01/79186) or benzamidine (WO 01/21582, WO 01/72742). Also described as an NHE-3 inhibitor, squalamine (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144) does not, as is known today, act immediately like the compounds according to formula I, but via an indirect mechanism and therefore achieves its maximum activity only after an hour.

Such mechanistically different NHE3 inhibitors are therefore suitable as combination partners for the compounds according to the present invention.

Clonidine, like the compounds described here, is known as a weak NHE inhibitor. Admittedly, the effect on NHE3 in the rat is extremely moderate with a half-maximal inhibitory concentration (IC50) of 620 uM. Instead, this compound exhibits some selectivity for NHE2 (J. Orlowski et al. J. Biol. Chem. 268, 25536). It is therefore better to describe it as an NHE2 inhibitor. In addition to its weak NHE action, clonidine has a high affinity for the adrenergic α2 receptor and the imidazoline II receptor, causing a strong blood pressure-lowering effect (Ernsberger et al. Eur. J. Pharmacol. 134,1,1987).

Clonidine-like compounds with a thiophene ring instead of the phenyl ring are known from DE1941761. These known compounds differ from the structures described here with formula I, by considerably smaller residues R<7> and R<8>, and in particular by the fact that R<7> and R<8> cannot form a common ring.

Due to these differences in the substituents R<7> and R<8>, the above-described clonidine-like, undesirable due to the α-adrenoceptor action mediated cardiovascular effects for these thiophene derivatives can be eliminated. At the same time, due to the substitution differences, the NHE-inhibiting property of the compounds described here is enhanced into the micromolar and submicromolar range, while the compounds known from DE1941761 show no, or only very weakly pronounced, NHE-inhibiting effects. Thus, the main representative from DE1941761, the blood pressure-lowering thiamenidine chosen as a development preparation, has no inhibitory effect already at 300 uM on the investigated NHE subtypes NHE1, NHE2, NHE3 and NHE5.

Compounds of formula I are distinguished by inhibition of the cellular sodium proton exchanger, and in particular by NHE3-inhibitory action.

NHE3 is found in the body in various species, and preferably in bile, intestine and kidney (Larry Fliegel et al, Biochem. Cell. Biol. 76: 735-741, 1998), but however cannot be detected in the brain (E. Ma et al .Neuroscience 79: 591-603).

Due to the NHE-inhibitory properties, the compounds of formula I are suitable for the prevention or treatment of diseases caused by an activation of NHE, respectively by an activated NHE, as well as diseases that are secondary to NHE-related damage.

As NHE inhibitors predominantly work via influencing the cellular pH regulation, they can be advantageously combined with other intracellular pH value-regulating compounds whereby inhibitors of the enzyme group of carbonic anhydratases, inhibitors of bicarbonate ion transporting systems such as the sodium bicarbonate cotransporter (NBC) or the sodium-dependent chloride bicarbonate yields (NCBE), as well as NHE inhibitors with an inhibitory effect on other NHE subtypes, come into consideration as combination partners because with these the pharmacologically relevant pH-regulating effects of the NHE inhibitors described here can be enhanced or modulated.

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 pharmacological effect of the compounds of formula I is characterized by the fact that it leads to an improvement in breathing. They can therefore be used for the treatment of disturbed respiratory conditions which can, for example, appear after clinical conditions and diseases: disturbed, central breathing (for example, central sleep apnoea, sudden infant death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after a long period of artificial respiration, respiratory disorders during adaptation to higher elevations, obstructive and mixed forms of sleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia. In addition, the compounds increase the muscle tone of the upper airways so that snoring is suppressed. The compounds are therefore advantageously used for the production of a drug for the prevention and treatment of sleep apnea and muscle-related breathing disorders, for the production of a drug for the prevention and treatment of snoring.

A combination of an NHE inhibitor of formula I with a carbonic anhydrase inhibitor (for example acetazolamide) may prove advantageous whereby the latter provides a metabolic acidosis and therefore already increases respiratory stability so that an enhanced effect and a reduced use of active substance can be achieved .

Due to the NHE3-inhibitory effect, the compounds of the invention spare the cellular energy reserves which are rapidly depleted during toxic or pathogenic events, and which therefore lead to cell damage or to cell death. Thereby, the energy-demanding ATP-consuming sodium resorption in the proximal tubule is temporarily stopped under the influence of the compounds of formula I, whereby the cells can survive an acute pathogenic, ischemic or toxic situation. The compounds are therefore suitable, for example, as drugs for the treatment of ischemic events, for example acute kidney failure.

Furthermore, the compounds are also suitable for the therapy of all chronic kidney diseases and forms of nephritis which, due to increased protein excretion, lead to chronic kidney failure. According to this, the compounds of formula I are suitable for the preparation of a drug for the therapy of diabetic late damage, diabetic nephropathy and chronic kidney diseases, in particular all kidney inflammations (nephritis) which are associated with an increased protein/albumin secretion.

It has been shown that the compounds according to the invention have a mild laxative effect, and they can therefore also be used with advantage as a laxative or in case of threatening intestinal constipation.

Furthermore, the compound's inventions can be advantageously used for the prevention or treatment of acute and chronic diseases in the intestinal tract, which are for example triggered by ischemic conditions in the intestinal area and/or by subsequent reperfusion, or by inflammatory conditions and events. Such complications can, for example, be observed with a lack of intestinal peristalsis, as often happens after surgical interventions, with constipation or with greatly reduced bowel activity.

With the compounds of the invention, there is also the possibility of preventing gallstone formation.

The NHE inhibitors of the invention are generally suitable for the treatment of diseases induced by ischemia or by reperfusion.

The compounds of the invention are, due to their pharmacological properties, suitable as antiarrhythmic drugs.

Due to their cardioprotective component, the NHE inhibitors of formula I are excellently suited for infarct prophylaxis and infarct treatment, as well as for the treatment of angina pectoris, whereby they also preemptively inhibit or greatly reduce the pathophysiological processes in the formation of ischemic-induced damage, particularly in the triggering of ischemic induced cardiac arrhythmias. Due to the protective effect against pathological hypoxic or ischemic situations, the compounds of the formula I of the invention, as a result of inhibition of the cellular NA<+>/H<+-> exchange mechanism, can be used as drugs for the therapy of all acute or chronic injuries triggered by ischemia, or thereby primarily or secondarily induced diseases.

This concerns their use as medicine for surgical interventions. Thus, the compounds of the invention can be used in organ transplants, whereby the compounds can be used both for the protection of organs in the donor before and during the removal, for the protection of removed organs, for example by treatment with, or their storage in physiological bath fluids, as well as by transfer to the one with compounds with formula I pre-treated recipient organism. The compounds are likewise valuable, protectively acting drugs when carrying out angioplasty operations, for example on the heart, but also on peripheral organs and tissues.

Since NHE inhibitors protect human tissues and organs, not only effectively against damage caused by ischemia and reperfusion, but also against the cytotoxic effect of drugs such as these find particular application in cancer therapy and therapy of autoimmune diseases, the combined administration with compounds of formula In suitable for reducing or inhibiting the cytotoxic effects of a therapy. Due to the reduction of these toxic effects, and in particular the cardiotoxicity, by co-medication with NHE inhibitors, the dose of the cytotoxic therapeutics can also be increased and/or the medication with such drugs can be prolonged. The therapeutic benefit of such cytotoxic therapies can be significantly increased by combination with NHE inhibitors.

The compounds of formula I are particularly suitable for improving therapy with drugs having an undesirable cardiotoxic component.

Corresponding to the protective effect against ischemically induced damage, the compounds of the invention are also suitable as pharmaceuticals for the treatment of ischaemia in the nervous system, and in particular the central nervous system, whereby they are also suitable, for example, for the treatment of strokes or cerebral oedema.

The compounds of formula I are also suitable for the treatment and prophylaxis of diseases and disorders that are triggered by hypersensitivity in the central nervous system, in particular for the treatment of diseases of the epileptic form circuit, centrally unresolved clonic and tonic spasms, mental depression states, anxiety disorders and psychoses. Thereby, the NHE inhibitors of the invention can be used alone or in combination with other, antiepileptic substances and antipsychotic active substances or carbonic anhydratase inhibitors, for example with acetazolamide, as well as with further inhibitors of NHE or the sodium-dependent chloride bicarbonate yielder (NCBE).

In addition to this, the compounds of formula I according to the invention are also suitable for treating forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds of formula I can likewise be used for the prevention or treatment of thrombotic diseases, since as NHE inhibitors they can also inhibit platelet aggregation. In addition to this, after ischemia and reperfusion, they can inhibit, or prevent, the excess release of inflammatory and clotting mediators, particularly von Willebrand factor and thrombogenic selectin proteins. Thereby, the pathogenic effect of thrombogenic and inflammation-relevant factors can be reduced or eliminated. Therefore, the NHE inhibitors according to the present invention can be combined with additional, anticoagulant and/or thrombolytically active ingredients, such as, for example, recombinant or natural tissue plasminogen activators, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, fibrinolytic drugs, thromboxane receptor antagonists, phosphodiesterase inhibitors , factor Vlla antagonists, clopidogrel, ticlopidine, etc. A combined use of the present NHE inhibitors with NCBE inhibitors and/or with inhibitors of carbonic anhydratase, such as for example acetazolamide, is particularly advantageous.

In addition to this, the compounds of formula I according to the invention are distinguished by a strong inhibitory effect on the proliferation of cells, for example fibroblast cell proliferation and proliferation of smooth muscle cells. Therefore, the compounds of formula I also come into consideration as valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause, and they can therefore be used as antiatherosclerotics, agents for chronic kidney failure or cancer diseases. They can thereby be used for the treatment of organ hypertrophies and hyperplasias, for example in the heart and prostate. Compounds of formula I are therefore suitable for the prevention and treatment of heart failure (congestive heart failure = CHF), as well as for the treatment and prevention of prostatic hyperplasia, respectively prostatic hypertrophy.

The compounds of formula I are further distinguished by retardation or inhibition of fibrotic diseases. They are therefore suitable as an excellent remedy for treating fibrosis in the heart, as well as pulmonary fibrosis, liver fibrosis, kidney fibrosis and other fibrotic diseases.

As NHE is significantly elevated in individuals with essential hypotension, the compounds of formula I are suitable for the prevention and treatment of high blood pressure, and for cardiovascular diseases.

Thereby, they can be used alone, or together with a suitable combination and formulation partner for the treatment of high blood pressure and for the treatment of cardiovascular diseases. Thus, for example, one or more thiazide-acting diuretics, loop diuretics, aldosterone and pseudoaldosterone antagonists such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerone, can be combined with compounds of formula I. Furthermore, NHE can -the inhibitors according to the invention are used in combination with calcium antagonists such as verapamil, diltiazem, amlodipine or nifedipine, as well as with ACE inhibitors such as ramipril, enalapril, lisinopril, fosinopril or captopril. Further favorable reaction partners are also P-blockers such as metoprolol, albuterol, etc., antagonists of the angiotensin receptor and its receptor subtypes such as losartan, irbesartan, valsartan, omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors, adenosine receptor agonists, inhibitors and activators of calcium channels such as gilbenclamide, glimepiride, diazoxide, cromokalim, minoxidil and their derivatives, activators of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of additional potassium channels, such as Kvi.5, etc.

Due to the anti-inflammatory effect, the NHE inhibitor can be used as an anti-inflammatory. Mechanistically, the inhibition of the release of inflammatory mediators is striking. The compounds can therefore be used alone or in combination with an antiphlogistic in the prevention or treatment of chronic or acute inflammatory diseases. As a combination partner, steroidal and non-steroidal anti-inflammatories are preferably used.

It has further been found that the compounds of formula I show a beneficial effect on serum lipoproteins. They can therefore be used for prophylaxis and regression of atherosclerotic changes as they switch off a clausal risk factor. This includes not only the primary hyperlipidemias, but also certain secondary hyperlipidemias, such as occur in diabetes. In addition to this, the compounds of formula I lead to a clear reduction of the infarcts induced due to metabolic abnormalities, and in particular to a significant reduction of the induced infarct size and their severity.

The aforementioned compounds are therefore advantageously used for the production of drugs for the therapy of hypercholesterolemia; for the manufacture of a medicament for the prevention of atherogenesis; for the manufacture of a medicament for the prevention and treatment of diseases triggered by elevated cholesterol levels; for the manufacture of a medicament for the prevention and treatment of diseases triggered by endothelial dysfunction; for the manufacture of a medicament for the prevention and treatment of atherosclerosis-induced hypertension; for the manufacture of a medicament for the prevention and therapy of atherosclerosis-induced thrombosis; for the manufacture of a medicament for the prevention and treatment of hypercholesterolemia- and endothelial dysfunction-induced ischemic injuries and post-ischemic reperfusion injuries; for the manufacture of a medicament for the prevention and treatment of cardiac hypertrophies and cardiomyopathies and cognitive heart failure (CHF); for the manufacture of a medicament for the prevention and treatment of hypercholesterolemia- and endothelial dysfunction-induced coronary tissue spasms and myocardial infarctions; for the production of a drug for the treatment of the aforementioned disorders in combination with blood pressure-lowering substances and preferably with angiotensin-converting enzyme (ACE) inhibitors and antiotensin receptor antagonists. A combination of NHE inhibitor of formula I with a blood fat level-lowering active ingredient, and preferably with HMG-CoA reductase inhibitor (for example lovastatin or pravastatin), whereby the latter provides a hypolipidemic effect and thereby increases the hypolipidemic property of the NHE inhibitors of formula I, proves to be a favorable combination with enhanced effect, and with a reduced amount of active ingredient.

Thus, the compounds of formula I lead to effective protection against endothelial damage of different genesis. With this protection of the tissue against syndromes of endothelial dysfunction, the compounds of formula I are valuable drugs for the prevention and for the treatment of coronary tissue spasms, peripheral tissue diseases and especially intermittent claudication, atherogenesis and atherosclerosis, the left ventricular hypertrophy and the dilated cardiomyopardy, as well as thrombotic diseases.

In addition, the NHE inhibitors of formula I are suitable for the treatment of non-insulin-dependent diabetes (NIDDM), whereby, for example, insulin resistance is pushed back. Thereby, in order to enhance the antidiabetic effect and quality of action for the compounds of the invention, it may be beneficial that these are administered together with a biguanide such as metformin, with an antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamide, etc., a glucosidase inhibitor, a PPAR agonist such as rosiglitazone , pioglitazone, etc., with an insulin preparation with varying administration form, with a DB4 inhibitor, with an insulin sensitizing compound or with meglitinide.

In addition to the acute, antidiabetic effects, the compounds of formula I counteract the formation of diabetic late complications, and can therefore be used as a drug for the prevention and treatment of diabetic late damage such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and others, as a result of diabetes arising, diseases. Thereby, they can advantageously be combined with the antidiabetic drugs described above under the NIDDM treatment. Combinations with a favorable administration form for insulin can therefore have a special significance.

The NHE inhibitors of the invention with formula I, in addition to the protective effects against acute ischemic events, and the subsequent equally acutely stressful reperfusion events, also show a direct therapeutically usable effect against diseases and disorders of the total mammalian organism that are associated with the appearance of chronic aging processes, and which, independently of acute conditions with lack of blood flow, can also occur under normal, non-ischemic conditions. These pathological and over a long period of ageing, age-related phenomena such as disease, infirmity and death, and which have recently been made available for treatment due to NHE inhibitors, are diseases and disorders that are obviously due to age-related changes in highly necessary organs and their function, and which is increasingly important in organisms that age. Diseases associated with an age-related functional disorder, with age-related wear and tear phenomena in organs, are for example the insufficient response and responsiveness of blood vessels to contraction and relational reactions. This age-related reduction in tissue reactivity to constrictive and relaxing challenges, and which is an essential process for the cardiovascular system, and thereby also life and health, can be significantly reversed, or reduced, with the help of NHE inhibitors. An important function and a measure of the maintenance of tissue reactivity is the blocking, or retardation, of the age-related progressive endothelial dysfunction which can be reversed in a highly significant way by NHE inhibitors. The compounds of formula I are therefore excellently suited for the treatment and prevention of age-related continuous endothelial dysfunctions, and in particular intermittent claudication. In addition, the compounds of formula I are excellently suited for the treatment and prevention of heart failure, congestive heart failure (CHF) for treatment and especially for the prevention of age-related forms of cancer.

In addition, one can imagine a combination with blood pressure-lowering drugs such as ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca<+2->antagonists, etc., or with metabolism-normalizing drugs such as cholesterol-lowering drugs. The compounds of formula I are therefore suitable for the prevention of age-related tissue changes and for life extension while maintaining a high quality of life.

The compounds of the invention are effective inhibitors of the cellular sodium-proton antiporter (Na/H exchange rate), which in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) is also increased in such cells that can be easily measured such as, for example, in erythrocytes, thrombocytes and leukocytes. The compounds used according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostics for determining and differentiating between different forms of hypertension, but also arteriosclerosis, diabetes and diabetic late complications, proliferative diseases, etc.

Furthermore, the NHE3 inhibitors are suitable for the treatment of diseases caused by bacteria, as well as diseases caused by protozoa in the field of human and veterinary medicine. In the case of diseases caused by protozoa, particular mention should be made of malarial diseases in humans and chicken coccidiosis.

In addition, the compounds are suitable as a means of combating sucking parasites in human and veterinary medicine, as well as in plant protection. Thereby, the use as an agent against blood-sucking parasites in human and veterinary medicine is preferred.

The compounds of formula I, in addition to their potent NHE inhibition values, the pharmacological properties and the absence of undesirable biological effects, are also distinguished by favorable pharmacokinetic properties which make their use as medicine particularly favorable.

The present invention therefore also relates to the use of a compound of formula I and/or pharmaceutically acceptable salts thereof for the preparation of a drug for the treatment or prophylaxis of respiratory disorders and in particular sleep-related respiratory disorders such as sleep apnea, or snoring, for the treatment or prophylaxis of acute or chronic kidney diseases, and in particular acute renal failure or chronic renal failure, or disorders of intestinal function, for the treatment or prophylaxis of high blood pressure, in particular the essential hypertension for the treatment or prophylaxis of acute or chronic injuries, diseases and indirect sequelae in organs or tissues caused by ischemia - or reperfusion events, from arrhythmias, atherosclerosis, hypercholesterolemia, diseases in which cell proliferation plays a primary or secondary cause, from cancer, from fibrotic diseases of the internal organs, from heart failure or congestive heart failure, from disturbances of the biliary function, an seizure of ectoparasites, for the treatment of shock conditions, diabetic and diabetic late damage, acute or chronic, inflammatory diseases or for the production of a drug for the conservation and storage of grafts for surgical events, for the production of a drug for use in surgical operations and organ transplants, for production of a drug to prevent age-related tissue changes

The present invention therefore relates to a medicinal product for human or veterinary medicinal use which contains an effective amount of a compound of formula I and/or a pharmaceutically acceptable salt thereof, as discussed above, together with pharmaceutically acceptable carriers and additives.

Medicines containing a compound of formula I can, for example, be administered orally, parenterally, intramuscularly, intravenously, rectally, nasally, by inhalation, subcutaneously or by a suitable transcutaneous form of administration, whereby the preferred administration depends on the relevant disease picture. The compounds of formula I can thereby be used alone or together with galenic excipients in both veterinary and human medicine.

Which excipients are suitable for the desired drug formulation is within the expert's area of knowledge. Alongside other solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, for example, antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers or dyes can be used.

For an oral form of application, the active ingredients are mixed with additives suitable for this purpose such as carriers, stabilizers or inert diluents and brought by usual methods to a suitable administration form such as tablets, dragees, suppositories, aqueous, alcoholic or oil solutions. For example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used as inert carriers. Thereby, the preparation can be done both as dry or moist granules. For example, vegetable or animal oils such as sunflower oil or cod liver oil can be used as an oil carrier or as a solvent.

For subcutaneous, percutaneous or intravenous administration, the active compounds used, possibly together with usual substances such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension or emulsion. As solvents, for example water, physiological saline solution or alcohols, such as ethanol, propanol or glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or a mixture of the various mentioned solvents can be used.

As a pharmaceutical formulation for administration in the form of aerosols or sprays, for example, solutions, suspensions or emulsions of the active ingredient of formula I, in a pharmaceutically acceptable solvent such as ethanol or water, or a mixture of such solvents, are suitable. If necessary, the formulation can also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as a propellant gas. Such a preparation usually contains the active ingredient in a

concentration of around 0.1 to 10% by weight and in particular around 0.3 to 3% by weight. The dosage of the active substance of formula I and frequency of administration depends on the potency and duration of action of the compound used, in addition also on the type and degree of the disease to be treated, as well as the sex, age,

weight and individual condition.

On average, the daily dose of a compound of formula I for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.1 mg/kg and at most 30 mg/kg, preferably around 1 mg/kg body weight. In acute situations, for example immediately after the onset of an apneic state in the high mountains, higher doses may also be necessary. Especially with intravenous use, for example in a heart attack patient in an intensive care unit, up to 200 mg/kg per day may be necessary. The daily dose can be divided into one or more, for example up to four single doses.

Test descriptions and examples:

If it is an enantiomeric compound, the configuration and/or sign of the optical rotation is indicated. If this is missing, they are racemates or optically inactive compounds.

The retention times (Rt) stated below apply to LCMS measurements with the following parameters:

Analytical methods:

A

Stationary phase: Merck Purospher 3u 2 x 55 mm

Mobile phase: 95% H2O (0.1% HCOOH) 95% acetonitrile (0.1% HCOOH); 5 5 min -► 95% acetonitrile (0.1% HCOOH); 2 min -► 95% H2O (0.1% HCOOH); 1 minute; 0.45 ml/min.

B

Stationary phase: YMC Tsphere H80 ~4u 2.1 x 33 mm

Mobile phase: 95% H2O (0.1% HCOOH) -> 95% acetonitrile (0.08% HCOOH);

0.5 min -► 95% H20 (0.1% HCOOH); 0.5 min; 1.3 ml/min.

c

Stationary phase: YMC Tsphere H80, 4u, 2.1 x 20 mm

Mobile phase: 90% H20 (0.05% TF A) -► 95% acetonitrile; 1.9 minutes; -► 95%

acetonitrile 0.5 min; 1 ml/min.

D

Stationary phase: Merck Purospher 3u, 2 x 55 mm

Mobile phase: 95% H2O (0.1% HCOOH) -> 95% acetonitrile (0.1% HCOOH);

3.4 min -► 95% acetonitrile (0.1% HCOOH); 1 min -> 95% H20

(0.1% HCOOH); 0.2 min; 0.75 ml/min.

E

Stationary phase: Merck Purospher 3(i, 2 x 55 mm

Mobile phase: 95% H20 (0.05% CF3COOH) -► 95% acetonitrile (0.05%

CF3COOH); 3.4 min -► 95% acetonitrile (0.05% CF300H); 1 minute; 0.75 ml/min.

F

Stationary phase: YMC Tsphere H80, 4u, 2.1 x 20 mm

Mobile phase: 96% H20 (0.05% CF3COOH) -► 95% acetonitrile; 2 minutes; -► 95%

acetonitrile 0.4 min; 1 ml/min.

Preparative HPLC is carried out under the following conditions:

Stationary phase: Merck Purospher RP18 (10 uM) 250 x 25 mm Mobile phase: 90% H20 (0.05% TF A) -> 90% acetonitrile; 40 minutes; 25 ml/min.

In the following, some examples are included which do not fall within the scope of the invention, but which nevertheless illustrate aspects of the preparation of the compounds according to the invention. These examples are marked with the indication (Reference example)

Example 1: 3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

a) 4-methyl-3-thienyl isothiocyanate

is prepared by reacting equimolar amounts of 3-amino-4-methylthiophene and N,N'-thiocarbonyldiimidazole in anhydrous tetrahydrofuran (THF) by stirring the reaction mixture for 5 hours at room temperature and further standing overnight at room temperature. The isolation of 4-methyl-3-thienyl isothiocyanate takes place by distilling off the solvent under reduced pressure on a rotary evaporator, dissolving the residue in ethyl acetate and washing the organic phase several times with water. After drying the organic phase over sodium sulphate, the organic solvent is distilled off on a rotary evaporator under reduced pressure, and 4-methyl-4-thienyl isocyanate is obtained as a brownish, oily residue. Furthermore, the use of 4-methyl-3-thienyl isothiocyanate can take place without further purification.

b) N-(2-amino-5-fluorophenyl)-N'-(4-methyl-3-thienyl)-thiourea

To a solution of 0.02 mol of 4-methyl-3-thienyl isothiocyanate in 60 ml of anhydrous THF

0.02 mol of 4-fluoro-1,2-diaminobenzene is added. After stirring the reaction mixture for 2 hours at room temperature and after standing overnight, the solvent is distilled off on a rotary evaporator under reduced pressure and the oily residue is purified on a silica gel column with a mixture of equal parts of toluene and acetic esters.

A brown-coloured, crystalline solid with a melting point of 180°C is obtained.

c) 3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 1.5 g (0.0054 mol) N-(2-amino-5-fluorophenyl)-N'-(4-methyl-3- thienyl)-thiourea is left in 50 ml

anhydrous ethanol added several times the molar amount (around 1.5 to 4 mol) of methyl iodide and the whole is boiled for 5 hours under a reflux condenser. After standing overnight at room temperature, the ethanol is distilled off on a rotary evaporator under reduced pressure, water is added to the residue and the pH value is adjusted to 8-9 with saturated, aqueous sodium bicarbonate solution. The whole is extracted several times with ethyl acetate, the organic phase is washed with water, dried over sodium sulphate, the solvent is distilled off at reduced pressure on a rotary evaporator and the residue is purified by column chromatography on silica gel with a solvent mixture of equal parts by volume

ethyl acetate and toluene (hereinafter referred to as "mixture 2") as eluent. The product obtained after distilling off the organic solvents in the form of an oily product is dissolved in ethyl acetate and acidified with a saturated solution of hydrogen chloride in dry diethyl ether and the crystalline precipitate, obtained after a longer period of time, is filtered off.

A crystalline solid with a melting point of 192°C +/- 2°C is obtained.

Example 2: 2-chloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and 2,5-dichloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl- 3-thienylamine hydrochloride

To a solution of 0.5 g (0.0018 mol) 3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride in 25 ml glacial acetic acid, a solution of 0.24 g (0.0018 mol) N-chlorosuccinimide in 15 ml of glacial acetic acid, after which the reaction mixture is stirred for 2 to 3 hours at room temperature and the solvent is distilled off under reduced pressure on a rotary evaporator. After water is added to the residue, the whole is made alkaline with 2N NaOH, it is extracted with ethyl acetate, after which the organic phase is washed with water, dried over sodium sulphate and the solvent is distilled off on a rotary evaporator under reduced pressure. The oily residue thus obtained is separated on a column by means of medium pressure chromatography and with a solvent mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid (hereinafter referred to as "mixture 17") as eluent and after treatment with a solution of hydrogen chloride gas in ether yields: 2-chloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride from fractions 1 and 2: colorless to slightly yellow crystals with melting point 200-202°C , 2,5-dichloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl 1-3-thienylamine hydrochloride from fraction 3: colorless to slightly yellow crystals with melting point 286-288°C. Example 3: 3N-(5,6-Dichloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

a) N-(2-amino-4,5-dichlorophenyl)-N'-(4-methyl-3-thienyl)-thiourea

is obtained analogously to the reaction indicated in example I b) from 4-methyl-3-thienyl isothiocyanate

and 4,5-dichloro-1,2-diaminobenzene.

A crystalline solid with a melting point of 310-320°C is obtained.

b) 3N-(5,6-dichloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the method indicated in example I c) from N-(2-amino-4,5-dichlorophenyl)-N '-(4-methyl-3-thienyl)-thiourea and methyl iodide.

A crystalline solid with a melting point of 290-294°C is obtained.

Example 4: 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

a) N-(2-aminophenyl)-N'-(4-methyl-3-thienyl)-thiourea

is obtained analogously to the reaction indicated in example I b) from 4-methyl-3-thienyl isothiocyanate and

1,2-diaminobenzene.

A crystalline solid is obtained with a first melting point of 177-182°C, and after renewed crystallization a second melting point of 285-290°C. b) 3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the method indicated in example lc) from N-(2-aminophenyl)-N'-(4-methyl-3-thienyl)-thiourea and methyl iodide.

A crystalline solid is obtained after recrystallization from acetic acid: ethanol, with a melting point of 194-200°C.

Example 5: 3N-(-4-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

a) 3-fluoro-1,2-diaminobenzene is obtained as an oily, amorphous product by hydrogenating 3-fluoro-2-nitrophenylhydrazine (prepared by reacting 2,6-difluoronitrobenzene with hydrazine hydrate) with hydrogen and 10% palladium catalyst on carbon in methanol at room temperature and normal pressure. b) N-(2-amino-3-fluorophenyl)-N'-(4-methyl-3-thienyl)-thiourea is obtained analogously to the method indicated in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3- fluoro-1,2-diaminobenzene.

A crystalline solid with a cleavage point > 240°C is obtained.

c) 3N-(4-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the method indicated in example 1 c) from N-(2-amino-3-fluorophenyl)-N'-(4 -methyl-3-thienyl)-thiourea and methyl iodide.

An amorphous precipitate is obtained which crystallizes under acetone in the form of a crystalline solid with a melting point of 220-230°C.

Example 6: 3N-(4,6-difluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

a) N-(2-amino-3,5-difluorophenyl)-N'-(4-methyl-3-thienyl)-thiourea is obtained according to the reaction indicated in example 1 b) from 4-methyl-3-thienyl -isothiocyanate and 3,5-difluoro-1,2-diaminobenzene.

A crystalline solid is obtained with a first melting point of 178-282°C, and after renewed crystallization a second melting point of 299-301°C. b) 3N-(4,6-difluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the method indicated in example 1 c) from N-(2-amino-3,5-difluorophenyl)-N '-(4-methyl-3-thienyl)-thiourea and methyl iodide. An amorphous precipitate is obtained which crystallizes under ethyl acetate and gives a crystalline solid with a melting point of 231-234°C. Example 7: 3N-(4,5,6,7-tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride a) N-(2-amino-3,4,5,6-tetrafluorophenyl)-N '-(4-methyl-3-thienyl)-thiourea is obtained analogously to the reaction indicated in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3,4,5,6-tetrafluoro-1,2-diaminobenzene.

A crystalline solid with a melting point of 286-290°C is obtained.

b) 3N-(3,4,5,6-tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylarnine hydrochloride is obtained analogously to the method indicated in example 1 c) from N-(2-amino-3,4, 5,6-tetrafluorophenyl)-N'-(4-methyl-3-thienyl)-thiourea and methyl iodide.

An amorphous precipitate is obtained which crystallizes under ethyl acetate and gives a crystalline solid with a melting point of 225-228°C.

Example 8: 3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

a) N-(2-amino-3-methylphenyl)-N'-(4-methyl-3-thienyl)-thiourea is obtained analogously to the reaction indicated in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3 -methyl-1,2-diaminobenzene.

A crystalline solid with a melting point of 184-186°C is obtained.

b) 3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the method indicated in example 1 c) from N-(2-amino-3-methylphenyl))-N'-(4 -methyl-3-thienyl)-thiourea and methyl iodide.

An amorphous precipitate is obtained which crystallizes under acetone and gives a crystalline solid with a cleavage point of 320°C.

Example 9: trans-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate) a) N-(2-amino-cyclohexyl )-N'-(4-methyl-3-thienyl)-thiourea (racemate) is obtained analogously to the reaction indicated in example 1 b) from 4-methyl-3-thienyl isothiocyanate and racemized trans-1,2-diaminocyclohexane.

A crystalline solid with a melting point of 205-210°C is obtained.

b) 3N-(3α,4,5,6,7,7α-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate). 0.6 g of racemic trans-N-(2-amino-cyclohexyl)-N'-(4-methyl-3-thienyl)-thiourea is suspended in 60 ml of toluene and dissolved by heating to 90°C. The whole is allowed to cool to 70°C, dripped to a solution of 0.376 g of dicyclohexylcarbodiimide in 5 ml of anhydrous toluene, stirred together for about 10 hours at 70°C and 2-3 days at room temperature. The crystalline solid is filtered off, the solvent is removed on a rotary evaporator under reduced pressure and the oily residue thus obtained is dissolved in a little ethyl acetate. After addition of anhydrous hydrogen chloride solution in diethyl ether, a viscous precipitate is obtained which, after addition of a little ethanol, crystallizes out and gives a crystalline solid with a melting point of 261-264°C. Example 10: trans-R,R-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride a) trans-R,R-N-( 2-amino-cyclohexyl)-N'-(4-methyl-3-thienyl)-thiourea is obtained analogously to the reaction indicated in example 1 b) from 4-methyl-3-thienyl isothiocyanate and trans-R,R-1,2- diaminocyclohexane by column chromatographic separation on silica gel by elution with a solvent mixture consisting of 10 parts ethyl acetate, 5 parts n-heptane, 5 parts methylene chloride, 5 parts methanol and 1 part 26% aqueous ammonia (hereinafter referred to as "mixture 4") as amorphous , oily product next to a high molecular weight crystalline product with melting point 94-100°C.

The amorphous product is processed further without further purification.

Trans-R,R-N-(3a,4,5,6Jα-hexahydro-1H-2-benzimidazolyl)-4-methyl-4-thienylamine hydrochloride is obtained analogously to the method indicated in example 1 c) by reaction of R,R-N-( 2-amino-cyclohexyl)-N'-(4-methyl-3-thienyl)-thiourea and methyl iodide in anhydrous ethanol as dissolution and reaction medium. The amorphous precipitate is eluted on silica gel with mixture 4 as eluent and crystallized from acetone whereby a crystalline solid with a melting point of 235-238°C is obtained.

Example 11: trans-S,S-3N-(3α,4,5,6,7,7α-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

a) trans-S,S-3N-(2-amino-cyclohexyl)-N'-(4-methyl-3-thienyl)-thiourea is obtained analogously to the reaction indicated in example 1 b) from 4-methyl-3-thienyl -isothiocyanate and trans-S,S-1,2-diaminocyclohexane by column chromatographic separation on silica gel with mixture 4 as eluent, as amorphous, oily product next to a higher molecular product with melting point 94-102°C.

The amorphous product is used in subsequent reactions without further purification.

b) trans-S,S-N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the method specified in example 1 c) by reaction

of S,S-N-(2-amino-cyclohexyl)-N'-(4-methyl-3-thienyl)-thiourea and methyl iodide in anhydrous ethanol as dissolution and reaction medium. The amorphous precipitate is chromatographed on silica gel with mixture 4 as eluent, and crystallized from acetone and a crystalline solid with a melting point of 225-230°C is obtained.

Example 12: 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and 2,5-dichloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

is obtained analogously to the method specified in example 2 from 3N-(2-benzimidazoly)-4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid. Column chromatography on silica gel with compound 17 as eluent leads to the separation of 2,5-dichloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (as a colorless, crystalline compound with a melting point of 291°C) from 2-chloro -3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (as colorless, crystalline compound with melting point 257-259°C). Example 13: 2-chloro-3N-(4-methyl-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride is obtained analogously to the method indicated in example 2 from 3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid. After column chromatography on silica gel with mixture 17 as eluent, 2-chloro-3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained as a colorless to slightly yellow-coloured, crystalline product with a melting point of 255-259° C. Example 14: 2 -chloro-3N-(4,5,6,7-tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

is obtained analogously to the method specified in example 2 from 3N-(4,5,6,7-tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid.

A crystalline product with a melting point of 233-235°C is obtained.

Example 15: trans-2-chloro-3N-(3α,4,5,6,7,7α-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate)

is obtained analogously to the method specified in example 2 from 3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (racemate) and N-chlorosuccinimide in glacial acetic acid .

A crystalline product with a melting point of 258-260°C is obtained.

Example 16: trans-R,R-2-chloro-3N-(3a,4,5,6.,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and trans-R ,R-2,5-dichloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thianylamine hydrochloride

is obtained analogously to the method specified in example 2 from trans-R,R-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N -chlorosuccinimide in glacial acetic acid after chromatographic separation of the two crystalline products in the order: a) trans-R,R-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl -3-thienylamine hydrochloride, with cleavage under foaming from 80°C, and b) trans-R,R-2-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl )-4-methyl-3-thienylamine hydrochloride, as a crystalline product with a melting point of 260-262°C. Example 17: trans-S.S-2-chloro-3N-(3a.4.5.6.7.7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

obtained analogously to the method indicated in example 2 from trans-S,S-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N- chlorosuccinimide in glacial acetic acid after chromatographic separation.

A colorless, crystalline product with a melting point of 258-260°C is obtained.

Example 18: 2-bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and 2,5-dibromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

is obtained analogously to the method indicated in example 2 from 3N-(2-benzmimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-bromosuccinimide (instead of N-chlorosuccinimide) in glacial acetic acid. After column chromatography on silica gel with a mixture of 5 parts of dichloromethane, 3 parts of n-heptane, 1 part of glacial acetic acid and 1 part of ethanol (hereinafter referred to as "mixture 1") as eluent, and after treatment with a solution of hydrogen chloride in ether, is obtained by fractional crystallization in ethyl acetate 2-bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, crystalline product with melting point 228-231°C and 2,5-dibromo-3N-(2-benzimidazolyl) )-4-methyl 1-3-thienylamine hydrochloride, crystalline product with melting point 208-210°C.

Example 19: trans-R,R-bromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and trans-R,R- 2,5-dibromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the method indicated in example 19 from trans-R ,R-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzmimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-bromosuccinimide in glacial acetic acid. After column chromatography on silica gel with mixture 1 as eluent and treatment with a solution of hydrogen chloride in ether, one obtains after fractional crystallization in ethyl acetate trans-R,R-2-bromo-3N-(3a,4,5,6,7,7a -hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, as crystalline product with melting point 215-218°C, and trans-R,R-2,5-dibromo-3N-(3a,4, 5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-4-thienylamine hydrochloride as crystalline product with melting point 218-220°C. Example 20: 3N-(4-chloro-2-benzimidazolyl-amino)-4-methylthiophene hydrochloride a) N-(2-amino-3-chlorophenyl)-N'-(4-methyl-3-thienyl)-thiourea is obtained analogously to the reaction indicated in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3-chloro-1,2-diaminobenzene (produced by catalytic hydrogenation of 3-chloro-2-nitraniline with platinum on activated carbon under normal pressure at room temperature ).

A crystalline solid with a melting point of 298-305°C is obtained.

b) 3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride is obtained analogously to the methods indicated in example 1 c) from N-(2-amino-3-chlorophenyl)-N'-(4-methyl-3 -thienyl)-thiourea and methyl iodide, and an amorphous precipitate is obtained which crystallizes under ethyl acetate and gives a crystalline solid with a cleavage point of 240-245°C. Example 21: 2-chloro-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride is obtained analogously to the method specified in example 2 from 3N-(4-chloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid. After column chromatography on silica gel with a mixture of 10 parts of methylene chloride and 1 part of methanol as eluent, 2-chloro-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride is obtained as a colorless to slightly yellowish colored solid after crystallization under ethyl acetate and with a melting point of 270-272°C. Example 22: 2-bromo-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride

is obtained analogously to the method specified in example 2 from 3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride and N-bromosuccinimide (instead of N-chlorosuccinimide) in glacial acetic acid. After column chromatography on silica gel with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid as eluent and after treatment with a solution of hydrogen chloride gas in ether, one obtains by fractional crystallization in ethyl acetate in the presence of hydrogen chloride-saturated ether, 2-bromo -3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride as a crystalline product with a melting point of 278-280°C.

Example 23: (2-bromo-4-methylthiophen-3-yl)-(5-ylnor-1H-benzoimidazol-2-yl)-amine hydrochloride

(5-Fluoro-1H-benzoimidazol-2-yl)-(4-methylthiophen-3-yl)-arnine (300 mg) (Example 1) is dissolved in 5 ml of glacial acetic acid. At room temperature, it is added slowly and with vigorous stirring to 207 g of N-bromosuccinimide dissolved in 10 ml of glacial acetic acid. After the addition is complete, it is stirred for a further 10 minutes, and then the glacial acetic acid is distilled off under vacuum, the residue is dissolved in acetic acid and washed with saturated potassium carbonate solution. After drying over magnesium sulphate, the whole is filtered and evaporated. The residue is purified by means of preparative chromatography, the product-containing fractions are combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases are combined, dried over MgSC*4 and filtered. After the solvent has been drawn off, water and 2 N hydrochloric acid are added to the residue, and the whole is freeze-dried. 245 g of the desired product is obtained.

LCMS-Rt (B): 0.95 min.

MS (ES<+>, M+H<+>): 326.09.

Example 24: 2-bromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride and 2,5-dibromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride

To a solution of 0.214 g of 3N-(4-fluoro-benzimidazolylamino)-4-methylthiophene hydrochloride in 6 ml of acetic acid, a solution of 0.161 g of N-bromosuccinimide in 6 ml of glacial acetic acid is added, after which the mixture is stirred for 30 minutes at room temperature. After distilling off the solvent, water is added to the residue, the whole is made alkaline with two normal NaOH and it is extracted with ethyl acetate. The organic phases are dried, the solvent is distilled off and the residue is separated by column chromatography on silica gel with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid. The hydrochloride of the two compounds is obtained by distilling off the fractionated solutions, dissolving in ethyl acetate and precipitation by adding hydrogen chloride-saturated diethyl ether. Crystallization is thereby accelerated by slight heating.

Example 24a: 2-bromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride as colorless crystals with melting point 212°C (under cleavage). Example 24b: 2,5-dibromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride as colorless crystals with melting point 242-244°C (under cleavage).

Example 25 (Reference Example) 3N-(5-Methoxy-2-benzimidazolylamino)-4-methylthiophene

a) N-(2-amino-4-methoxyphenyl)-N'-(4-methyl-3-thienyl)-thiourea.

A mixture of 5.89 g of 4-methylthiophene-3-isothiocyanate and 5 g of 4-methoxy-1,2-diaminobenzene in 60 ml of anhydrous THF is stirred for 2 hours at room temperature and the solvent is distilled off. Water is added to the residue, it is extracted with ethyl acetate, after which the dark solution is treated with activated charcoal and the organic solvent is evaporated again. The residue is treated several times under slight heating with diisopropyl ether, and the solid is filtered.

A brown, crystalline solid with a melting point of 143-146°C is obtained.

b) A mixture of 2.83 g of N-(2-amino-4-methoxyphenyl)-N'-(4-methyl-3-thienyl)-thiourea, 8.5 g of methyl iodide and 100 ml of anhydrous ethanol is boiled for 5 hours during reflux,

the solvent is distilled off and water is added to the residue. The whole is made alkaline with 2 N caustic soda, it is extracted with ethyl acetate, after which the organic phase is treated with water and then with activated carbon, and purified by column chromatography on silica gel with an elution mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid. 3N-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene is obtained as an amorphous product.

Example 26 (Reference example): 3N-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

is obtained by precipitation of a solution of 0.2 g of 3N-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene (Example 25) in 10 ml of ethyl acetate with a saturated solution of hydrogen chloride in diethyl ether, as a crystalline precipitate with a melting point of 222-225° C. Example 27: 3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

a) 3-Methoxy-1,2-diaminobenzene is obtained as a brown oil by hydrogenating 2-methoxy-6-nitroaniline with hydrogen gas and Raney nickel as a catalyst at room temperature and 3

bar pressure. The product was converted to thiourea without further purification.

b) N-(2-amino-3-methoxyphenyl)-N'-(4-methyl-3-thienyl)-thiourea is obtained according to the method described in example 25 a) from 3-methoxy-1,2-diaminobenzene, 4 -methyl-3-thienyl isothiocyanate in anhydrous THF and finally medium pressure chromatography on silica gel with a mixture of one part toluene and one part ethyl acetate.

A crystalline solid with a melting point of 148-153°C is obtained. The melt solidifies, and the next melting point is at 260°C. c) 3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride is obtained analogously to the methods described in examples 25 and 26 from N-(2-amino-3-methoxyphenyl)-N'-(4-methyl-3 -thienyl)-thiourea by heating with ethyl iodide in THF, analogous work-up and treatment of the benzeneimidazole with HC1 in ether.

A crystalline solid with a melting point of 230-235°C is obtained.

Example 28: 2-chloro-3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

A mixture of 0.1 g of 3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride, 0.046 g of N-chlorosuccinimide and 10-15 ml of acetic acid is heated for 2 to 2.5 hours at 40°C. The glacial acetic acid is then distilled off, water is added to the residue and the pH value is adjusted to 9-10 2 N NaOH. The whole is extracted with ethyl acetate, the solvent is evaporated and the residue is chromatographed on silica gel on a medium pressure column with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid. The base thus obtained is converted in ethyl acetate with a saturated, ethereal hydrogen chloride solution to the corresponding hydrochloride and a colorless to light yellow, crystalline solid with a melting point of 248-250°C is obtained.

Example 29: 2-chloro-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride

to 0.234 g of 3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene hydrochloride in 20 ml of glacial acetic acid is added 0.132 g of N-chlorosuccinimide, after which the whole is stirred for 30 minutes at room temperature, and a further hour and a half at 50-60°C. After distilling off the acetic acid under reduced pressure, water is added to the residue and the pH value is adjusted to 10-11 with 2N NaOH, extracted with ethyl acetate which is then distilled off. The residue is chromatographed on silica gel on a column under medium pressure conditions with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid. After evaporation, the residue is dissolved in a little ethyl acetate, and the hydrochloride is precipitated by adding hydrogen chloride-saturated diethyl ether.

A colorless to light yellow, crystalline solid with a melting point of 268-270°C is obtained.

Example 30: 2-chloro-3N-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

A suspension of 0.13 g of 2-chloro-3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride in around 20 ml of anhydrous methylene chloride is added to a suspension of 0.29 g of active, anhydrous aluminum chloride in 10 ml of anhydrous methylene chloride and the reaction mixture is stirred for 2 hours at 55°C. After cooling, the reaction mixture is poured into ice water, the whole is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off. The residue is purified on a silica gel column under medium pressure conditions with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid and the eluate is evaporated under reduced pressure. The residue is dissolved in ethyl acetate and the hydrochloride is separated by adding hydrogen chloride-saturated diethyl ether.

A crystalline solid with a melting point of 236-248°C is obtained.

Example 31: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene

is obtained by adding 2 N NaOH to a solution of 3 g of 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene hydrochloride in 200 ml of water until a pH value of 10 is set. The crystals are filtered off and washed several times with water.

2.52 g of colorless crystal powder with a melting point of 182-185°C is obtained.

Example 32: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene hydrobromide

0.25 g of 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene is dissolved in 10 ml of ethanol, 0.1 ml of 48% HBr is added and the whole is stirred for a short while at room temperature. The solvent is distilled off, and the residue is crystallized from ethyl acetate.

0.29 g of colorless crystals with a melting point of 252-254°C are obtained.

Example 33: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene adipic acid salt

is obtained analogously to the method described in example 32 from 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene with an equivalent of adipic acid.

Colorless crystals with melting point 155-157°C.

Example 34: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene oxalic acid salt

is obtained analogously to the procedure described in example 32 by reacting 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene with an equivalent of oxalic acid in ethyl acetate.

Colorless crystals with a melting point of 220-222°C are obtained.

Example 35: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene phosphoric acid salt

is obtained analogously in the method described in example 5 from 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene with an equivalent of phosphoric acid.

Colorless crystals with a cleavage range of 113-175°C are obtained.

Example 36: (1H-benzimidazol-2-yl)-(2-chloro-4-methylthiophen-3-yl)-methylamine

66 mg of finely powdered, dried potassium carbonate is added to a solution of 125 mg of 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine from example 31 and 20 ml of dry methanol. Then, while excluding moisture and with vigorous stirring, 74 mg of methyl iodide is added dropwise and the reaction mixture is maintained under reflux. After extraction of the solvent, the residue is distributed between ethyl acetate and water, the ethyl acetate phase is dried with magnesium sulphate, the magnesium sulphate is filtered off and the filtrate is brought to a dry state. It is then purified using preparative HPLC. The product-containing fractions are purified and freeze-dried after removal of the acetonitrile. For further purification, the whole is chromatographed on silica gel with acetic acid heptane (1:4). After combining the product-containing fractions, the whole is brought to a dry state, taken up in HCL and freeze-dried. 5 mg of solid is obtained.

LCMS-Rt (A): 2.04 min.

MS (ES<+>, M+H<+>): 278.05.

Example 37: (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)-amine-trifluoroacetic acid

To a solution of 1 g of 1,2-diamino-4,5-difluorobenzene (1 g) in 20 ml of absolute tetrahydrofuran, 1.08 g of 3-isothiocyanate-4-methylthiophene dissolved in 30 ml of absolute tetrahydrofuran is dripped. The whole thing was then stirred for 2 hours at room temperature, and then left overnight. After adding 0.44 ml of methyl iodide, it was stirred for 8 hours and left overnight. Tetrahydrofuran was then drawn off, the residue distributed between ethyl acetate and water, the phases separated and the ethyl acetate phase dried over magnesium sulfate. The residue was applied to silica gel and chromatographed with heptane: ethyl acetate = 1:1 as eluent. 229 mg of the desired compound were obtained as free base. A contaminated fraction from the above-mentioned chromatography was purified by means of preparative HPLC and after freeze-drying 42.2 mg of the desired compound was isolated as trifluoroacetic acid salt.

LCMS-Rt (A): 1.98 min.

MS (ES + , M + H + ): 266.13.

Example 38: (2-Chloro-4-methylthiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine hydrochloride

To a solution of 225 mg of (5,6-difluoro-1H-benzoimidazol-2-yl)-(4-methylthiophen-3-yl)-amine in 5 ml of glacial acetic acid, a solution of 124.6 mg of N-chlorosuccinimide was added dropwise at room temperature in 5 ml glacial acetic acid. It was then stirred for 3.5 hours at room temperature. The glacial acetic acid was then removed, the residue taken up in water and brought to pH 10 with 2 M caustic soda. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases dried over magnesium sulfate and the solvent removed. The residue was purified by preparative chromatography, the product-containing fractions combined, freed from acetonitrile, basified and extracted three times with ethyl acetate. The organic phases were purified, dried over MgSO 4 , filtered and evaporated. The remainder was taken up in water, acidified with 10% hydrochloric acid and freeze-dried. 81 mg of the desired product was obtained as a solid.

LCMS-Rt (A): 2.15 min.

MS (ES + , M + H + ): 300.11.

Example 39: (2-bromo-4-methylthiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine

At room temperature, in a ReaktiVial, a solution of 15 mg of (5,6-difluoro-1H-benzoimidazol-2-yl)-(4-methylthiophen-3-yl)-amine-trifluoroacetic acid salt from Example 37 was added in 0.5 ml of glacial acetic acid dripped a solution of 8 mg of N-bromosuccinimide in 0.5 ml of glacial acetic acid, and the whole thing was stirred for half an hour at room temperature. Acetic acid was then drawn off, and saturated potassium carbonate solution and ethyl acetate were added to the residue. After separation of the organic phase, it was extracted twice with ether. The combined organic phases were dried over magnesium sulfate and then the drying agent was filtered off. The residue remaining after removal of the solvent was purified by means of preparative chromatography. The product-containing fractions were purified, freed from acetonitrile, saturated sodium bicarbonate solution was added and extracted three times with ethyl acetate. The organic phases were purified, dried over MgSCu and filtered. After extraction of the acetic ester, the residue was extracted with toluene and then dried under high vacuum. 8.1 mg of the desired compound was obtained.

LCMS-Rt (D): 1.45 min.

MS (ES<+>, M+H<+>): 343.96.

Example 40: [(2-chloro-4-methylthiophen-3-yl)-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl]-amine hydrochloride

a) 1,4-dioxa-spiro[4.5]dec-6-ylamine

The amine required as a precursor was prepared according to GB 1131191. Thereby 2-chlorocyclohexanone was reacted with phthalimide to 2-(2-oxo-cyclohexyl)-isoindole-1,3-dione which was then ketalized with ethylene glycol in the presence of paratoluenesulfonic acid to 2-(1,4-dioxa-spiro[4.5]dec-6-yl)-isoindole-1,3-dione. After treatment with hydrazine hydrate to cleave off the phthalimide residue, the desired 1,4-dioxa-spiro[4.5]dec-6-ylamine was obtained.

b) 1-(1,4-dioxa-spiro[4.5]dec-6-yl)-3-(4-methylthiophen-3-yl)-thiourea

To a solution of 300 mg of 1,4-dioxa-spiro[4.5]dec-6-ylamine in 10 ml of tetrahydrofuran

a solution of 296.2 mg of 3-isothiocyanato-4-methylthiophene (Example 1a) in 10 ml of tetrahydrofuran was added dropwise, the whole was then stirred for 2 hours at room temperature and finally

the solvent drawn off. The residue was purified by means of preparative chromatography, the product-containing fractions combined, freed from acetonitrile, made basic and extracted three times with acetic esters. The organic phases were purified, dried over MgSO4 and filtered and 428 mg of the desired product was obtained.

LSMC-Rt (A): 3.57 min.

MS (ES<+>,M+H<+>): 313.19.

c) 1-(1,4-dioxa-spiro[4.5]dec-6-yl)-2-methyl-3-(4-methylthiophen-3-yl)-isothiourea

393 mg of 1-(1,4-dioxa-spiro[4.5]dec-6-yl)-3-(4-methylthiophen-3-yl)-thiourea was dissolved in 8.5 ml of absolute tetrahydrofuran, and a solution of 179 mg methyl iodide in 0.5 ml absolute tetrahydrofuran. The mixture was then stirred for two days in a sand bath at 70°C. Then acetic acid was added to the reaction mixture, and the whole was washed twice with water. The organic phase was dried over magnesium sulfate, and the solvent removed after filtration. The residue was purified by preparative chromatography, de

product-containing fractions were combined, freed from acetonitrile, basified and extracted three times with ethyl acetate. The organic phases were purified, dried over MgSO4 and filtered. 59 mg of the desired product was obtained, which was used directly in the next step. LCMS-Rt (A): 1.05 min.

MS (ES<+>, M+H<+>): 327.4.

d) NB-(1,4-dioxa-spiro[4.5]dec-6-yl)-N'-(4-methylthiophen-3-yl)-guanidine

In a ReactiVial, 2 ml of 7 M ammoniacal methanol solution, and the whole heated for 16 hours to about 100°C in a sand bath. After removal of the solvent, 51 mg of an oily product remained which was used directly further.

LCMS-Rt (C): 1.00 min.

MS (ES<+>, M+H<+>): 296.4.

e) N-(2-chloro-4-methylthiophen-3-yl)-N'-(1,4-dioxa-spiro[4.5]dec-6-yl)-guanidine

49 mg of N-(1,4-dioxa-spiro[4.5]dec-6-yl)-N'-(4-methylthiophen-3-yl)-guanidine was dissolved in 3 ml of glacial acetic acid, and to this was slowly added a solution of 20.3 mg of N-chlorosuccinimide in 5 ml of glacial acetic acid. After stirring for several hours and standing over the weekend at room temperature, the glacial acetic acid was drawn off, the residue taken up in water and the pH value brought to 10 using 2 N sodium hydroxide solution. The basic phase was extracted three times with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was purified by means of preparative chromatography, the product-containing fractions combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were purified, dried over MgSO 4 and filtered. After removal of the solvent, 24 mg of the desired product was obtained, which was used directly in the next step.

LCMS-Rt (C): 1.09 min.

MS (ES<+>, M+H<+>): 30.4.

f) ((2-chloro-4-methylthiophen-3-yl)-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-amine hydrochloride

24 mg of N-(2-chloro-4-methylthiophen-3-yl)-N'-(1,4-dioxa-spiro[4.5]dec-6-yl)-guanidine was dissolved in 1 ml of 2 N hydrochloric acid and stirred for 30 minutes at room temperature. Then 1 ml of concentrated hydrochloric acid was added and stirred for a further two hours. The whole thing was then diluted with water and freeze-dried. Toluene was added to the residue, which was then distilled off under vacuum. After this process was repeated twice, 22 mg of the desired product remained as a solid.

LCMS-Rt (B): 0.95 min.

MS (ES<+>, M+H<+>): 268.07.

Example 41: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene benzenesulfonate

250 mg of 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene was dissolved in 5 ml of THF, and 150 mg of benzenesulfonic acid, dissolved in 5 ml of THF, was added while stirring. After 3 hours, the reaction mixture was placed overnight in a refrigerator. After suctioning off the precipitate and drying at 75°C under high vacuum, the desired product was obtained as colorless crystals with a melting point of 235°C. Example 42: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene methanesulfonate

The method described in example 41 was obtained analogously from 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene with an equivalent of methanesulfonic acid.

Colorless crystals with a melting point of 227°C were obtained.

Example 43: 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene benzoate

was obtained analogously to the method described in example 41 from 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene with an equivalent of benzoic acid. For precipitation, the reaction mixture was evaporated to half, and then 30 ml of ether was added.

Colorless crystals with a melting point of 198°C were obtained.

Example 44: 2,4-dichloro-3N-(2-benzimidazolylamino)thiophene hydrochloride

a) 3-acetylaminothiophene-2-carboxylic acid methyl ester

To a mixture of 942 g of 3-aminothiophene-2-carboxylic acid methyl ester and 1000 ml of toluene

dropwise while heating in an oil bath, 567 ml of acetic anhydride. The whole was boiled for one and a half hours under reflux conditions, and then cooled in an ice bath to around 0°C. The crystals were filtered off, washed twice with a little cold isopropanol and twice with diisopropyl ether. From the filtrate, by further concentration and crystallization, 3-acetylaminothiophene-2-carboxylic acid methyl ester with a melting point of 93-95°C could be obtained.

b) 3-acetylamino-4,5-dichlorothiophene-2-carboxylic acid methyl ester To a solution of 19.9 g 3-acetylaminothiophene-2-carboxylic acid methyl ester in 100

ml of chloroform is added dropwise under magnetic stirring and at a reaction temperature of 20-30°C, 17.9 g of sulphuryl chloride SO2CI2. They are then stirred for a further two hours at 40°C, and the whole is further boiled for 15 minutes under reflux conditions. After distilling off the solvent under reduced pressure, acetic acid was added to the residue and the crystals were filtered after settling.

Obtained crystals with melting point 136-138°C.

c) 3-acetylamino-4-chlorothiophene-2-carboxylic acid methyl ester

A mixture of 25 g of 3-acetylamino-4,5-dichlorothiophene-2-carboxylic acid methyl ester, about 10 g

triethylamine, 300 ml of methanol and 1 g of palladium on carbon were hydrogenated at room temperature under normal pressure until hydrogen absorption ceased. After filtering off the catalyst, the whole was concentrated by distillation under reduced pressure until crystallization began, then water was added and the solid filtered off.

Colorless crystals with a melting point of 142-147°C were obtained from isopropanol.

d) 3-amino-4-chlorothiophene-2-carboxylic acid methyl ester

7 g of 3-acetylamino-4-chlorothiophene-2-carboxylic acid methyl ester was stirred in a mixture of 50 ml of methanol and 50 ml of concentrated hydrochloric acid for 4 hours at 60°C, 5 hours under reflux and a further 3 days at room temperature. Any precipitate was filtered off, and approximately 1/3 of the solvent volume was removed by distillation under reduced pressure. After the addition of around 100 ml of water, it was stirred for a further 15 minutes at room temperature, after which the colorless crystals were filtered off and dried in an air stream. The crystals obtained had a melting point of 62-64°C.

e) 3-amino-4-chlorothiophene

18.02 g of 3-amino-4-chlorothiophene-2-carboxylic acid methyl ester was added to a solution of

11.1 g KOH and 160 ml water, then boiled for 3 hours with attached reflux condenser and after cooling, added dropwise to a 60°C hot solution of 15 ml concentrated hydrochloric acid in 30 ml water. Thereby, a clear CCV development took place. After further stirring at 60°C for about 40 minutes, the whole was allowed to cool, then 50-100 ml of methyl tert-butyl ether was added, and the whole was made alkaline with concentrated caustic soda, after which the aqueous phase was extracted in a separatory funnel. The aqueous phase was extracted twice more with methyl tert-butyl ether and the combined organic extraction phases washed once in a separatory funnel with water. The organic phase was dried, the solvent distilled off and the oily amorphous residue chromatographed on a silica gel column with one part ethyl acetate and one part toluene.

f) 4-chloro-3-thienyl isothiocyanate

To a solution of 1.1 g of 3-amino-4-chlorothiophene in 20 ml of anhydrous THF is added 1.46 g

thiocarbonyldiimidazole and the whole is stirred for one hour at room temperature. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, the organic phase is washed twice with water in a separatory funnel, dried and the solvent is evaporated again under vacuum. 4-Chloro-3-thienyl isothiocyanate is obtained as a dark oil which was then reacted further without further purification operations.

g) N-(2-aminophenyl)-N'-(4-chloro-3-thienyl)thiourea

To a solution of 1.4 g of 4-chloro-4-thienyl isothiocyanate in 400 ml of anhydrous THF is added 0.86

g 1,2-diaminobenzene (o-phenylenediamine), after which the whole is stirred for about 20 hours at room temperature and the solvent is distilled off under reduced pressure. The residue is treated with water, extracted with ethyl acetate, after which the solvent is distilled off again and the residue is purified using medium pressure column chromatography on silica gel with ethyl acetate:toluene (1:1) as eluent. A yellow-brown solid is obtained.

h) 4-chloro-3N-(2-benzimidazolylamino)thiophene

To a solution of 0.5 g of N-(2-aminophenyl)-N'-(4-chloro-3-thienyl)thiourea in 25 ml

anhydrous THF, a solution of 0.169 g of sodium hydroxide in 5 ml of water is added, and then a solution of 0.363 g of p-toluenesulfonic acid chloride in 10 ml of THF. The whole is stirred for 3 hours at room temperature, after which the solvent is distilled off under reduced pressure, the residue is treated with water and the whole is extracted with ethyl acetate. After distilling off the solvent, the product is purified by medium pressure chromatography on silica gel with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid.

For characterization, a small part of this 4-chloro-3N-(2-benzimidazolylamino)thiophene was transferred to 4-chloro-3N-(2-benzimidazolylamino)thiophene hydrochloride in ethyl acetate and with ethereal hydrogen chloride solution and characterized.

Colorless crystals with a melting point of 256-260°C were obtained.

i) 2,4-dichloro-3N-(2-benzimidazolylamino)thiophene hydrochloride

A solution of 0.3 g of 4-chloro-3N-(2-benzimidazolylamino)thiophene in 10 ml of glacial acetic acid was added to a solution of 0.16 g of N-chlorosuccinimide in 5 ml of glacial acetic acid. The reaction mixture is stirred for 15 minutes at 40°C, and around 4 hours at room temperature, the acetic acid is then distilled off at reduced pressure and the residue is treated with water. After it had all been made alkaline with caustic soda, it was extracted with ethyl acetate, washed with water, the organic phase dried and the solvent distilled off under reduced pressure. The residue was purified by medium pressure column chromatography with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid and then separated from ethyl acetate by addition of hydrogen chloride solution in diethyl ether.

A colorless, crystalline product with a melting point of 264-268°C was obtained.

Example 45: 2-bromo-4-chloro-3N-(2-benzimidazolylamino)thiophene hydrochloride

To a solution of 0.5 g of 4-chloro-3N-(2-benzimidazolylamino)thiophene in 15 ml of glacial acetic acid

a solution of 0.356 g of N-bromosuccinimide in 6 ml of glacial acetic acid is dropped, and the whole was then stirred further for 15 minutes at room temperature. The solvent was distilled off, the residue treated with water and the whole made alkaline with caustic soda. After extraction with ethyl acetate, the organic phase was washed with water, dried and distilled off under reduced pressure. The residue was chromatographed under medium pressure conditions on silica gel with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid as eluent. After distilling off the solvent, the residue was taken up in ethyl acetate, and 2-bromo-4-chloro-3N-(2-benzimidazolylamino)thiophene hydrochloride was precipitated by adding a solution of hydrogen chloride in diethyl ether.

A colorless, crystalline product with a melting point of 264-266°C was obtained.

Example 46: (2,4-dichlorothiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine hydrochloride

a) 1-(2-amino-4-fluorophenyl)-3-(4-chlorothiophen-3-yl)-thiourea

900 mg of 4-fluoro-1,2-phenylenediamine was dissolved in 25 ml of THF and 4-chloro-3-thienyl isothiocyanate (Example 44c), dissolved in 15 ml of THF, was added dropwise with stirring. The solution was stirred for about 3 hours at room temperature and then left overnight. The reaction mixture was then evaporated and the residue purified by means of preparative HPLC. The product-containing fractions were purified, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were purified, dried over MgSO 4 and filtered. After removal of the solvent, 625 mg of the desired product was obtained.

LCMS-Rt (F): 1.28 min.

MS (ES<+>, M+H<+>): 302.0.

b) (4-chlorothiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine

625 mg of 1-(2-amino-4-fluorophenyl)-3-(4-chlorothiophen-3-yl)-thioureable dissolved in THF, and a solution of 0.208 NaOH in 9 ml of water was added. In the course of 5 minutes, a solution of 0.395 g of p-toluenesulfonic acid chloride in 10 ml of THF was added dropwise. After the addition was complete, it was stirred for 1 hour at room temperature. For work-up, water and acetic acid were added to the reaction mixture and the whole separated in a separatory funnel. The aqueous phase was extracted three times with ethyl acetate and the combined ethyl acetate phases were dried over magnesium sulfate, clarified with carbon, filtered and evaporated. 135 mg of the desired product was obtained.

LCMS-Rt (F): 0.90 min.

MS (ES<+>, M+H<+>): 268.0.

c) (2,4-dichlorothiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine hydrochloride

85 mg of chlorothiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine were dissolved in 4 ml of glacial acetic acid

and at room temperature and vigorous stirring, 42 mg of N-chlorosuccinimide, dissolved in 4 ml of glacial acetic acid, were slowly added. After the addition was complete, it was stirred for 45 minutes at room temperature, followed by 5 hours at 50°C. After adding a further 4 mg of N-chlorosuccinimide, it was stirred for a further 1 hour at 50°C. Then 20 ml of toluene was added to the reaction mixture and the glacial acetic acid distilled off. The residue was dissolved in glacial acetic acid and eluted with saturated potassium carbonate solution. The acetic ester phase was dried over magnesium sulphate, filtered and evaporated. The residue was purified by means of preparative HPLC, the product-containing fractions combined were freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were purified, dried over MgSO 4 and filtered. After removal of the solvent, the residue was added to water, 2N hydrochloric acid and freeze-dried. 17 mg of the desired product was obtained.

LCMS-Rt (E): 2.65 min.

MS (ES + , M + H + ): 301.93.

Example 47: (2-bromo-4-chlorothiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine hydrochloride

50 mg of (4-chlorothiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine (Example 46 b) was dissolved in 4 ml of glacial acetic acid and, at room temperature and under vigorous stirring, slowly added 33 mg of N-bromosuccinimide, dissolved in 4 ml of glacial acetic acid. After the addition was complete, it was stirred for 45 minutes at room temperature and then 20 ml of toluene was added to the reaction mixture and the glacial acetic acid was distilled off. The residue was dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The acetic ester phase was dried over magnesium sulphate, filtered and evaporated. The residue was purified by preparative chromatography, the product-containing fractions combined, freed from acetonitrile, basified and extracted three times with glacial acetic acid. The organic phases were combined, dried over MgSO4 and filtered. After removal of the solvent, water and 2 N hydrochloric acid were added to the residue and then freeze-dried. 27 mg of the desired product was obtained.

LCMS-Rt (E): 2.29 min.

MS (ES<+>, M+H<+>): 347.87.

Example 48: (2,4-dichlorothiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine hydrochloride

a) 1-(2-amino-4,5-difluorophenyl)-3-(4-chlorothiophen-3-yl)-thiourea

To 1.02 g of 1,2-diamino-4,5-difluorobenzene in 15 ml of absolute THF was added dropwise 1.25 g of 4-chloro-3-thienyl isothiocyanate (Example 44c) in 15 ml of absolute THF. The further process analogous to example 46 a) gave 773 mg of the desired compound.

LCMS-Rt (F): 1.32 min.

MS (ES<+>, M+H<+>): 320.0.

b) (4-chlorothiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine

To 773 mg of 1-(2-amino-4,5-difluorophenyl)-3-(4-chlorothiophen-3-yl)-thiourea in 20 ml of THF was

a solution of 240 mg of NaOH in 9 ml of water was added and then a solution of 528 mg of tosyl chloride in 10 ml of THF. The further process took place analogously to example 46 b) and gave 275 mg of the desired compound.

LCMS-Rt (F): 0.95 min.

MS (ES<+>, M+H<+>): 286.

c) (2,4-dichlorothiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine hydrochloride

To 125 mg of (4-chlorothiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine in 8 ml

acetic acid, a solution of 59 mg of Cl-succinimide in 2 ml of acetic acid was added dropwise. The further process took place analogously to example 46 c) and gave 58 mg of the desired product. LCMS-Rt (E): 2.97 min.

MS (ES<+>,M+H<+>): 319.88.

Example 49: (2-bromo-4-chlorothiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine hydrochloride

125 mg of (4-chlorothiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine (Example 47 b) was dissolved in 8 ml of glacial acetic acid and added at room temperature and under vigorous stirring added 78 mg of N-bromosuccinimide, dissolved in 2 ml of glacial acetic acid. In the further process analogous to Example 47 occurred and gave 77 mg of the desired product.

LCMS-Rt (E): 2.39 min.

MS (ES<+>, M+H<+>): 365.86.

Example 50: 4-chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride

a) N-(2-amino-3-methylphenyl)-N'-(4-chloro-3-thienyl)thiourea was obtained analogously to the process indicated in example 44 g) from 4-chloro-3-thienisocyanate and 1,2 -diamino-3-methylbenzyl and application of medium pressure column chromatography on silica gel with a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 1 part ethyl acetate.

A brown colored solid with a melting point of 193-196°C was obtained.

b) e) 4-chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene was obtained analogously to the method indicated in example 44 h) from N-(2-amino-3-methylphenyl)-N'-(4- chloro-3-thienyl)thiourea using medium pressure column chromatography on silica gel with a mixture of ten parts dichloromethane and one part methanol, as amorphous foamy product. Preparation of the 4-chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride in ethyl acetate with hydrogen chloride gas-saturated diethyl ether gave a crystalline product with a melting point of 325-327°C. Example 51: 2,4-dichloro-3N-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride analogously to the methods indicated in example 44 i) from 4-chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene and N-chlorosuccinimide in glacial acetic acid by analogous work-up. A crystalline product with a melting point of 296-298°C was obtained. Example 52: trans-(3aS,7aS)-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride a) trans-S,S -3N-(2-amino-cyclohexyl)-N'-(4-chloro-3-thienyl)-thiourea was obtained analogously to the reaction indicated in example 1 b) from 4-chloro-3-thienyl isothiocyanate and trans-S ,S-1,2-diaminocyclohexane by column chromatographic separation on silica gel with a mixture of 10 parts ethyl acetate, 5 parts dichloromethane, 5 parts n-heptane, 5 parts methanol and 1 part 35-37% ammonia, as amorphous, dark product, which was used further without further processing. b) trans-(3aS, 7aS)-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine is obtained analogously to that indicated in example 44 h) process from trans-S,S-3N-(2-amino-cyclohexyl)-N'-(4-chloro-3-thienyl)-thiourea, p-toluenesulfonic acid chloride and subsequent application of medium pressure column chromatography on silica gel with a mixture of 10 parts dichloromethane and 1 part methanol, as amorphous, foamy product. Preparation of trans-S,S-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochlorides in ethyl acetate and a little ethanol with hydrogen chloride gas-saturated diethyl ether.

A crystalline product with a melting point of 196-200°C was obtained.

Example 53: trans-(3aR, 7aR)-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride

a) trans-(1R,2R)-3N-(2-amino-cyclohexyl)-N'-(4-chloro-3-thienyl)-thiourea is obtained analogously to that in example 1 b) indicated in reaction from 4-chloro- 3-thienyl isothiocyanate and trans-(1R,2R)-(-)-1,2-diaminocyclohexane by subsequent column chromatographic separation on silica gel with a mixture of 10 parts ethyl acetate, 5 parts n-heptane, 5 parts dichloromethane, 5 parts methanol and 1 part 35-37% ammonia as an amorphous, dark product which was used further without further work-up. b) trans-(3aR, 7aR)-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine is obtained analogously to that indicated in example 44 h) method from trans-R,R-3N-(2-amino-cyclohexyl)-N'-(4-chloro-3-thienyl)-thiourea, p-toluenesulfonic acid chloride and then the subsequent application of medium pressure column chromatography on silica gel with a mixture of 10 parts ethyl acetate, 5 parts n-heptane, 5 parts dichloromethane, 5 parts methanol and 1 part 35-37% ammonia as an amorphous, oily product.

Preparation of trans-R,R-chloro-3N-(3α,4,5,6,7,7α-hexahydro-1H-2-benzimidazaolyl)-3-thienylamine hydrochloride in ethyl acetate with a little ethanol with hydrogen chloride saturated in ethyl ether, and a crystalline product with a melting point of 240-244°C is obtained.

Example 54: cis-4-chloro-3N-(3a,4,5.,6,7,7a-hexahydro-1H-2-beizimidazolyl)-3-thienylamine hydrochloride

a) cis-3N-(2-amino-cyclohexyl)-N'-(4-chloro-3-thienyl)-thiourea is obtained analogously to the reaction indicated in example 1 b) from 4-chloro-3-thienyl isothiocyanate and cis -1,2-diaminocyclohexane with subsequent column chromatographic separation on silica gel with a mixture of time or ethyl acetate, 5 parts n-heptane, 5 parts dichloromethane, 5 parts methanol and 1 part 35-37% ammonia as an amorphous, dark product which is used further without further purification. b) cis-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine is obtained analogously to the method indicated in example 44 h) from 3N-(cis -2-amino-cyclohexyl)-N'-(4-chloro-3-thienyl)-thiourea, p-toluenesulfonic acid chloride and then the following application of a medium pressure column chromatography on silica gel with a mixture of 10 parts ethyl acetate, 5 parts n-heptane, 5 parts dichloromethane, 5 parts methanol and 1 part 35-37% ammonia as a brown, oily product. Preparation of the 4-chloro-3N-(cis-3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride is carried out in ethyl acetate and a little ethanol with hydrogen chloride gas saturated in ethyl ether.

A crystalline product with a melting point of 228-231°C is obtained.

Example 55: trans-R,R-2,4-dichloro-3N-(3α,4.(5,6,7,7α-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride

is obtained analogously to the method indicated in example 44 i) by reacting trans-R,R-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine with N-chlorosuccinimide and analogous work-up.

A crystalline product is obtained which foams and sublimes from 165°C.

Example 56: cis-2,4-dichloro-3N-(3α,4,5,6,7,7α-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride

is achieved analogously to the method indicated in example 44 i) conversion of cis-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-hexahydro-1H-2-benzimidazolyl)-3- thienylamine with N-chlorosuccinimide and analogous work-up.

A crystalline product with a melting point of 270-274°C is obtained.

Example 57: 4-chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride

a) 1-N-(2-amino-3-chlorophenyl)-3-N-(4-chloro-3-thienyl)thiourea is obtained from 3-chloro-1,2-diaminobenzene and 4-chloro-3-thienyl isothiocyanate analogously to that in example 1 b) described

the procedure and crystallization from isopropyl ether.

A solid with two melting points is obtained: melting point 1: 152-155°C during recrystallization; and melting point 2: >310°C. b) 4-chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene is obtained analogously to the method described in example 44 h) by reaction of 1-N-(2-amino-3-chlorophenyl)-3N-(4-chloro- 3-thienyl)thiourea with p-toluenesulfonic acid chloride and column chromatography on silica gel with a mixture of 3 parts toluene and one part ethyl acetate as eluent, and then the following distillation of the solvent under reduced pressure as a foamy, amorphous product which is further converted to the hydrochloride.

c) 4-chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride is obtained by treating a solution of 4-chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene in ethyl acetate with

a hydrogen chloride gas-saturated solution in diethyl ether as a crystalline precipitate.

The product has a melting point of 276-280°C.

Example 58: 2,4-dichloro-3N-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride

is obtained analogously to the method indicated in example 44 i) from 4-chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene and N-chlorosuccinimide in glacial acetic acid by analogous work-up.

A crystalline product with a melting point of 294-297°C is obtained.

Analogous to the examples above, the following thiophene derivatives can be prepared: 2-bromo-4-chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride, with melting point 284-286°C,

2-bromo-4-chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride, with melting point 304-306°C,

trans-R,R-2-bromo-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride, with a decomposition point of 215°C,

trans-(3aS, 7aS)-2-bromo-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride 243-254°C,

2,4-dibromo-3N-(2-benzimidazoly l)-3-thienylamine hydrochloride,

2,4-dimethyl-3N-(2-benzimidazolyl)-3-thienylamine hydrochloride,

2,4-dimethyl-3N-(4-methyl 1-2-benzimidazolyl)-3-thienylamine hydrochloride, 2,4-dimethyl-3N-(5-fluoro-2-benzimidazolyl)-3-thienylamine hydrochloride, 2-chloro -3N-(4-butoxy-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, 2-chloro-3N-(4-trifluoromethyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, 2-chloro -3N-(4-methylsulfonyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride.

Pharmacological data:

Test description: In this test, the recovery of the intracellular pH values (pH,) after an acidification was determined, as it also takes place in functional NHE under bicarbonate-free conditions. For this purpose, the pH value was determined with the pH-sensitive fluorescent dye BCECF (Calbiochem, the preferred BCECF - AM was used). The cells were first loaded with BCECF. The BCECF fluorescence was determined on a "Ratio Fluorescence Spectrometer" (Photon Technology International, South Brunswick, N.J., USA) at excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and converted using calibration curves to pHj. Already at the BCECF loading, the cells were incubated in NH4Cl buffer (pH 7.4) (NH4Cl buffer: 115 mM NaCl, 20 mM NH4Cl, 5 mM KC1, 1 mM CaCl2, 1 mM MgSO4, 20 mM Hepes, 5 mM glucose, 1 mg/ml BSA; adjusted to a pH value of 7.4 with 1 M NaOH). The intracellular acidification was induced by adding 975 µl of an NH4Cl-free buffer (see below) to 25 µl aliquots of the cell incubated in NHtCl buffer. The subsequent rate of pH recovery was recorded by NHE1 to two minutes, at NHE2 to five minutes and at NHE3 to three minutes. For calculation of the inhibitory potency of the tested substances, the cells were first examined in the buffer in which a 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 KC1, 1.25 mM CaCl2, 1.25 mM MgCl2, 0.97 mM Na2HP04, 0.23 mM NaH2PO4, 5 mM hepes, 5 mM glucose, adjusted to a pH -value of 7.0 with 1 M NaOH).To determine the 0% value, cells were incubated in a Na<+->free buffer (133.8 mM choline chloride, 4.7 mM KC1, 1.25 mM CaCl2, 1.25 mM MgCl2, 0.97 mM K2HPO4, 0.23 mM KH2PO4, 5 mM Hepes, 5 mM glucose, adjusted to pH 7.0 with 1 M KOH.The substances for testin g was set up in the Na<+->containing buffer. The restoration of the intracellular pH values was for each tested concentration of a substance expressed as a percentage of the maximum restoration. From the percentage values of the pH recovery, the IC50 value for the substance in question for the individual NHE subtypes could be calculated using the program Sigma-Plot.

Results:

Claims (11)

1. Compounds, characterized by formula I, in which R<1> means H, F, Cl, Br, I, CN or NO 2 ; R<2> means H, F, Cl, Br, I, CN, NO 2 or C 1 -C 6 alkyl; n is zero; q is zero, 1, 2, 3, 4, 5 or 6; Z is hydrogen; R<3> means hydrogen, F, Cl, Br, I or CN; R<4> means hydrogen or -CrH2r-Y; r is zero, 1, 2, 3 or 4; Y means hydrogen; R<5> and R6 mean hydrogen or together form a bond; R<7> and R<8> together mean a butylene chain; or R<7> and R8 together form a residue where R<5> and R6 together may form a bond; R<10> and R<n> are independently hydrogen, fluorine, chlorine, bromine; R<9> and R<12> are hydrogen or F; or one of the substituents R<9> and R12 is hydrogen; and the second is F, Cl, Br, I or -(X)n-CqH2Q-Z; n is zero or 1; X is oxygen; q is zero, 1,2, 3,4, 5 or 6; and Z is hydrogen; As well as their pharmaceutically acceptable salts, as well as their trifluoroacetic acid salts. 2. Compound according to claim 1, characterized in that R<1> is FLF, Cl, Br; R<2> is F, Cl, Br or CH3; R<3> is hydrogen, F or Cl; R<4> is hydrogen or C1-4 alkyl; R<5> and R6 are hydrogen or a common bond; R T and R R together form a butylene chain, or R7 and R<8> together form a residue where R<5> and R<6> together form a bond; R<1>0 and R1<1>, independently of each other, are hydrogen, fluorine or chlorine; R<9> and R<12> are hydrogen; or one of the substituents R<9> and R<12> is hydrogen; and the other is F, Cl, Br or -(X)n - CqH2q-Z; n is zero or 1, X is oxygen; q is zero, 1, 2, 3 or 4; Z is hydrogen; as well as their pharmaceutically acceptable salt, as well as their trifluoroacetic acid salts. 3. Compound according to claim 1 and/or 2, characterized in that R<1> and R2 independently of each other are F, Cl or Br; •1 R is hydrogen; R<4> is hydrogen, methyl or ethyl; R 5 and R 6 are hydrogen or together form a bond; R<7> and R8 together are a butylene chain; or R<7> and R8 together are a residue where R<5> and R<6> together form a bond; R<10> and R<11> are independently hydrogen or fluorine; R<9> and R<12> are hydrogen; or one of the substituents R<9> and R<12> is hydrogen; and the other is F, Cl, Br or -(X)n - CiH2q-Z; n is zero or 1; X is oxygen; q is zero or 1; Z is hydrogen; as well as their pharmaceutically acceptable salts, as well as trifluoroacetic acid salts thereof. 4. Compound of formula I according to any one of claims 1, 2 or 3, characterized in that they are selected from the group: trans-R,R-2-chloro-3N-(3a,4,5,6,7,7a -hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine, trans-R,R-2-bromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl )-4-methyl-3-thienylamine, 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, 2-bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine , 2-chloro-3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine, 2-chloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine, 2 -chloro-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene, 2-bromo-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene, 2-bromo-3N-(4-fluoro- 2-benzimidazolylamino)-4-methylthiophene, 2-chloro-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene, 2-chloro-3N-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene, (1H-benzimidazol-2-yl)-(2-chloro-4-methylthiophen-3-yl)-methylamine, (2-bromo-4-methylthiophen-3-yl)-(5-fluoro-1H- benzimidazol-2-yl)-amine, 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene and 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene, as well as their pharmaceutically acceptable salts. 5. Compound according to claim 1 and/or their pharmaceutically acceptable salts according to one or more of claims 1-4 for use as a medicine. 6. Use of a compound of formula I and/or pharmaceutically acceptable salts thereof according to one or more of claims 1-4, for the production of a drug for the treatment or prophylaxis of respiratory disorders and in particular sleep-related respiratory disorders such as sleep apnea, or snoring, for treatment or prophylaxis of acute or chronic kidney diseases, and in particular acute kidney failure or chronic kidney failure, or disorders of intestinal function, for the treatment or prophylaxis of high blood pressure, in particular the essential hypertension for the treatment or prophylaxis of acute or chronic injuries, diseases and indirect sequelae of organs or tissue caused by ischemia or reperfusion events, by arrhythmias, atherosclerosis, hypercholesterolemia, diseases in which cell proliferation plays a primary or secondary cause, by cancer, by fibrotic diseases of the internal organs, by heart insufficiency or cognitive heart failure, by disorders of biliary function,attack by ectoparasites, for the treatment of shock states, diabetic and diabetic late damage, acute or chronic, inflammatory diseases or for the production of a drug for the preservation and storage of grafts for surgical events, for the production of a drug for use in surgical operations and organ transplants, for production of a drug to prevent age-related tissue changes. 7. Use of a compound of formula I and/or its pharmaceutically acceptable salts according to claim 6, for the preparation of a medicament for the treatment or prophylaxis of respiratory disorders, in particular sleep-related respiratory disorders such as sleep apnea. 8. Use of a compound compound of formula I and/or its pharmaceutically acceptable salts according to claim 6, for the preparation of a medicament for the treatment or prophylaxis of snoring. 9. Use of a compound compound of formula I and/or its pharmaceutically acceptable salts according to claim 6, for the preparation of a medicament for the treatment or prophylaxis of acute and chronic kidney diseases, in particular acute renal failure or chronic renal failure. 10. Use of a compound compound of formula I and/or its pharmaceutically acceptable salts according to claim 6, for the preparation of a medicament for the treatment or prophylaxis of disorders of intestinal function. 11. Medicinal product for human or veterinary medical use, characterized in that it contains an effective amount of a compound of formula I and/or pharmaceutically acceptable salts thereof according to one or more of claims 1-4, together with pharmaceutically acceptable carriers and additives.