HK1076460A1

HK1076460A1 - Substituted thiophenes, method for the production thereof, their use as a medicament or diagnostic reagent, and a medicament containing the same

Info

Publication number: HK1076460A1
Application number: HK05108392A
Authority: HK
Inventors: Hans-Jochen Lang; Uwe Heinelt; Armin Hofmeister; Klaus Wirth; Michael Gekle; Markus Bleich
Original assignee: 塞诺菲-安万特德国有限公司
Priority date: 2002-06-04
Filing date: 2003-05-26
Publication date: 2006-01-20
Also published as: ATE320425T1; AR040239A1; RU2004138812A; JP4511924B2; EP1513834A1; OA12827A; MA27204A1; KR101087966B1; CN1659163A; TNSN04240A1; PT1513834E; CA2488242C; IL165519A; CR7577A; BR0311548A; JP2005533038A; CN1324024C; PL372589A1; DE50302673D1; NO20045504L

Abstract

The invention relates to substituted thiophene derivatives of formula (I), wherein: R1 to R8 have the meanings as cited in the claims. Medicaments containing compounds of this type are useful in preventing or treating various diseases. Thus, these compounds can be used, among other things, for treating breathing disturbances and snoring, for improving the breathing drive, for treating acute and chronic diseases, diseases triggered by ischemic and/or reperfusion events as well as by proliferative or fibrotic events, for the treatment or prophylaxis of diseases of the central nervous system, lipid metabolism and diabetes, blood clotting and parasitic infection.

Description

Substituted thiophenes, process for their preparation, their use as medicaments or diagnostic reagents and medicaments containing them

no marking

Substituted thiophenes, processes for their preparation, their use as medicaments or diagnostic reagents and medicaments containing them.

The invention relates to compounds of the substituted thiophene derivative type of formula I. Medicaments comprising such compounds are useful in the prevention or treatment of various disorders. Such compounds may therefore be used, inter alia, for the treatment of respiratory disorders and snoring, for improving respiratory drive, for the treatment of acute and chronic disorders, disorders triggered by ischemic and/or reperfusion events and by proliferative or fibrotic events, for the treatment or prevention of disorders of the central nervous system and lipid metabolism as well as diabetes, blood coagulation and infections caused by parasites.

The present invention relates to compounds of formula I:

wherein:

r1 and R2 independently of one another are H, F, Cl, Br, I, CN, NO₂、-(X)_n-C_qH_2q-Z, cycloalkyl having 3, 4, 5 or 6 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl or alkyl alkynyl having 3 or 4 carbon atoms;

n is 0 or 1;

x is oxygen, NH, N-CH₃、S(O)_k；

k is 0, 1 or 2;

q is 0, 1, 2, 3, 4, 5 or 6;

z is hydrogen or C_mF_2m+1；

m is 0, 1, 2, 3 or 4;

r3 is hydrogen, methyl, F, Cl, Br, I, CN, S (O)_k-CH₃、-NO₂、-O-CH₃；

k is 0, 1 or 2;

r4 is hydrogen, cycloalkyl having 3, 4, 5 or 6 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl or alkyl having 3 or 4 carbon atomsAlkynyl, -C_rH_2r-Y；

r is 0, 1, 2, 3 or 4;

y is hydrogen or trifluoromethyl;

r5 and R6 are hydrogen or together are a bond;

r7 and R8 are independently of each other (C)₃-C₅) Alkyl radicals, (C)₂-C₅) -alkenyl, (C)₂-C₅) -alkynyl, (C)₃-C₆) -cycloalkyl or (C)₄-C₆) -a cycloalkenyl group; or

R7 and R8 together are an alkylene chain containing from 3 to 8 carbon atoms;

wherein none, some or all of their hydrogen atoms may be replaced by fluorine atoms; or

R7 and R8 together are a group of the formula:

wherein R5 and R6 together form a bond;

r10 and R11 are each independently of the other hydrogen, fluorine, chlorine, bromine, methyl, CN, OH, -O-CH₃、

NO₂、NH₂or-CF₃；

R9 and R12 are hydrogen or F; or

One of the substituents R9 and R12 is hydrogen and the other is F, Cl, Br, I, CN, NO₂、COOH、CO-NR13R14、SO₂-NR13R14, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl, alkylalkynyl having 3 or 4 carbon atoms or- (X)_n-C_qH_2q-Z；

R13 and R14 are the same or different and are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or

R13 and R14 together with the nitrogen to which they are attached form a saturated 5-, 6-, or 7-membered ring;

n is 0 or 1;

x is oxygen, NH, N-CH₃、S(O)_k；

k is 0, 1 or 2;

q is 0, 1, 2, 3, 4, 5 or 6; and is

Z is hydrogen or C_mF_2m+1；

m is 0, 1, 2, 3 or 4;

and pharmaceutically acceptable salts thereof and the trifluoroacetates thereof.

One embodiment relates to compounds of formula I wherein:

n is 0 or 1;

x is oxygen, NH, N-CH₃、S(O)_k；

k is 0, 1 or 2;

q is 0, 1, 2, 3, 4, 5 or 6;

z is hydrogen or C_mF_2m+1；

m is 0, 1, 2, 3 or 4;

r3 is hydrogen, methyl, F, Cl, Br, I, CN, S (O)_k-CH₃、-NO₂、-O-CH₃；

R4 is hydrogen, cycloalkyl having 3, 4, 5 or 6 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl or alkinyl having 3 or 4 carbon atoms, -C_qH_2q-Z；

q is 0, 1, 2, 3 or 4;

z is hydrogen or trifluoromethyl;

r5 and R6 are hydrogen or together are a bond;

R7 and R8 together are an alkylene chain containing from 3 to 8 carbon atoms;

R7 and R8 together are a group of the formula:

wherein R5 and R6 together form a bond;

r9, R10 and R11 are each independently of the others hydrogen, fluorine, chlorine, bromine, methyl, CN, OH, -O-CH₃、

NO₂、NH₂or-CF₃；

R9 and R12 are hydrogen; or

R13 and R14 are the same or different and are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

n is 0 or 1;

x is oxygen, NH, N-CH₃、S(O)_k；

k is 0, 1 or 2;

q is 0, 1, 2, 3, 4, 5 or 6; and is

Z is hydrogen or C_mF_2m+1；

m is 0, 1, 2, 3 or 4;

Preferred are compounds of formula I, wherein:

r1 and R2 independently of one another are H, F, Cl, Br, CH₃、CF₃、SO₂CH₃、SO₂NH₂；

But not more than one of the substituents R1 and R2 is hydrogen;

r3 is hydrogen, F or Cl;

r4 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cyclopropyl;

r5 and R6 are hydrogen or together are a bond;

r7 and R8 together are an alkylene chain containing 3, 4, 5, 6, 7 or 8 carbon atoms; or

R7 and R8 together are a group of the formula:

wherein R5 and R6 together form a bond;

r10 and R11 are independently from each other hydrogen, OH, fluorine or chlorine;

r9 and R12 are hydrogen; or

One of the substituents R9 and R12 is hydrogen and the other is F, Cl, Br, CN, COOH,

CO-NR13R14、SO₂-NR13R14 or- (X)_n-C_qH_2q-Z；

R13 and R14 are the same or different and are hydrogen or methyl;

n is 0 or 1;

x is oxygen, NH, N-CH₃Or S (O)_k；

k is 0, 1 or 2;

q is 0, 1, 2, 3 or 4;

z is hydrogen or CF₃；

Particular preference is given to compounds of the formula I in which:

r1 and R2 independently of one another are F, Cl, Br, CH₃Or CF₃；

R3 is hydrogen;

r4 is hydrogen, methyl, ethyl;

r5 and R6 are hydrogen or together are a bond;

R7 and R8 together are a group of the formula:

wherein R5 and R6 together form a bond;

r10 and R11 are independently from each other hydrogen, OH or fluorine;

r9 and R12 are hydrogen; or

One of the substituents R9 and R12 is hydrogen and the other is F, Cl, Br or- (X)_n-C_qH_2q-Z；

n is 0 or 1;

x is oxygen, NH, N-CH₃Or S (O)_k；

k is 0, 1 or 2;

q is 0 or 1;

z is hydrogen or CF₃；

Very particular preference is given to compounds of the following formula I, which are selected from:

trans-R, R-2-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine,

trans-R, R-2-bromo-3N- (3a, 4, 5, 6, 7, 7 a-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

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

2-bromo-4-chloro-3N- (2-benzimidazolylamino) thiophene,

2, 4-dichloro-3N- (4-methyl-2-benzimidazolylamino) thiophene,

trans-R, R-2, 4-dichloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine, or

2, 4-dichloro-3N- (4-chloro-2-benzimidazolylamino) thiophene and their pharmaceutically acceptable salts, such as the hydrochloride or hydrobromide or mesylate salts of each compound.

The compounds of formula I may exist in the form of their salts. Suitable acid addition salts are all salts of pharmaceutically acceptable acids, for example chlorides, especially the hydrochloride, hydrobromide, lactate, sulphate, citrate, tartrate, acetate, phosphate, methanesulphonate, benzenesulphonate, p-toluenesulphonate, adipate, fumarate, gluconate, glutamate, glycerophosphate, maleate, benzoate, oxalate and pamoate salts. This group also corresponds to physiologically acceptable anions, and also trifluoroacetate. If the compounds contain acidic groups, they are capable of forming salts with bases, for example alkali metal salts, preferably sodium or potassium salts, or ammonium salts, for example salts with ammonia or organic amines or amino acids. They may also be present as zwitterions.

If the compound of formula I contains one or more asymmetric centers, the compound may be independently in the S-configuration and the R-configuration. The compounds may exist as optical isomers, diastereomers, racemates or mixtures thereof.

The compounds of formula I may further exist as tautomers or mixtures of tautomeric structures. This refers, for example, to the following tautomers:

(if R4 ═ H).

The alkyl group may be linear or branched. This also applies when the alkyl group bears a substituent or is present as a substituent of another group, for example in a fluoroalkyl group or an alkoxy group. Examples of alkyl 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 groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl. In the alkyl group, one or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen atoms may be replaced by fluorine atoms. Examples of such fluoroalkyl groups are trifluoromethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, heptafluoroisopropyl. The substituted alkyl group may be substituted at any position.

The alkenyl group may be straight-chain or branched. The same applies when they are present as substituents, for example in alkenylalkylene. The alkenyl groups may be unsaturated in different positions. Examples of alkenyl are ethenyl, propenyl or butenyl.

The alkynyl group may be linear or branched. The same applies when they are present as substituents, for example in alkynylalkylene. Alkynyl groups may be unsaturated at various positions. Examples of alkynyl groups are ethynyl, propynyl or butynyl.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Substituted cycloalkyl groups may be substituted at any position. Cycloalkyl groups may also be present as a branching to an alkylcycloalkyl or cycloalkylalkyl group.

Methods of making the compounds of the invention are also described. Thus, the materials described by formula I can be prepared from the isothiocyanate II parent compound and the appropriate diamine III in a manner known to those skilled in the art.

Cyclization of the thiourea derivatives formed as intermediates with methyl iodide (Synthesis, 1974, 41-42) or carbodiimide (Synthesis, 1977, 864-865) or with p-toluenesulfonyl chloride gives the corresponding compounds of the formula I. If the isothiocyanates II employed here are not commercially available, they can be prepared in a manner known from the literature from the corresponding aminothiophene derivatives using methods known to those skilled in the art, for example by treatment with thiophosgene (J.Med.Chem., 1975, 18, 90-99) or thiocarbonyldiimidazole (Justus Liebigs Ann.Chem., 1962, 657, 104).

Isocyanates IV can also be used successfully in addition to the isothiocyanates II mentioned above

With an amine of formula III to give a compound of formula I. Here, the urea derivative formed as intermediate is cyclized using phosphorus oxychloride to give the corresponding compound of the formula I.

In the present invention, it has surprisingly been shown that said compounds are potent inhibitors of sodium/proton exchangers (NHE), especially of the sodium/proton exchanger (NHE) subtype 3.

The currently known NHE3 inhibitors are derived from compounds of the acylguanidine type (EP825178), norbornylamine type (DE19960204), 2-guanidino-quinazoline type (WO0179186) or benzamidine type (WO0121582, WO 172742). Squalamine (Squalamine) is also described as an NHE3 inhibitor (m. donowitz et al, am. j. physiol.276(Cell physiol.45): C136-C144), which, according to current knowledge, is not as effective as the compound of formula I immediately, but rather by an indirect mechanism, thus reaching its maximum efficacy only after 1 hour. Such NHE3 inhibitors, which act by different mechanisms, are therefore suitable as combination partners for the compounds of the invention.

Clonidine, like the compounds described herein, is known to be a weak NHE inhibitor. However, its effect on NHE3 in mice was extremely mild, with a half maximal inhibitor concentration (IC50) of 620 μ M. In contrast, it showed some selectivity for NHE2 (j. orlowski et al, j. biol. chem.268, 25536). Thus, more precisely clonidine is referred to as NHE2 inhibitor. In addition to weak NHE effects, clonidine has a high affinity for adrenergic α 2 and imidazoline 11 receptors, mediating a strong hypotensive effect (Ernsberger et al, eur.j. pharmacol.134, 1, 1987).

Cola-like compounds having a thiophene ring instead of a phenyl ring are known from DE 1941761. These known compounds differ from the structures of formula I described in the present invention in that they have significantly smaller groups R7 and R8, in particular in the fact that R7 and R8 cannot form a junction ring. Due to these differences between the substituents R7 and R8, it is possible to abolish the above-mentioned undesirable clonidine-like cardiovascular effects, which are mediated by α -adrenergic receptor action. While the NHE-inhibiting properties of the compounds described herein are enhanced to the micromolar and submicromolar range due to these differences in substituents, the compounds known from DE1941761 show only very weak NHE-inhibiting effects, if any. Thus, the main representative compound of DE1941761, namely the hypotensive drug thiamenidine selected as the product under development, had no inhibitory effect on the tested NHE subtypes NHE1, NHE2, NHE3 and NHE5 at 300 μ M in each case.

The compounds of formula I are characterized in that they inhibit the cellular sodium/proton exchanger, and in particular their NHE3 inhibitory effect.

NHE3 is found in the body of various species, preferably in the gallbladder, intestine and kidney (Larry Fliegel et al, biochem. cell. biol. 76: 735-Asn 741, 1998), but can also be detected in the brain (E. Ma et al, Neuroscience 79: 591-Asn 603).

Due to the NHE inhibiting properties, the compounds of formula I are suitable for the prevention and treatment of diseases caused by activated or activated NHE and diseases of the sequelae of injury caused by NHE.

Since NHE inhibitors act primarily by influencing the pH regulation of the cell, they can be combined in an advantageous manner with other compounds which likewise regulate the intracellular pH, wherein suitable combination partners are inhibitors of the carbonic anhydrase group, inhibitors of the bicarbonate-ion-transport system such as sodium bicarbonate cotransporter (NBC) or sodium-dependent chloride/bicarbonate ion exchanger (NCBE) and NHE inhibitors having an inhibitory effect on other NHE subtypes, since they can modulate or enhance the pharmacologically relevant pH-regulating effect of the NHE inhibitors described herein.

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 actions of the compounds of formula I are characterized in that: they induce an improvement in respiratory drive. They are therefore useful in the treatment of respiratory disorders which may for example present the following clinical conditions and diseases: central respiratory drive disorders (e.g. central sleep apnea, sudden infant death, post-operative hypoxia), muscle-related breathing disorders, breathing disorders after long-term ventilation, breathing disorders during adaptation in the plateau region, obstructive and mixed forms of sleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia.

In addition, the compounds of the present invention also increase the muscle tone of the upper respiratory tract, thereby inhibiting snoring. As a result, the compounds are advantageously used for the preparation of medicaments for the prophylaxis and treatment of sleep apnoea and muscle-related respiratory disorders and for the preparation of medicaments for the prophylaxis and treatment of snoring.

The combination of the NHE inhibitors of formula I with carbonic anhydrase inhibitors (e.g. acetazolamide) may prove advantageous, wherein the latter leads to metabolic acidosis and thus already increased respiratory activity, thus allowing an enhanced action and a reduced use of the active compound.

Due to their NHE3 inhibitory effect, the compounds of the invention can save cellular energy, which is rapidly depleted in toxic and pathogenic events, leading to cell damage or cell death. Here, in the proximal tubule, the uptake of high-energy ATP-depleted sodium is temporarily cut off under the influence of the compound of formula I, so that the cell can survive in acute, ischemic or toxic conditions. These compounds are therefore suitable, for example, as medicaments for the treatment of ischemic diseases, such as acute renal failure.

In addition, the compounds are suitable for the treatment of all chronic kidney diseases and various forms of nephritis, which lead to chronic renal failure due to increased protein elimination. The compounds of formula I are therefore suitable for the preparation of medicaments for the treatment of diabetic end-stage injury, diabetic nephropathy and chronic kidney disease, in particular all the various renal inflammations (nephritis) associated with an increased elimination of protein/albumin.

The compounds used according to the invention have been shown to have a mild laxative effect and can therefore also be used advantageously as laxatives or for preventing intestinal obstruction.

Furthermore, the compounds of the invention can be advantageously used for the prophylaxis and treatment of acute and chronic intestinal disorders of the intestine which are triggered, for example, by ischemic states in the intestinal region and/or by subsequent reperfusion or by inflammatory states and events. These complications may occur, for example, due to a lack of intestinal peristalsis, as is often observed after surgical intervention, intestinal obstruction, or a substantial reduction in intestinal activity.

By using the compound of the present invention, the formation of cholelithiasis can be prevented.

The NHE inhibitors of the invention are widely applicable to the treatment of diseases caused by ischemia and reperfusion.

Due to their pharmacological profile, the compounds of the invention are suitable for use as antiarrhythmic agents.

The NHE inhibitors of formula I are highly potent due to the cardioprotective component of the NHE inhibitors of formula ISuitable for infarct prevention and infarct treatment and for the treatment of angina pectoris, and they also inhibit or strongly reduce in a preventive manner the pathophysiological processes which play a role in ischemia-induced damage, especially those which trigger ischemia-induced arrhythmias. Due to the protective effect of the compounds of the formula I used according to the invention on pathological hypoxic and ischemic states, they can act as cellular Na⁺/H⁺Inhibitors of the exchange mechanism are useful as medicaments for the treatment of all acute or chronic injuries caused by ischemia or diseases caused by the primary or secondary consequences of such injuries.

This relates to their use as surgical intervention drugs. Thus, the compounds of the present invention are useful in organ transplantation, where these compounds are useful in protecting organs in donors prior to or during removal, protecting organs that have been removed, for example during treatment or storage in physiological baths, and during transfer to recipient organisms pretreated with compounds of formula I.

These compounds are also useful drugs having a protective effect during the intervention of angioplasty, for example on the heart and peripheral organs and blood vessels.

Since NHE inhibitors protect human tissues and organs not only effectively against damage caused by ischemia and reperfusion, but also against the cytotoxic effects of drugs used in particular in cancer therapy and in the treatment of autoimmune diseases, the combined administration of compounds of formula I is suitable for inhibiting or reducing the cytotoxic effects of the therapy. By reducing cytotoxic effects, especially cardiotoxicity, in combination with NHE inhibitors, the dose of cytotoxic therapeutic agents may also be increased and/or treatment with such drugs prolonged. The therapeutic benefit of such cytotoxic therapy can be significantly enhanced by the combination of NHE inhibitors. The compounds of the formula I are particularly suitable for improving therapy with medicaments having an undesired cardiotoxic effect component.

Since the compounds of the invention have a protective effect on ischemia-induced damage, they are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, where they can be used, for example, for the treatment of stroke or cerebral edema.

The compounds of formula I are also suitable for the treatment and prevention of diseases and disorders which are caused by an excessive excitation of the central nervous system, in particular for the treatment of epilepsy, centrally induced paroxysmal and spasmodic spasticity, psychological depressive states, anxiety and psychosis. Here, the NHE inhibitors of the present invention can be used alone or in combination with other substances having an antiepileptic effect or with antipsychotic active compounds or carbonic anhydrase inhibitors such as acetazolamide and with other NHE or inhibitors of sodium-dependent chloride/bicarbonate ion exchanger (NCBE).

In addition, the compounds of formula I according to the invention are also suitable for the treatment of various types of shock, such as anaphylactic, cardiogenic, hypovolemic and bacterial shock.

The compounds of formula I are also useful in the prevention and treatment of thrombotic disorders, since as NHE inhibitors they are themselves also capable of inhibiting platelet aggregation. In addition, they can prevent or inhibit the excessive release of inflammatory and clotting mediators, particularly von willebrand factor and thromboselectin, which occurs after ischemia and reperfusion. Thus, the pathogenic effects of important thrombotic factors can be reduced and eliminated. Thus, the NHE inhibitors of the invention may be combined with other compounds having anti-coagulant and/or thrombolytic effects, such as recombinant or native tissue plasminogen activators, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, agents having fibrinolytic effects, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor vila antagonists, clopidogrel, ticlopidine, and the like. The combined use of the NHE inhibitors of the invention with NCBE inhibitors and/or with carbonic anhydrase inhibitors such as acetazolamide is particularly advantageous.

Furthermore, the compounds of the formula I according to the invention have a strong inhibitory effect on cell proliferation, for example on fibroblast proliferation and on proliferation of smooth muscle cells. Accordingly, the compounds of formula I are useful therapeutic agents for diseases in which cell proliferation is a primary or secondary cause, and thus useful as anti-atherosclerotic agents, anti-chronic renal failure and anti-neoplastic diseases. They are therefore useful in the treatment of organ hypertrophy and hyperplasia, such as of the heart and prostate. The compounds of the formula I are therefore suitable for the prophylaxis and treatment of cardiac insufficiency (congestive heart failure ═ CHF) and for the treatment and prophylaxis of prostatic hyperplasia and prostatic hypertrophy.

The compounds of formula I furthermore delay or prevent fibrotic disorders. Therefore, they are excellent drugs for the treatment of cardiac fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis and other fibrotic disorders.

Due to the marked increase in NHE in essential hypertension, the compounds of formula I are suitable for the prevention and treatment of hypertension and cardiovascular disorders.

Here, they can be used alone or together with suitable combination and formulation ingredient auxiliaries for the treatment of hypertension and cardiovascular disorders. Thus, for example, one or more of the following components may be combined with a compound of formula I: diuretics having a thiazine-like action, loop diuretics, aldosterone and aldosterone mimetic antagonists, such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerone. In addition, the NHE inhibitor of the present invention may be used in combination with a calcium antagonist such as verapamil, diltiazem, amlodipine or nifedipine, and may also be used in combination with an ACE inhibitor such as ramipril, enalapril, lisinopril, fosinopril or captopril. Other advantageous combination partners include beta-blockers such as metoprolol, salbutamol and the like, angiotensin receptors and their receptor subtype antagonists such as losartan, irbesartan, valsartan, omapatrilat (omapatrilat), gemopatrilat, endothelin antagonists, renin inhibitors, adenosine receptor agonists, inhibitors and activators of calcium channels such as glibenclamide, glimepiride, diazoxide, cloacarin, minoxidil and derivatives thereof, activators of mitochondrial ATP-sensitive potassium channels (mitok (ATP) channels); other potassium channel inhibitors such as inhibitors of Kv1.5 and the like.

Due to their anti-inflammatory effects, NHE inhibitors may be useful as anti-inflammatory agents. Of mechanistic interest is the inhibition of the release of inflammatory mediators. Thus, the compounds of the present invention may be used alone or in combination with anti-inflammatory agents to prevent or treat chronic and acute inflammation. The combination partners employed are advantageously steroidal and non-steroidal anti-inflammatory agents.

Furthermore, it has been found that the compounds of formula I exert a beneficial effect on serum lipoproteins. Thus, they can be used to prevent and resolve atherosclerotic changes by eliminating incidental risk factors. This includes not only primary hyperlipidemia, but also certain secondary hyperlipidemia, as encountered, for example, in diabetes. In addition, the compounds of formula I greatly reduce infarctions induced by metabolic abnormalities and, in particular, result in a significant reduction in the size and severity of the induced infarctions.

Therefore, the compounds are advantageously used for the preparation of medicaments for the treatment of hypercholesterolemia, for the preparation of medicaments for the prevention of atherogenesis, for the preparation of medicaments for the prevention and treatment of atherosclerosis, for the preparation of medicaments for the prevention and treatment of illnesses induced by an elevated cholesterol level, for the preparation of medicaments for the prevention and treatment of illnesses induced by endothelial dysfunction, for the preparation of medicaments for the prevention and treatment of hypertension induced by atherosclerosis, for the preparation of medicaments for the prevention and treatment of thrombosis induced by atherosclerosis, for the preparation of medicaments for the prevention and treatment of ischemic injury and post-ischemic reperfusion injury induced by hypercholesterolemia and endothelial dysfunction, for the preparation of medicaments for the prevention and treatment of cardiac hypertrophy and cardiomyopathy and Congestive Heart Failure (CHF), for the preparation of medicaments for the prevention and treatment of coronary vasospasm and myocardial infarction induced by hypercholesterolemia and endothelial dysfunction, For the preparation of a medicament for use in combination with a hypotensive substance, preferably with an Angiotensin Converting Enzyme (ACE) inhibitor and an angiotensin receptor antagonist, for the treatment of said disorders. The combination of an NHE inhibitor of formula I with an active compound lowering the lipid concentration in the blood, preferably an HMG-CoA reductase inhibitor (e.g. lovastatin or pravastatin), the latter of which has a hypolipidemic effect, thereby enhancing the hypolipidemic properties of the NHE inhibitor of formula I, has been found to be an advantageous combination of increased action and reduced use of the active compound.

Therefore, the compound of the formula I brings effective protection effect to endothelial injury from various sources. Due to the vasoprotective effect on endothelial dysfunction syndrome, the compounds of formula I are useful medicaments for the prevention and treatment of coronary vasospasm, peripheral vascular diseases, especially intermittent claudication, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and thrombotic disorders.

Furthermore, NHE inhibitors of formula I are suitable for the treatment of non-insulin dependent diabetes mellitus (NIDDM) in which e.g. insulin resistance is inhibited. Here, in order to enhance the antidiabetic efficacy and the quality of action of the compounds of the invention, these compounds can advantageously be combined with biguanides, for example metformin, with antidiabetic sulfonylureas, for example glibenclamide, glimepiride, tolbutamide and the like, glucosidase inhibitors, PPAR agonists, for example rosiglitazone, pioglitazone and the like, with insulin products in different administration forms, with DB4 inhibitors, with insulin sensitizers or with metritinib.

In addition to the acute anti-diabetic effect, the compounds of formula I are active against the development of anti-diabetic late complications and therefore they are useful as medicaments for the prevention and treatment of diabetic late damage such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and other conditions resulting from diabetes. In this connection, they can advantageously be combined with antidiabetic drugs as described above for the treatment of NIDDM. The combination with an advantageous administration form of insulin may be of particular importance.

In addition to a protective effect against acute ischemic events and also against subsequent acute reperfusion events, the NHE inhibitors of formula I of the invention have a direct therapeutically useful effect on the conditions and injuries of the whole mammalian organism which are associated with the manifestation of a long-standing aging process, but not with an acute state of hypoperfusion, which also occurs in general non-ischemic conditions. These age-related pathological manifestations, such as diseases, illnesses and deaths, which are induced by prolonged aging, can now be treated with NHE inhibitors, which are conditions and disorders that are caused to a significant extent by age-related changes in the key organs and their functions that are of increasing importance in aging organisms.

Organ wasting disorders associated with age-related dysfunction and age-related symptoms are for example inadequate responsiveness and responsiveness of blood vessels to systolic and diastolic responses. This reduced responsiveness of blood vessels to systolic and diastolic stimuli, which are critical processes of the cardiovascular system and thus life and health, can be significantly attenuated or eliminated by NHE inhibitors. An important function and measure of maintaining vascular responsiveness is to block or slow down the age-related progression of endothelial dysfunction, which can be highly significantly abrogated by NHE inhibitors. The compounds of formula I are therefore very suitable for the treatment and prevention of age-related progression of endothelial dysfunction, in particular intermittent claudication. Furthermore, the compounds of the formula I are therefore very suitable for the treatment and prophylaxis of cardiac insufficiency, Congestive Heart Failure (CHF), and for the treatment and in particular prophylaxis of various age-related types of cancer.

Likewise, hypotensive agents such as ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca are contemplated²⁺Antagonists and the like or in combination with metabolism-normalizing drugs such as cholesterol lowering agents. The compounds of formula I are therefore suitable for preventing age-related tissue changes and prolonging life, while maintaining a high quality of life.

The compounds of the invention are potent inhibitors of the cellular sodium/proton antiporter (Na/H exchanger) which is also elevated in cells which are readily assayed, such as in erythrocytes, platelets or leukocytes, in a number of conditions (essential hypertension, atherosclerosis, diabetes, etc.). The compounds used according to the invention are therefore suitable as excellent and simple scientific tools, for example as diagnostic aids for determining and distinguishing specific types of hypertension as well as atherosclerosis, diabetes, late complications of diabetes and proliferative disorders, etc.

NHE3 inhibitors are furthermore suitable for the treatment of (human and veterinary) disorders caused by bacteria and protozoa. For the disorders caused by protozoa, mention may be made in particular of malaria in humans and coccidiosis in poultry.

Furthermore, the compounds according to the invention are suitable as active agents for controlling hematophagous parasites in human and veterinary medicine and in crop protection. Here, preference is given to use as active agents against hematophagous parasites in human and veterinary medicine.

In addition to their value as potent NHE inhibitors, their pharmacological profile and absence of undesirable biological effects, the compounds of formula I are characterized by advantageous pharmacokinetic properties which make them appear particularly advantageous for use as medicaments.

The invention therefore also relates to a medicament for human, veterinary or plant protection comprising an effective amount of a compound of formula I and/or a pharmaceutically acceptable salt thereof, alone or in combination with other pharmacologically active compounds or medicaments.

Medicaments comprising compound I can be administered, for example, orally, parenterally, intramuscularly, intravenously, rectally, nasally, by inhalation, subcutaneously or by suitable transdermal administration forms, wherein the preferred mode of administration depends on the specific manifestation of the disorder. Here, compound I can be used alone or together with pharmaceutically acceptable excipients in veterinary, human medicine and crop protection.

Excipients suitable for the desired pharmaceutical preparation are familiar to the skilled worker on the basis of their expert knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active ingredient carriers, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, masking flavors, preservatives, solubilizers or colorants.

For oral use, the active compound is mixed with additives suitable for the purpose, such as carriers, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms, such as tablets, coated tablets, two-piece capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In addition, it can be prepared in dry granules and wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or cod liver oil.

For subcutaneous, transdermal or intravenous administration, the active compounds used are converted, if desired, into solutions, suspensions or emulsions with the substances customary for this purpose, such as solubilizers, emulsifiers or other excipients. Examples of suitable solvents are water, physiological saline or alcohols, for example ethanol, propanol, glycerol, and also sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Pharmaceutical preparations which are suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of the formula I in pharmaceutically acceptable solvents, such as, in particular, ethanol or water, or mixtures of these solvents.

If desired, the formulation may also contain other pharmaceutically acceptable excipients such as surfactants, emulsifiers and stabilizers, and a gas propellant. Such formulations typically contain the active compound in a concentration of about 0.1 to 10%, especially about 0.3 to 3%, by weight.

The dosage and frequency of administration of the active compounds of the formula I depend on the potency and duration of action of the compounds used and also on the nature and severity of the disease to be treated and on the sex, age, weight and individual response of the mammal to be treated.

On average, for a patient weighing about 75kg, the daily dosage of a compound of formula I is at least 0.001mg/kg, preferably 0.1mg/kg, and up to a dosage of not more than 30mg/kg, preferably 1mg/kg body weight. In acute situations, e.g. immediately after a high altitude respiratory disorder, even higher doses may be required. Especially for intravenous use, e.g. for infarcted patients in a critical care unit, the dose may have to be as high as 200mg/kg per day. The daily dose may be divided into single doses one or more times, e.g. up to 4 times.

Description of the experiments and examples:

if the compound is enantiomerically pure, an optically active conformation and/or label is given. Without these data, the compound is racemic or non-optically active.

The residence times (Rt) given below refer to LCMS measurements with the following parameters:

A

stationary phase: merek Purospher 3 mu 2X 55mm

95％H₂O (0.1% HCOOH) → 95% acetonitrile (0.1% HCOOH); 5

Mobile phase: min → 95% acetonitrile (0.1% HCOOH); 2min → 95% H₂O(0.1％HCOOH)；1min；0.45ml/min。

B

Stationary phase: YMC J' sphere H80-4 mu 2.1 x 33mm 95% H₂O (0.1% HCOOH) → 95% acetonitrile (0.08% HCOOH); 2.5min

Mobile phase: → 95% acetonitrile (0.08% HCOOH); 0.5min → 95% H₂O(0.1％HCOOH)；0.5min；1.3ml/min。

C

Stationary phase: YMC J' sphere H80, 4. mu.2.1X 20mm

Mobile phase: 90% H₂O (0.05% TFA) → 95% acetonitrile; 1.9 min; → 95% acetonitrile 0.5 min; 1 ml/min.

D

Stationary phase: merck Purospher 3. mu.2X 55mm 95% H₂O (0.1% HCOOH) → 95% acetonitrile (0.1% HCOOH); 3.4min

Mobile phase: → 95% acetonitrile (0.1% HCOOH); 1min → 95% H₂O(0.1％HCOOH)；0.2min；0.75ml/min。

E

Stationary phase: merck Purospher 3. mu.2X 55mm

Mobile phase: 95% H₂O(0.05％CF₃COOH) → 95% acetonitrile (0.05% CF₃COOH); 3.4min → 95% acetonitrile (0.05% CF)₃COOH)；1min；0.75ml/min。

F

Stationary phase: YMC J' sphere H80, 4. mu.2.1X 20mm

Mobile phase: 96% H₂O(0.05％CF₃COOH) → 95% acetonitrile; 2 min; → 95% acetonitrile 0.4 min; 1 ml/min.

Preparative HPLC was carried out under the following conditions:

stationary phase: merck Purospher RP18 (10. mu.M) 250X 25mm

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

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

a) Isothiocyanates 4-methyl-3-thienyl

The title compound was obtained by reacting equimolar amounts of 3-amino-4-methylthiothiophene and N, N' -thiocarbonyldiimidazole in anhydrous Tetrahydrofuran (THF) by stirring the reaction mixture at room temperature for 5 hours and then allowing the mixture to stand at room temperature overnight. 4-methyl-3-thienyl isothiocyanate was isolated by evaporating the solvent under reduced pressure using a rotary evaporator, dissolving the residue in ethyl acetate and repeatedly washing the organic phase with water. The organic phase was dried over sodium sulfate, and then the organic solvent was distilled off under reduced pressure using a rotary evaporator to give 4-methyl-3-thienyl isothiocyanate as a brown oily residue. 4-methyl-3-thienyl isothiocyanate may be used without further purification.

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

0.02mol of 4-fluoro-1, 2-diaminobenzene was added to a solution of 0.02mol of 4-methyl-3-thienyl isothiocyanate in 60mL of anhydrous THF. The reaction mixture was stirred at room temperature for 2 hours and then left overnight, then the solvent was distilled off under reduced pressure using a rotary evaporator and the oily residue was purified on a silica gel column using a mixture of toluene and ethyl acetate in equal proportions.

A brown crystalline solid. Melting point: 180 ℃ is carried out.

c)3N- (5-fluoro-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride

A molar excess (about 1.5-4mol) of methyl iodide was added to 1.5g (0.0053mol) of N- (2-amino-5-fluorophenyl) -N' - (4-methyl-3-thienyl) thiourea in 50mL of absolute ethanol, and the mixture was boiled under reflux for 5 hours. The mixture was allowed to stand at room temperature overnight, then ethanol was evaporated off under reduced pressure using a rotary evaporator, water was added to the residue and the pH was adjusted to 8-9 using saturated aqueous sodium bicarbonate solution. The mixture was repeatedly extracted with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure using a rotary evaporator, and the residue was purified by silica gel column chromatography using a solvent mixture of ethyl acetate and toluene in equal proportions (hereinafter referred to as "mixture 2") as a mobile phase. The oily product obtained after removal of the organic solution by distillation was dissolved in ethyl acetate, rendered highly acidic with a saturated solution of hydrogen chloride in anhydrous diethyl ether, and the precipitate which crystallized out was filtered off after standing for a longer time. Crystalline solid, melting point: 192+/-2 deg.C.

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

A solution of 0.24g (0.0018mol) of N-chlorosuccinimide in 15mL of glacial acetic acid was added dropwise to a solution of 0.5g (0.0018mol) of 3N- (5-fluoro-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride in 25mL of glacial acetic acid. The reaction mixture was stirred at room temperature for about 2 to 3 hours, and the solvent was distilled off under reduced pressure using a rotary evaporator. Water was added to the residue, the mixture was then made alkaline with 2N NaOH and extracted with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure using a rotary evaporator. An oily residue obtained by medium-pressure column chromatography using a solvent mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid (hereinafter referred to as "mixture 17") as a mobile phase separation and treated with a solution of hydrogen chloride gas was obtained: 2-chloro-3N- (5-fluoro-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride from fractions 1 and 2: colorless to pale yellow crystalline product, melting point: 200-202 ℃ of the temperature of the reaction kettle,

2, 5-dichloro-3N- (5-fluoro-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride from fraction 3: colorless to pale yellow crystalline product, melting point: 286 ℃ and 288 ℃.

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

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and 4, 5-dichloro-1, 2-diaminobenzene. Crystalline solid, melting point: 310 ℃ and 320 ℃.

b)3N- (5, 6-dichloro-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) from N- (2-amino-4, 5-dichlorophenyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide. Crystalline solid, melting point: 290 ℃ and 294 ℃.

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

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

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and 1, 2-diaminobenzene. The first melting point of the crystallized solid is 177-182 ℃ and then the crystallized solid is recrystallized, and the second melting point is 285-290 ℃.

b)3N- (2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) from N- (2-aminophenyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide. Recrystallization from ethyl acetate/ethanol gave a crystalline solid with melting point: 194 ℃ to 200 ℃.

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

a) 3-fluoro-1, 2-diaminobenzene

The title compound was obtained as an oily amorphous product by hydrogenation of 3-fluoro-2-nitrophenylhydrazine (prepared by reacting 2, 6-difluoronitrobenzene with hydrazine hydrate) in methanol at room temperature and atmospheric pressure using hydrogen and 10% palladium on carbon catalyst.

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

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and 3-fluoro-1, 2-diaminobenzene. Crystalline solid, decomposition temperature > 240 ℃.

c)3N- (4-fluoro-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) from N- (2-amino-3-fluorophenyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide. An amorphous precipitate is obtained, which is crystallized in acetone. Crystalline solid, melting point: 220 ℃ and 230 ℃.

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

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

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and 3, 5-difluoro-1, 2-diaminobenzene. First melting point of crystalline solid: 178 ℃ and 182 ℃. Second melting point of recrystallization: 299 and 301 ℃.

b)3N- (4, 6-difluoro-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) from N- (2-amino-3, 5-difluorophenyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide. An amorphous precipitate was obtained which was crystallized from ethyl acetate. Crystalline solid, melting point: 232 ℃ and 234 ℃.

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

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thiophenylisothiocyanate and 3, 4, 5, 6-tetrafluoro-1, 2-diaminobenzene. Crystalline solid, melting point: 286 ℃ and 290 ℃.

b)3N- (4, 5, 6, 7-tetrafluoro-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) from N- (2-amino-3, 4, 5, 6-tetrafluorophenyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide. An amorphous precipitate was obtained which was crystallized from ethyl acetate. Crystalline solid, melting point: 225 ℃ and 228 ℃.

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

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

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and 3-methyl-1, 2-diaminobenzene. Crystalline solid, melting point: 184-186 ℃.

b)3N- (4-methyl-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) from N- (2-amino-3-methylphenyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide. An amorphous precipitate is obtained, which is crystallized in acetone. Crystalline solid, decomposition temperature: at 320 ℃.

Example 9: trans-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride (racemate)

a) trans-N- (2-aminocyclohexyl) -N' - (4-methyl-3-thienyl) thiourea (racemate)

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and racemic trans-1, 2-diaminocyclohexane. Crystalline solid, melting point: 205 ℃ and 210 ℃.

b) trans-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride (racemate)

0.6g of racemic trans-N- (2-aminocyclohexyl) -N' - (4-methyl-3-thienyl) thiourea was suspended in 60mL of toluene and dissolved by heating at 90 ℃. The mixture was allowed to cool to 70 ℃, a solution of 0.376g dicyclohexylcarbodiimide in 5mL anhydrous toluene was added dropwise, the mixture was stirred at 70 ℃ for a total of 10 hours and at room temperature for 2-3 days. The crystalline solid was filtered off, the solvent was removed under reduced pressure using a rotary evaporator and the resulting oily residue was dissolved in a small amount of ethyl acetate. After addition of an anhydrous solution of hydrogen chloride in diethyl ether, a viscous precipitate formed which crystallized after addition of a small amount of ethanol. Crystalline solid, melting point: 261 ℃ and 264 ℃.

Example 10: trans-R, R-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

a) trans-R, R-N- (2-aminocyclohexyl) -N' - (4-methyl-3-thienyl) thiourea

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and trans-R, R-1, 2-diaminocyclohexane by silica gel column chromatography eluting with a solvent mixture consisting of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part of 26% strength aqueous ammonia (hereinafter referred to as "mixture 4") as an amorphous oily product, in addition to a crystalline product with a higher molecular weight having a melting point of 94-100 ℃. The amorphous product was worked up without further purification.

b) trans-R, R-N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) by reacting R, R-N- (2-aminocyclohexyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide in anhydrous ethanol as solvent and reaction medium. An amorphous precipitate is obtained which is chromatographed on silica gel using mixture 4 as mobile phase and crystallized in acetone. Crystalline solid, melting point: 235 ℃ and 238 ℃.

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

a) trans-S, S-3N- (2-aminocyclohexyl) -N' - (4-methyl-3-thienyl) thiourea

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and trans-S, S-1, 2-diaminocyclohexane by silica gel column chromatography using mixture 4 as mobile phase separation as amorphous oily product, in addition to the product with higher molecular weight having a melting point of 94-102 ℃.

The amorphous product was further processed without further purification.

b) trans-S, S-N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) by reacting S, S-N- (2-aminocyclohexyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide in anhydrous ethanol as solvent and reaction medium. An amorphous precipitate is obtained which is chromatographed on silica gel using mixture 4 as mobile phase and crystallized in acetone. Crystalline solid, melting point: 225 ℃ and 230 ℃.

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

The title compound was obtained in analogy to the procedure described in example 2 from 3N- (2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid. 2-chloro-3N- (2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride (colorless crystalline compound, melting point: 257-259 ℃ C.) and 2, 5-dichloro-3N- (2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride (colorless crystalline compound, melting point: 291 ℃ C.) were separated by column chromatography on silica gel using mixture 17 as a mobile phase.

Example 13: 2-chloro-3N- (4-methyl-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described 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 using mixture 17 as mobile phase, 2-chloro-3N- (4-methyl-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride was obtained as colorless to pale yellow crystalline product. Melting point: 255 ℃ and 259 ℃.

Example 14: 2-chloro-3N- (4, 5, 6, 7-tetrafluoro-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 2 from 3N- (4, 5, 6, 7-tetrafluoro-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid. Crystalline product, melting point: 233-.

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

The title compound was obtained in analogy to the procedure described in example 2 from 3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride (racemate) and N-chlorosuccinimide in glacial acetic acid. Crystalline product, melting point: 258 ℃ and 260 ℃.

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

The title compound was obtained in analogy to the procedure described in example 2 from trans-R, R-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid and was chromatographed in the following order to isolate two crystalline products:

a) trans-R, R-2, 5-dichloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride, which initiates decomposition of the vesicles at 80 ℃.

b) trans-R, R-2-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride, crystalline product. Melting point: 260 ℃ and 262 ℃.

Example 17: trans-S, S-2-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 2 from the reaction of trans-S, S-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid followed by chromatography. Colorless crystalline product, melting point: 258 ℃ and 260 ℃.

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

The title compound was obtained in analogy to the procedure described in example 2 from 3N- (2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride and N-bromosuccinimide (instead of N-chlorosuccinimide) in glacial acetic acid. After column chromatography on silica gel using a mixture of 5 parts of methylene chloride, 3 parts of N-heptane, 1 part of glacial acetic acid and 1 part of ethanol (hereinafter referred to as "mixture 1") as a mobile phase and treatment with a solution of hydrogen chloride gas in diethyl ether, 2-bromo-3N- (2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride, i.e., a crystalline product having a melting point of 228-.

Example 19: trans-R, R-2-bromo-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride and trans-R, R-2, 5-dibromo-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 18 from trans-R, R-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride and N-bromosuccinimide in glacial acetic acid. After column chromatography on silica gel using mixture 1 as mobile phase and treatment with a solution of hydrogen chloride in diethyl ether, obtaining trans-R, R-2-bromo-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride through fractional crystallization in ethyl acetate, namely, the crystalline product having a melting point of 215-218 ℃ and trans-R, R-2, 5-dibromo-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride, namely, the crystalline product having a melting point of 218-220 ℃.

Example 20: 3N- (4-chloro-2-benzimidazolylamino) -4-methylthiophene hydrochloride

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

The title compound was obtained in analogy to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and 3-chloro-1, 2-diaminobenzene (prepared by catalytic hydrogenation of 3-chloro-2-nitroaniline at atmospheric pressure and room temperature using Pt on activated carbon). Crystalline solid, melting point: 298-305 ℃.

b)3N- (4-chloro-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The title compound was obtained in analogy to the procedure described in example 1c) from N- (2-amino-3-chlorophenyl) -N' - (4-methyl-3-thienyl) thiourea and methyl iodide. An amorphous precipitate was obtained which was crystallized from ethyl acetate. Crystalline solid, decomposition temperature 240-245 ℃.

Example 21: 2-chloro-3N- (4-chloro-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The title compound was obtained in analogy to the procedure described in example 2 from 3N- (4-chloro-2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride and N-chlorosuccinimide in glacial acetic acid. After separation by column chromatography on silica gel using a mixture of 10 parts of dichloromethane and 1 part of methanol as mobile phase and crystallization in ethyl acetate, 2-chloro-3N- (4-chloro-2-benzimidazolylamino) -4-methylthiophene hydrochloride is obtained as a colorless to pale yellow solid. Melting point: 270 ℃ and 272 ℃.

Example 22: 2-bromo-3N- (4-chloro-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The title compound was obtained in analogy to the procedure described in example 2 from 3N- (4-chloro-2-benzimidazolylamino) -4-methylthiophene hydrochloride and N-bromosuccinimide (instead of N-chlorosuccinimide) in glacial acetic acid. After separation by silica gel column chromatography using a mixture of 20 parts of ethyl acetate, 10 parts of N-heptane and 3 parts of glacial acetic acid as mobile phase and treatment with a solution of hydrogen chloride gas in diethyl ether, 2-bromo-3N- (4-chloro-2-benzimidazolylamino) -4-methylthiophene hydrochloride is obtained by fractional crystallization in the presence of hydrogen chloride-saturated diethyl ether. Crystalline product, melting point: 278 ℃ and 280 ℃.

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

(5-fluoro-1H-benzimidazol-2-yl) - (4-methylthiophen-3-yl) amine (300mg) (example 1) was dissolved in glacial acetic acid (50 mL). N-bromosuccinimide (207mg) dissolved in glacial acetic acid (10mL) was slowly added dropwise at room temperature with vigorous stirring. After the addition was complete, stirring was continued for a further 10 minutes, and then glacial acetic acid was distilled off under reduced pressure, the residue being dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography, the fractions containing the product were combined, acetonitrile was removed, rendered basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. After removing the solvent under reduced pressure, water and 2N hydrochloric acid were added to the residue, and the mixture was lyophilized. 245mg of the desired product are obtained.

LCMS-Rt (B): 0.95 minutes.

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

A solution of 0.161g N-bromosuccinimide in 6mL of glacial acetic acid was added to a solution of 0.214g of 3N- (4-fluoro-2-benzimidazolylamino) -4-methylthiophene hydrochloride in 6mL of glacial acetic acid, and the mixture was stirred at room temperature for 30 minutes. After removal of the solvent by distillation, water was added to the residue, the mixture was made alkaline with 2N NaOH and extracted with ethyl acetate. The organic phase is dried, the solvent is distilled off and the residue is isolated by column chromatography on silica gel using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The hydrochloride salts of the two compounds were obtained by distilling the fractionated solution, dissolving the residue in ethyl acetate and precipitating the product by adding hydrogen chloride saturated diethyl ether. Crystallization was promoted by mild warming.

Example 24 a: 2-bromo-3N- (4-fluoro-2-benzimidazolylamino) -4-methylthiophene hydrochloride: colorless crystals; melting point; 212 deg.C (decomposition).

Example 24 b: 2, 5-dibromo-3N- (4-fluoro-2-benzimidazolylamino) -4-methylthiophene hydrochloride: colorless crystals: melting point; 242 ℃ and 244 ℃ (decomposition).

Example 25: 3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene

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

A mixture of 5.89g of 4-methylthiophene-3-isothiocyanate and 5g of 4-methoxy-1, 2-diaminobenzene in 60mL of anhydrous THF was stirred at room temperature for 2 hours, and the solvent was distilled off. Water was added to the residue, the mixture was extracted with ethyl acetate, the dark solution was treated with activated carbon and the organic solvent was evaporated again. The residue was treated repeatedly with diisopropyl ether with gentle warming and the solid was filtered off. Brown crystalline solid, melting point: 143 ℃ and 146 ℃.

b) A mixture of 2.83g N- (2-amino-4-methoxyphenyl) -N' - (4-methyl-3-thienyl) thiourea, 8.5g methyl iodide and 100mL anhydrous ethanol was boiled under reflux for 5 hours, then the solvent was distilled off, and water was added to the residue. The mixture was made basic using 2N aqueous sodium hydroxide solution and then extracted with ethyl acetate, the organic phase was treated with water and then activated carbon, and the product was purified by silica gel column chromatography using a mixture of 20 parts of ethyl acetate, 10 parts of N-heptane and 3 parts of glacial acetic acid as the mobile phase. 3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene is obtained as amorphous product.

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

The title compound was obtained by precipitation of a solution of 0.2g of 3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene (example 25) in 10mL of ethyl acetate using a saturated solution of hydrogen chloride gas and diethyl ether, giving a crystalline precipitate. Melting point: 222 ℃ and 225 ℃.

Example 27: 2-chloro-3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride

A mixture of 0.519g of 3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride, 0.046g N-chlorosuccinimide and 10-15mL of glacial acetic acid was heated at 45 ℃ for about 2-2.5 hours. The glacial acetic acid is then distilled off, water is added to the residue and the mixture is adjusted to pH 9-10 using 2N NaOH. The mixture is extracted with ethyl acetate, the solvent is evaporated and the residue is chromatographed on a silica gel medium-pressure column using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The base obtained after removal of the solvent by distillation was converted into the hydrochloride in ethyl acetate using saturated ethereal hydrogen chloride and the product was crystallized in ethyl acetate. Crystalline solid, melting point: 182 ℃ and 186 ℃.

Example 28: 2, 5-dichloro-3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The reaction mixture of 3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride, N-chlorosuccinimide and glacial acetic acid was similarly worked up at 55 ℃ for about 2-2.5 hours to give 2, 5-dichloro-3N- (5-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride. Crystalline solid, melting point: 278 ℃ and 282 ℃.

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

a) 3-methoxy-1, 2-diaminobenzene

The title compound is obtained by hydrogenation of 2-methoxy-6-nitroaniline at room temperature and 3 bar pressure using hydrogen and Raney nickel as catalyst. The product was converted to thiourea without further purification.

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

The title compound is obtained in analogy to the procedure described in example 25a) from 3-methoxy-1, 2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF followed by medium pressure chromatography on silica gel using a mixture of 1 part toluene and 1 part ethyl acetate. Crystalline solid, melting point: 148 ℃ and 153 ℃. The melt solidifies, the next melting point: at 260 ℃.

c)3N- (4-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The title compound was obtained in analogy to the procedures described in examples 25 and 26 from N- (2-amino-3-methoxyphenyl) -N' - (4-methyl-3-thienyl) thiourea by heating with methyl iodide in THF, analogous work-up and treatment of the benzimidazole with HCL/diethyl ether. Crystalline solid, melting point: 230 ℃ and 235 ℃.

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

A mixture of 0.1g of 3N- (4-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride, 0.046g of N-chlorosuccinimide and 10-15mL of glacial acetic acid is heated at 40 ℃ for about 2-2.5 hours. The glacial acetic acid was then distilled off, water was added to the residue and the pH was adjusted to 9-10 using 2N NaOH. The mixture is extracted with ethyl acetate, the solvent is evaporated and the residue is chromatographed on a silica gel medium-pressure column using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The resulting base was converted to the hydrochloride salt in ethyl acetate using saturated ethereal hydrogen chloride. Colorless to pale yellow crystalline solid, melting point: 248-250 ℃.

Example 31: 3N- (4-chloro-6-trifluoromethyl-2-benzimidazolylamino) -4-methylthiophene hydrochloride

a) N- (2-amino-3-chloro-5-trifluoromethylphenyl) -N' - (4-methyl-3-thienyl) thiourea

The title compound was obtained in analogy to the procedure described in example 25a) by reacting 3-chloro-5-trifluoromethyl-1, 2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF at room temperature for 3 days. The solvent was distilled off, water was added to the residue, the mixture was extracted with ethyl acetate, the solvent was distilled off again and the amorphous residue was crystallized from diisopropyl ether. Melting point: is > 310 ℃.

b)3N- (4-chloro-6-trifluoromethyl-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The title compound was obtained in analogy to the procedures described in examples 25 and 26 from N- (2-amino-3-chloro-5-trifluoromethylphenyl) -N' - (4-methyl-3-thienyl) thiourea by boiling with methyl iodide in THF under reflux conditions for 5 hours, analogous work-up and purification by medium-pressure silica gel column chromatography using a mixture of equal parts by volume of ethyl acetate and toluene. The solvent was evaporated and the residue was dissolved in ethyl acetate and 3N- (4-chloro-6-trifluoromethyl-2-benzimidazolylamino) -4-methylthiophene hydrochloride was obtained as a crystalline precipitate by addition of saturated ethereal hydrogen chloride. Solid, melting point: 210 ℃ and 213 ℃.

Example 32: 2-chloro-3N- (4-chloro-6-trifluoromethyl-2-benzimidazolylamino) -4-methylthiophene hydrochloride

A mixture of 0.34g of 3N- (4-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride, 0.151g of N-chlorosuccinimide and 20mL of glacial acetic acid was stirred at room temperature for 0.5 h and heated at 60 ℃ for 1 h. The glacial acetic acid was then distilled off, water was added to the residue and the pH was adjusted to 9-10 using 2N NaOH. The mixture is extracted with ethyl acetate, the solvent is evaporated and the residue is chromatographed on a silica gel medium-pressure column using an equal part of a mixture of toluene and ethyl acetate. The solvent was distilled off, and the resulting base was converted into the hydrochloride salt in ethyl acetate using saturated hydrogen chloride in ether. Colorless to pale yellow crystalline solid. Melting point: 247 ℃ and 250 ℃.

Example 33: 3N- (4-carboxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride

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

The title compound is obtained in analogy to the procedure described in example 25a) from 3-carboxy-1, 2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF and then by medium pressure chromatography on silica gel using a mixture of 12 parts dichloromethane and 1 part methanol. An amorphous product.

b)3N- (4-carboxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The title compound was obtained by boiling a solution of 1.12g N- (2-amino-3-carboxyphenyl) -N' - (4-methyl-3-thienyl) thiourea and 3.1g methyl iodide in 60mL ethanol under reflux. The solvent was evaporated, water was added to the residue, the pH was adjusted to 5 using 2N aqueous HCl, and the precipitate was filtered off. Crystalline solid, decomposition temperature: 265 ℃ and 285 ℃.

Example 34: 2-chloro-3N- (4-carboxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride

The title compound is obtained in analogy to the procedure described in example 32 from 0.2g of 3N- (4-carboxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride and 0.103g N-chlorosuccinimide in 20 to 25mL of glacial acetic acid, precipitation of the corresponding hydrochloride in ethyl acetate using HCl-saturated diethyl ether and subsequent crystallization in diisopropyl ether and ethyl acetate. The decomposition temperature is 170 ℃.

Example 35: 3N- [4- (1-piperidinocarbonyl) -2-benzimidazolylamino ] -4-methylthiophene hydrochloride

0.215g N, N' -carbonyldiimidazole was added to a mixture of 0.330g of 3N- (4-carboxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride, 30mL of anhydrous THF and 5mL of anhydrous dimethylacetamide. The mixture is stirred at room temperature for about 4 hours, at which point the evolution of carbon dioxide ceases, and 0.411g of piperidine is added. The solution was stirred at room temperature for 2 hours, and after standing overnight the solvent was distilled off under reduced pressure. The residue was triturated with water, the solid was filtered off and dissolved in ethyl acetate, the insoluble fraction was removed by filtration and the solvent was distilled off under reduced pressure. A foamy amorphous product is obtained.

Example 36: 2-chloro-4-methyl-3N- [4- (1-piperidinocarbonyl) -2-benzimidazolylamino ] -thiophene hydrochloride

A mixture of 0.2g of 3N- [4- (1-piperidinocarbonyl) -2-benzimidazolylamino ] -4-methylthiophene hydrochloride and 0.086g N-chlorosuccinimide in about 20mL of glacial acetic acid was stirred at room temperature for 1.5 hours and at 35 ℃ for about 30 minutes, the solvent was distilled off, and the residue was made basic using 2N NaOH after the addition of water. After extraction with ethyl acetate, the solvent was evaporated and the residue was purified by medium pressure silica gel column chromatography using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The solvent was distilled off, the residue was dissolved in ethyl acetate and the mixture was acidified using a hydrogen chloride-saturated ether solution. The amorphous residue was crystallized from a mixture of ethyl acetate and small amounts of acetone and ethanol. Amorphous solid, decomposition temperature: at 100 ℃.

Example 37: 2-chloro-3N- (4-fluoro-2-benzimidazolylamino) -4-methylthiophene hydrochloride

0.132g N-chlorosuccinimide was added to 0.234g of 3N- (4-fluoro-2-benzimidazolylamino) -4-methylthiophene hydrochloride in about 20mL of glacial acetic acid, and the mixture was stirred at room temperature for 30 minutes and at 50-60 ℃ for another 1.5 hours. Acetic acid was distilled off under reduced pressure, then water was added to the residue, the pH was adjusted to about 10-11 using 2N NaOH, and the mixture was extracted with ethyl acetate, and then ethyl acetate was distilled off. The residue is chromatographed on a silica gel column at medium pressure using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. After concentration, the residue was dissolved in a small amount of ethyl acetate and the hydrochloride salt was precipitated by adding hydrogen chloride saturated diethyl ether. Colorless to pale yellow crystalline solid. Melting point: 268 ℃ and 270 ℃.

Example 38: 2-chloro-3N- (4-hydroxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride

A suspension of 0.13g of 2-chloro-3N- (4-methoxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride in about 20mL of anhydrous dichloromethane was added to a suspension of 0.29g of activated anhydrous aluminum chloride in 10mL of anhydrous dichloromethane, and the reaction mixture was stirred at 55 ℃ for 2 hours. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was distilled off. The residue is chromatographed on a silica gel column at medium pressure using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The eluate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the hydrochloride salt was precipitated by addition of hydrogen chloride saturated diethyl ether. Crystalline solid, melting point: 246-248 ℃.

Example 39: 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene

The title compound was obtained by adding 2N NaOH to a solution of 3g 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene hydrochloride in 200mL water until the pH was set to 10. The crystals are filtered off and washed repeatedly with water. Yield: 2.52g, colorless crystalline powder. Melting point: 182 ℃ and 185 ℃.

Example 40: 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene hydrobromide

0.25g of 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene is dissolved in 10mL of ethanol, then 0.1mL of 48% strength HBr are added and the mixture is stirred at room temperature for a while. The solvent was distilled off and the residue was crystallized from ethyl acetate. Yield: 0.29 g. Colorless crystals, decomposition temperature: 252 ℃ and 254 ℃.

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

The title compound was obtained in analogy to the procedure described in example 40 from 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene using one equivalent of adipic acid. Colorless crystals. Melting point: 155 ℃ and 157 ℃.

Example 42: 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene oxalate

The title compound was obtained in analogy to the procedure described in example 40 by reacting 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene with one equivalent of oxalic acid in ethyl acetate. Colorless crystals. Melting point: 220 ℃ and 222 ℃.

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

The title compound was obtained in analogy to the procedure described in example 40 from 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene using one equivalent of phosphoric acid. Colorless crystals. Decomposition range: 113 ℃ and 175 ℃.

Example 44: (1H-benzimidazol-2-yl) - (2-chloro-4-methylthiophen-3-yl) methylamine

Finely powdered dry potassium carbonate (66mg) was added to a solution of 2-chloro-3N- (2-benzimidazolyl) -4-methyl-3-thiophenylamine (125mg, from example 39) and dry methanol (20 mL). Then, methyl iodide (74mg) was added dropwise under dehumidification and vigorous stirring, and the mixture was kept under reflux for 3 days. The solvent was removed under reduced pressure, the residue was then partitioned between ethyl acetate and water, the ethyl acetate phase was dried over magnesium sulfate, the magnesium sulfate was filtered off and the filtrate was evaporated to dryness. The product was then purified by preparative HPLC. The product-containing fractions were combined and lyophilized after removal of acetonitrile under reduced pressure. For further purification, the product was finally chromatographed on silica gel using ethyl acetate/heptane (1/4). The product-containing fractions were combined and then evaporated to dryness, and the residue was added HCl and lyophilized. 5mg of solid are obtained.

LCMS-Rt (A): 2.04 minutes.

MS(ES⁺，M+H⁺)：278.05。

Example 45: (5, 6-difluoro-1H-benzimidazol-2-yl) - (4-methylthiophen-3-yl) amine trifluoroacetate salt

3-isothiocyanato-4-methylthiophene (1.08g) dissolved in anhydrous tetrahydrofuran (30mL) was added dropwise to a solution of 1, 2-diamino-4, 5-difluorobenzene (1g) in anhydrous tetrahydrofuran (20 mL). The mixture was then stirred at room temperature for 2 hours and left to stand overnight. Methyl iodide (0.44mL) was added, and the mixture was stirred for 8 hours and allowed to stand overnight. The tetrahydrofuran was then removed under reduced pressure, the residue was partitioned between ethyl acetate and water, the phases were separated and the ethyl acetate phase was dried over magnesium sulfate. The residue is taken up under silica gel and chromatographed on silica gel using the mobile phase n-heptane ethyl acetate 1: 1. 229mg of the desired compound are obtained in the form of a free base. Impure fractions from the above chromatographic separation were purified by preparative HPLC. After lyophilization, 42.2mg of the desired compound was isolated as the trifluoroacetate salt.

LCMS-Rt (A): 1.98 minutes.

MS(ES⁺，M+H⁺)：266.13。

Example 46: (2-chloro-4-methylthiophen-3-yl) - (5, 6-difluoro-1H-benzimidazol-2-yl) amine hydrochloride

A solution of N-chlorosuccinimide (124.6mg) in glacial acetic acid (5mL) was added dropwise to a solution of (5, 6-difluoro-1H-benzimidazol-2-yl) - (4-methylthiophen-3-yl) amine (225mg) in glacial acetic acid (5mL) at room temperature. The mixture was then stirred at room temperature for 3.5 hours. The glacial acetic acid was then removed, water was added to the residue and adjusted to pH 10 using 2M aqueous sodium hydroxide solution. The aqueous phase was extracted 3 times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was removed. The residue was purified by preparative chromatography, the product-containing fractions were combined, acetonitrile was removed, rendered basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) Filtered and concentrated. Water was added to the residue, acidified with 10% strength hydrochloric acid and lyophilized. 81mg of the desired product are obtained in solid form.

LCMS-Rt (A): 2.15 minutes.

MS(ES⁺，M+H⁺)：300.11。

Example 47: (2-bromo-4-methylthiophen-3-yl) - (5, 6-difluoro-1H-benzimidazol-2-yl) amine

At room temperature, adding N-bromoamberA solution of the imide (8mg) in glacial acetic acid (0.5mL) was added dropwise to a solution of (5, 6-difluoro-1H-benzimidazol-2-yl) - (4-methylthiophen-3-yl) amine trifluoroacetate (15mg, example 45) in Reactivisual (0.5mL) and the mixture was stirred at room temperature for 0.5H. Then, acetic acid was removed under reduced pressure, and a saturated potassium carbonate solution and ethyl acetate were added to the residue. The organic phase was removed and the aqueous phase was extracted 2 times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and the drying agent was filtered off. The residue which remained after removal of the solvent under reduced pressure was purified by preparative chromatography. The product-containing fractions were combined, acetonitrile was removed, saturated sodium bicarbonate solution was added to the residue and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. After removal of ethyl acetate under reduced pressure, the residue was co-evaporated with toluene and then dried under high vacuum. 8.1mg of the desired compound are obtained.

LCMS-Rt (D): 1.45 minutes.

MS(ES⁺，M+H⁺)：343.96。

Example 48: [ (2-chloro-4-methylthiophen-3-yl) - (4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-yl) ] amine hydrochloride

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

The amines required as precursors were prepared according to GB 1131191. Reacting 2-chlorocyclohexanone with phthalimide to give 2- (2-oxocyclohexyl) isoindole-1, 3-dione, and ketalizing the compound with ethylene glycol in the presence of p-toluenesulfonic acid to give 2- (1, 4-dioxaspiro [4.5] dec-6-yl) isoindole-1, 3-dione. Treatment with hydrazine hydrate removes the phthalimido group to give the desired 1, 4-dioxaspiro [4.5] decan-6-ylamine.

b)1- (1, 4-dioxaspiro [4.5] decan-6-yl) -3- (4-methylthiophen-3-yl) thiourea

A solution of 3-isothiocyanato-4-methylthiophene (296.2mg, see example 1a) in anhydrous tetrahydrofuran (10mL) was added dropwise to 1, 4-dioxaspiro [4.5] spiro]To a solution of dec-6-ylamine (300mg) in anhydrous tetrahydrofuran (10mL), the mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was purified by preparative chromatography, the product-containing fractions were combined, acetonitrile was removed, rendered basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. 428mg of the desired product are obtained.

LCMS-Rt (A): 3.57 minutes.

MS(ES⁺，M+H⁺)：313.19。

c)1- (1, 4-dioxaspiro [4.5] decan-6-yl) -2-methyl-3- (4-methylthiophen-3-yl) isothiourea

1- (1, 4-dioxaspiro [4.5]]Dec-6-yl) -3- (4-methylthiophen-3-yl) thiourea (393mg) was dissolved in anhydrous tetrahydrofuran (8.5mL), and a solution of methyl iodide (179mg) in anhydrous tetrahydrofuran (0.5mL) was added. The mixture was then stirred in a sand bath at 70 ℃ for 2 days. Ethyl acetate was then added to the reaction mixture, and the mixture was washed 2 times with water. The organic phase was dried over magnesium sulfate and after filtration the solvent was removed. The residue was purified by preparative chromatography, the product-containing fractions were combined, acetonitrile removed, made basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. 59mg of the desired product are obtained and are used directly in the next step.

LCMS-Rt (C): 1.05 minutes.

MS(ES⁺，M+H⁺)：327.4。

d) N- (1, 4-dioxaspiro [4.5] decan-6-yl) -N' - (4-methylthiophen-3-yl) guanidine

In ReactiVial, a 7M solution of ammonia in methanol (2mL) was added to 1- (1, 4-dioxaspiro [4.5] dec-6-yl) -2-methyl-3- (4-methylthiophen-3-yl) isothiourea (58.8mg), and the mixture was stirred in a sand bath at about 100 ℃ for 16 hours. The solvent was removed to give 51mg of oily product which was used directly for further reaction.

LCMS-Rt (C): 1.00 min.

MS(ES⁺，M+H⁺)：296.4。

e) N- (2-chloro-4-methylthiophen-3-yl) -N' - (1, 4-dioxaspiro [4.5] decan-6-yl) guanidine

Reacting N- (1, 4-dioxaspiro [4.5]]Decan-6-yl) -N' - (4-methylthiophen-3-yl) guanidine (49mg) was dissolved in glacial acetic acid (3mL) and a solution of N-chlorosuccinimide (20.3mg) in glacial acetic acid (5mL) was added slowly. The mixture was stirred for several hours and then left to stand at room temperature over the weekend, after which glacial acetic acid was removed under reduced pressure, water was added to the residue and the mixture was adjusted to pH 10 using 2N sodium hydroxide solution. The base phase was extracted 3 times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography, the product-containing fractions were combined, acetonitrile removed, made basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. The solvent was removed under reduced pressure to give 24mg of the desired product, which was used directly in the next step.

LCMS-Rt (C): 1.09 minutes.

MS(ES⁺，M+H⁺)：330.4。

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

N- (2-chloro-4-methylthiophen-3-yl) -N' - (1, 4-dioxaspiro [4.5] dec-6-yl) guanidine (24mg) was dissolved in 2N hydrochloric acid (1mL) and stirred at room temperature for 30 minutes. Concentrated hydrochloric acid (1mL) was then added and the mixture was stirred for an additional 2 hours. The mixture was then diluted with a small amount of water and lyophilized. Toluene was added to the residue, which was then distilled off under reduced pressure. This procedure was repeated 2 times to give 22mg of the desired product in solid form.

LCMS-Rt (B): 0.95 minutes.

MS(ES⁺，M+H⁺)：268.07。

Example 49: 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophenebenzenesulfonate

2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene (250mg) was dissolved in THF (5mL), and benzenesulfonic acid (150mg) dissolved in THF (5mL) was added with stirring. After 3 hours, the reaction mixture was placed in a freezer overnight. The precipitate was suction filtered off and dried under high vacuum at 75 ℃ to give the desired product. Colorless crystals. Melting point: 235 ℃.

Example 50: 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene methanesulfonate

The title compound was obtained in analogy to the procedure described in example 49 from 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene using one equivalent of methanesulfonic acid. Colorless crystals, melting point: 227 ℃.

Example 51: 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene benzoate

The title compound was obtained in analogy to the procedure described in example 49 from 2-chloro-3N- (2-benzimidazolylamino) -4-methylthiophene using one equivalent of benzoic acid. For precipitation, the reaction mixture was concentrated to half of its initial volume, then diethyl ether (30mL) was added. Colorless crystals, melting point: 198 deg.C.

Example 52: 2, 4-dichloro-3N- (2-benzimidazolylamino) thiophene hydrochloride

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

567mL of acetic anhydride were added dropwise, while heating simultaneously in an oil bath, to a mixture of 942g of methyl 3-aminothiophene-2-carboxylate and 1000mL of toluene, which was then boiled under reflux for 1.5 hours and subsequently cooled to about 0 ℃ in an ice bath. The crystals were filtered off and washed 2 times with a small amount of isopropanol and 2 times with diisopropyl ether. Methyl 3-acetylaminothiophene-2-carboxylate can be obtained from the filtrate by further concentration and crystallization. Melting point: 93-95 ℃.

b) 3-Acetylamino-4, 5-dichlorothiophene-2-carboxylic acid methyl ester

Under the condition of magnetic stirring and reaction temperature of 20-30 deg.C 17.9g of sulfuryl chloride SO₂Cl₂Was added dropwise to a solution of 19.9g of methyl 3-acetylaminothiophene-2-carboxylate in 100mL of chloroform. Then mixing the mixtureThe compound was stirred at 40 ℃ for another 2 hours and boiled under reflux for another 15 minutes. The solvent was distilled off under reduced pressure, then ethyl acetate was added to the residue, and the crystals were filtered off after standing. Melting point: 136 ℃ and 138 ℃.

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

A mixture of 25g of methyl 3-acetylamino-4, 5-dichlorothiophene-2-carboxylate, about 10g of triethylamine, 300mL of methanol and 1g of palladium on carbon was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. The catalyst is filtered off and the mixture is then concentrated by distillation under reduced pressure until crystallization begins, then water is added and the solid is filtered off. Crystallization from isopropanol gave colorless crystals. Melting point: 142 ℃ and 147 ℃.

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

In a mixture of 50mL of methanol and 50mL of concentrated hydrochloric acid, 7g of methyl 3-acetylamino-4-chlorothiophene-2-carboxylate were stirred at 60 ℃ for 4 hours, under reflux for 5 hours and at room temperature for a further 3 days. Any precipitate formed was removed by filtration and about 1/3 volumes of solvent were removed by distillation under reduced pressure. After addition of about 100mL of water, the mixture is stirred at room temperature for a further 15 minutes, the colourless crystals are filtered off and dried in an air stream. Melting point: 62-64 ℃.

e) 3-amino-4-chlorothiophene

18.02g of methyl 3-amino-4-chlorothiophene-2-carboxylate are added to a solution of 11.1g of KOH and 160mL of water, and the mixture is then boiled under reflux for 3 hours and, after cooling, added dropwise to a 60 ℃ solution of 15mL of concentrated hydrochloric acid and 30mL of water. This leads to a vigorous evolution of CO₂. After stirring for about 40 minutes at 60 ℃ the mixture was allowed to cool, a 50-100mL methyl tert-butyl ether layer was added, the mixture was made basic using concentrated aqueous sodium hydroxide solution and the aqueous phase was extracted in a separatory funnel. The aqueous phase is extracted 2 more times with methyl tert-butyl ether, the combined organic extracts are washed 1 time with water in a separating funnel, the organic phase is dried, the solvent is distilled off and 1 part of ethyl acetate are usedThe oily amorphous residue was chromatographed on a silica gel column using a mixture of portions of toluene.

f) Isothiocyanates 4-chloro-3-thienyl

1.46g of thiocarbonyldiimidazole were added to a solution of 1.1g of 3-amino-4-chlorothiophene in 20mL of anhydrous THF, and the mixture was stirred at room temperature for 1 hour. The solid was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, the organic phase was treated 2 times with water in a separating funnel and then dried, and the solvent was distilled off again under reduced pressure. 4-chloro-3-thienyl isothiocyanate was obtained as a dark oil, which was then used in the reaction without further purification steps.

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

0.86g of 1, 2-diaminobenzene (o-phenylenediamine) was added to a solution of 1.4g of 4-chloro-3-thienyl isothiocyanate in 40mL of anhydrous THF, the mixture was stirred at room temperature for about 20 hours, and the solvent was distilled off under reduced pressure. The residue was treated with water and extracted with ethyl acetate, the solvent was again distilled off and the residue was purified by medium-pressure silica gel column chromatography using a 1: 1 mixture of ethyl acetate and toluene. A tan solid.

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

A solution of 0.169g of sodium hydroxide in 5mL of water and a solution of 0.363g of p-toluenesulfonyl chloride in 10mL of THF were added sequentially to a solution of 0.5g N- (2-aminophenyl) -N' - (4-chloro-3-thienyl) thiourea in 25mL of anhydrous THF. The mixture was stirred at room temperature for 3 hours, then the solvent was distilled off under reduced pressure, and the residue was treated with water and extracted with ethyl acetate. After removal of the solvent by distillation, the product is purified by medium-pressure silica gel chromatography using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid as eluent.

For characterization, an aliquot of 4-chloro-3N- (2-benzimidazolylamino) -thiophene was converted to 4-chloro-3N- (2-benzimidazolylamino) thiophene hydrochloride in ethyl acetate using ethereal hydrogen chloride and characterized. Colorless crystals. Melting point: 256-260 ℃.

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

A solution of 0.16g N-chlorosuccinimide in 5mL of glacial acetic acid was added to a solution of 0.3g of 4-chloro-3N- (2-benzimidazolylamino) thiophene in 10mL of glacial acetic acid. The reaction mixture was stirred at 40 ℃ for 15 minutes and at room temperature for about 4 hours, then acetic acid was distilled off under reduced pressure and the residue was treated with water. The mixture was made basic using aqueous sodium hydroxide solution and then extracted with ethyl acetate, the extracts were washed with water, the organic phase was dried and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography under medium pressure using a mixture of 20 parts ethyl acetate, 10 parts n-heptane and 3 parts glacial acetic acid as eluent, and then precipitated from ethyl acetate by adding a solution of hydrogen chloride in diethyl ether. The product was colorless and crystalline. Melting point: 264 ℃ and 268 ℃.

Example 53: 2-bromo-4-chloro-3N- (2-benzimidazolylamino) thiophene hydrochloride

A solution of 0.356, 0.356g N-bromosuccinimide in 6mL of glacial acetic acid was added dropwise to a solution of 0.5g of 4-chloro-3N- (2-benzimidazolylamino) thiophene in 15mL of glacial acetic acid, and the mixture was stirred at room temperature for a further 15 minutes. The solvent was distilled off, the residue was treated with water and made alkaline with aqueous sodium hydroxide solution. After extraction with ethyl acetate, the organic phase is washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on silica gel using medium-pressure conditions and a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid as eluent. After the solvent was distilled off, ethyl acetate was added to the residue and 2-bromo-4-chloro-3N- (2-benzimidazolylamino) thiophene hydrochloride was precipitated by adding a solution of hydrogen chloride in diethyl ether. The product was colorless and crystalline. Melting point: 264 ℃ and 266 ℃.

Example 54: (2, 4-dichlorothien-3-yl) - (5-fluoro-1H-benzimidazol-2-yl) amine hydrochloride

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

4-fluoro-1, 2-phenylenediamine (900mg) was dissolved in THF (25mL) and 4-chloro-3-thienyl isothiocyanate (example 52c), dissolved in THF (15mL), was added dropwise with stirring. The solution was stirred at room temperature for about 3 hours and then left to stand overnight. The reaction mixture is then concentrated and the residue is purified by preparative HPLC. The product-containing fractions were combined, freed from acetonitrile, made basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. The solvent was removed to give 625mg of the desired product.

LCMS-Rt (F): 1.28 minutes.

MS(ES⁺，M+H⁺)：302.0。

b) (4-chlorothien-3-yl) - (5-fluoro-1H-benzimidazol-2-yl) amine

1- (2-amino-4-fluorophenyl) -3- (4-chlorothien-3-yl) thiourea (625mg) was dissolved in THF and a solution of NaOH (0.207g) in water (9mL) was added. A solution of p-toluyl chloride (0.395g) in THF (10mL) was added dropwise over 5 minutes. After the addition was complete, the mixture was stirred at room temperature for 1 hour. For work-up, water and ethyl acetate were added to the reaction mixture and the phases were separated in a separatory funnel. The aqueous phase was extracted 3 times with ethyl acetate and the combined ethyl acetate phases were dried over magnesium sulfate, purified with charcoal, filtered and concentrated. 135mg of the desired product are obtained.

LCMS-Rt (F): 0.90 minutes.

MS(ES⁺，M+H⁺)：268.0。

c) (2, 4-dichlorothien-3-yl) (5-fluoro-1H-benzimidazol-2-yl) amine hydrochloride

(4-chlorothien-3-yl) (5-fluoro-1H-benzimidazol-2-yl) amine (85mg) was dissolved in glacial acetic acid (4mL), and N-chlorosuccinimide (42mg) dissolved in glacial acetic acid (4mL) was slowly added at room temperature under vigorous stirring. After the addition was complete, the mixture was stirred at room temperature for 45 minutes and then at 50 ℃ for 5 hours. After addition of N-chlorosuccinimide (4mg), stirring was continued at 50 ℃ for 1 hour. Toluene (20ml) was then added to the reaction mixture, and glacial acetic acid was distilled off. The residue was dissolved in ethyl acetate and eluted with saturated potassium carbonate solution. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC, the product-containing fractions were combined, acetonitrile removed, made basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. After removal of the solvent, water and 2N hydrochloric acid were added to the residue, followed by lyophilization. 17mg of the desired product are obtained.

LCMS-Rt (E): 2.65 minutes.

MS(ES⁺，M+H⁺)：301.93。

Example 55: (2-bromo-4-chlorothien-3-yl) (5-fluoro-1H-benzimidazol-2-yl) amine hydrochloride

(4-Chlorothien-3-yl) (5-fluoro-1H-benzimidazol-2-yl) amine (50mg, example 54b) was dissolved in glacial acetic acid (4mL) and N-bromosuccinimide (33mg) dissolved in glacial acetic acid (4mL) was added slowly at room temperature with vigorous stirring. After the addition is complete, the mixture is addedAfter stirring at room temperature for 45 minutes, toluene (20mL) was added to the reaction mixture and glacial acetic acid was distilled off. The residue was dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography, the product-containing fractions were combined, acetonitrile removed, made basic and extracted 3 times with ethyl acetate. The combined organic phases were dried (MgSO)₄) And filtered. After removal of the solvent, water and 2N hydrochloric acid were added to the residue, followed by lyophilization. 27mg of the desired product are obtained.

LCMS-Rt (E): 2.29 minutes.

MS(ES⁺，M+H⁺)：347.87。

Example 56: (2, 4-dichlorothien-3-yl) (5, 6-difluoro-1H-benzimidazol-2-yl) amine hydrochloride

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

1, 2-diamino-4, 5-difluorobenzene (1.02g) was first added to anhydrous THF (15mL) and 4-chloro-3-thienyl isothiocyanate (1.25g, example 52c), dissolved in anhydrous THF (15mL), was added dropwise. Further work-up in analogy to example 54a) gave 773mg of the desired compound.

LCMS-Rt (F): 1.32 minutes.

MS(ES⁺，M+H⁺)：320.0。

b) (4-chlorothien-3-yl) (5, 6-difluoro-1H-benzimidazol-2-yl) amine

1- (2-amino-4, 5-difluorophenyl) -3- (4-chlorothien-3-yl) thiourea (773mg) was first added to THF (20mL), followed by a solution of NaOH (240mg) in water (9mL) and then tosyl chloride (528mg) in THF (10 mL). Further work-up in analogy to example 54b) gave 275mg of the desired compound.

LCMS-Rt (F): 0.95 minutes.

MS(ES⁺，M+H⁺)：286。

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

(4-Chlorothien-3-yl) (5, 6-difluoro-1H-benzimidazol-2-yl) amine (125mg) was first added to glacial acetic acid (8mL), and a solution of Cl-succinimide (59mg) in acetic acid (2mL) was added dropwise. Further work-up in analogy to example 54c) gave 58mg of the desired product.

LCMS-Rt (E): 2.97 minutes.

MS(ES⁺，M+H⁺)：319.88。

Example 57: (2-bromo-4-chlorothien-3-yl) (5, 6-difluoro-1H-benzimidazol-2-yl) amine hydrochloride

(4-Chlorothien-3-yl) (5, 6-difluoro-1H-benzimidazol-2-yl) amine (125mg, example 55b) was dissolved in glacial acetic acid (8mL) and N-bromosuccinimide (78mg) dissolved in glacial acetic acid (2mL) was slowly added at room temperature with vigorous stirring. Further work-up in analogy to example 55c) gave 77mg of the desired product.

LCMS-Rt (E): 2.39 minutes.

MS(ES⁺，M+H⁺)：365.86。

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

a) N- (2-amino-3-methylphenyl) -N' - (4-chloro-3-thienyl) thiourea

The title compound is obtained in analogy to the procedure described in example 52g) from the reaction of 4-chloro-3-thienyl isothiocyanate and 1, 2-diamino-3-methylbenzene by medium pressure column chromatography on silica gel using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 1 part of ethyl acetate. Tan solid, melting point: 193 ℃ and 196 ℃.

b) 4-chloro-3N- (4-methyl-2-benzimidazolylamino) thiophene

The title compound was obtained in analogy to the procedure described in example 52h) from N- (2-amino-3-methylphenyl) -N' - (4-chloro-3-thienyl) thiourea by medium pressure column chromatography on silica gel using a mixture of 10 parts of dichloromethane and 1 part of methanol as amorphous foam product. 4-chloro-3N- (4-methyl-2-benzimidazolylamino) thiophene hydrochloride was prepared in ethyl acetate using diethyl ether saturated with hydrogen chloride gas. Crystalline product, melting point: 325 ℃ and 327 ℃.

Example 59: 2, 4-dichloro-3N- (4-methyl-2-benzimidazolylamino) thiophene hydrochloride

The title compound was obtained in analogy to the procedure described in example 52i) from 4-chloro-3N- (4-methyl-2-benzimidazolylamino) thiophene and N-chlorosuccinimide in glacial acetic acid and in analogous work-up. Crystalline product, melting point: 296 ℃ and 298 ℃.

Example 60: trans- (3aS, 7aS) -4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride

a) trans-S, S-3N- (2-amino-cyclohexyl) -N' - (4-chloro-3-thienyl) thiourea

The title compound is obtained in analogy to the reaction described in example 1b) from the reaction of 4-chloro-3-thienyl isothiocyanate and trans-S, S-1, 2-diaminocyclohexane by separation by column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of dichloromethane, 5 parts of n-heptane, 5 parts of methanol and 1 part of ammonia (35-37%) as amorphous dark-colored product which is worked up without further workup.

b) Trans- (3aS, 7aS) -4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine

The title compound was obtained as amorphous foam product from trans-S, S-3N- (2-amino-cyclohexyl) -N' - (4-chloro-3-thienyl) thiourea and p-toluenesulfonyl chloride with the procedure described in example 52h), followed by medium pressure column chromatography on silica gel using a mixture of 10 parts dichloromethane and 1 part methanol. trans-S, S-4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride was prepared using hydrogen chloride gas saturated diethyl ether in ethyl acetate and a small amount of ethanol. Crystalline product, melting point: 196 ℃ and 200 ℃.

Example 61: trans- (3aR, 7aR) -4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride

a) Trans- (1R, 2R) -3N- (2-amino-cyclohexyl) -N' - (4-chloro-3-thienyl) thiourea

The title compound is obtained in analogy to the reaction described in example 1b) from 4-chloro-3-thienyl isothiocyanate and trans- (1R, 2R) - (-) -1, 2-diaminocyclohexane and subsequently by column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of dichloromethane, 5 parts of n-heptane, 5 parts of methanol and 1 part of ammonia (35-37%) as amorphous dark-colored product which is worked up without further workup.

b) Trans- (3aR, 7aR) -4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine

The title compound was obtained in analogy to the procedure described in example 52h) from trans-R, R-3N- (2-amino-cyclohexyl) -N' - (4-chloro-3-thienyl) thiourea and p-toluenesulfonyl chloride, subsequently by medium pressure column chromatography on silica gel using a mixture of 10 parts ethyl acetate, 5 parts dichloromethane, 5 parts N-heptane, 5 parts methanol and 1 part ammonia (35-37%) as amorphous oily product. trans-R, R-4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride was prepared using diethyl ether saturated with hydrogen chloride gas in ethyl acetate and a small amount of ethanol. Crystalline product, melting point: 240 ℃ and 244 ℃.

Example 62: cis-4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride

a) cis-3N- (2-amino-cyclohexyl) -N' - (4-chloro-3-thienyl) thiourea

The title compound is obtained in analogy to the reaction described in example 1b) from 4-chloro-3-thienyl isothiocyanate and cis-1, 2-diaminocyclohexane by subsequent column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of dichloromethane, 5 parts of n-heptane, 5 parts of methanol and 1 part of ammonia (35-37%) as amorphous dark-colored product which is worked up without further workup.

b) cis-4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine

The title compound was obtained in analogy to the procedure described in example 52h) from 3N- (cis-2-amino-cyclohexyl) -N' - (4-chloro-3-thienyl) -thiourea and p-toluenesulfonyl chloride, subsequently by medium pressure column chromatography on silica gel using a mixture of 10 parts ethyl acetate, 5 parts dichloromethane, 5 parts N-heptane, 5 parts methanol and 1 part ammonia (35-37%) as brown oily product. 4-chloro-3N- (cis-3 a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride was prepared using diethyl ether saturated with hydrogen chloride gas in ethyl acetate and a small amount of ethanol. Crystalline product, melting point: 228 ℃ and 231 ℃.

Example 63: trans-R, R-2, 4-dichloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 52i) by reacting trans-R, R-4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine with N-chlorosuccinimide and similar workup. The product was crystallized. Sublimation foaming started at 165 ℃.

Example 64: cis-2, 4-dichloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride

The title compound was obtained in analogy to the procedure described in example 52i) by reacting cis-4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thiophenylamine with N-chlorosuccinimide and similar workup. The product was crystallized. Melting point: 270 ℃ and 274 ℃.

Example 65: 4-chloro-3N- (4-chloro-2-benzimidazolylamino) thiophene hydrochloride

a)1-N- (2-amino-3-chlorophenyl) -3-N- (4-chloro-3-thienyl) thiourea

The title compound was obtained in analogy to the procedure described in example 1b) from 3-chloro-1, 2-diaminobenzene and 4-chloro-3-thienyl isothiocyanate and crystallized in diisopropyl ether as a solid having two melting points, melting point 1: 152-155 ℃; recrystallization, melting point 2: is > 310 ℃.

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

The title compound was obtained in analogy to the procedure described in example 52h) by reacting 1-N- (2-amino-3-chlorophenyl) -3-N- (4-chloro-3-thienyl) thiourea and p-toluenesulfonyl chloride and performing column chromatography on silica gel using a mixture of 3 parts toluene and 1 part ethyl acetate as mobile phase and subsequently distilling off the solvent under reduced pressure to give a foamy amorphous product which was further converted into the hydrochloride salt.

c) 4-chloro-3N- (4-chloro-2-benzimidazolylamino) thiophene hydrochloride

The title compound was obtained by treating a solution of 4-chloro-3N- (4-chloro-2-benzimidazolylamino) thiophene in ethyl acetate with a solution of diethyl ether saturated with hydrogen chloride gas, as a crystalline precipitate, melting point: 276 ℃ and 280 ℃.

Example 66: 2, 4-dichloro-3N- (4-chloro-2-benzimidazolylamino) thiophene hydrochloride

The title compound was obtained in analogy to the procedure described in example 52i) from the reaction of 4-chloro-3N- (4-methyl-2-benzimidazolylamino) thiophene and N-chlorosuccinimide in glacial acetic acid and similar work-up. Crystalline product, melting point: 294-.

In analogy to the compounds listed in the working examples, the following thiophene derivatives can be prepared:

2-bromo-4-chloro-3N- (4-methyl-2-benzimidazolylamino) thiophene hydrochloride, melting point: 284-286 deg.c,

2-bromo-4-chloro-3N- (4-chloro-2-benzimidazolylamino) thiophene hydrochloride, melting point: 304-306 deg.c,

trans-R, R-2-bromo-4-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride, decomposition temperature: 215 ℃ of the reaction solution is added,

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

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

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

2, 4-dimethyl-3N- (4-methyl-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-thiophenylamine hydrochloride.

Pharmacological data:

description of the experiments:

in this experiment, the recovery of intracellular ph (phi) after acidification was determined, which was initiated when NHE was able to function, even without bicarbonate.For this purpose, the pH is determined using the fluorescent dye BCECF (Calbiochem, using the precursor BCECF-AM) which is sensitive to pH. Cells were first loaded with BCECF. BCECF fluorescence was measured in a "ratiometric fluorescence spectrophotometer" (Photon Technology International, south brunswick, n.j., USA) with excitation wavelengths of 505 and 440nm and emission wavelength of 535nm and converted to pHi using a calibration curve. Placing the cells in NH₄Cl buffer (pH 7.4) (NH)₄Cl buffer: 115mM NaCl, 20mM NH₄Cl，5mM KCl，1mM CaCl₂，1mM MgSO₄20mM Hepes, 5mM glucose, 1mg/ml BSA; pH 7.4 with 1M NaOH), even during loading of BCECF. Acidification in cells was achieved by adding 975. mu.l NH free₄Cl buffer (see below) was added to the solution in NH₄Induction in 25 μ l aliquots of cells cultured in Cl buffer. The subsequent rate of pH recovery was recorded for 2 minutes for NHE1, 5 minutes for NHE2 and 3 minutes for NHE 3. To calculate the inhibitory potency of the test substances, the cells were first studied in a buffer in which no or no pH recovery at all occurred. To restore pH completely (100%), cells were incubated in the presence of Na⁺Buffer (133.8mM NaCl, 4.7mM KCl, 1.25mM CaCl)₂，1.25mM MgCl₂，0.97mM Na₂HPO₄，0.23mM NaH₂PO₄5mM hepes, 5mM glucose, pH 7.0 using 1M NaOH). To determine the value of 0%, cells were incubated in the absence of Na⁺Buffer (133.8mM choline chloride, 4.7mM KCl, 1.25mM CaCl)₂，1.25mM MgCl₂，0.97mM K₂HPO₄，0.23mM KH₂PO₄5mM hepes, 5mM glucose, pH 7.0 with 1M KOH). Dissolving the substance to be tested in Na-containing solution⁺In the buffer of (1). The recovery of intracellular pH at each tested concentration of the substance was expressed as a percentage of the maximum recovery. The IC of the substance in question for each NHE subtype was calculated as a percentage of pH recovery using the Sigma-Plot program₅₀The value is obtained.

As a result:

examples	IC₅₀[μM]
examples	IC₅₀[μM]	16: trans-R, R-2-chloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride	0.27(rNHE3)
12: 2-chloro-3N- (2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride	0.12(rNHE3)		0.27(rNHE3)
	0.12(rNHE3)	54: 2-bromo-4-chloro-3N- (2-benzimidazolylamino) thiophene hydrochloride	0.22(hNHE3)
53: 2, 4-dichloro-3N- (2-benzimidazolylamino) thiophene hydrochloride	0.14(hNHE3)		0.22(hNHE3)
	0.14(hNHE3)	56: 2, 4-dichloro-3N- (4-methyl-2-benzimidazolylamino) thiophene hydrochloride	0.22(hNHE3)
60: trans-R, R-2, 4-dichloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine hydrochloride	0.19(hNHE3)		0.22(hNHE3)
	0.19(hNHE3)	63: 2, 4-dichloro-3N- (4-chloro-2-benzimidazolylamino) thiophene hydrochloride	0.54(hNHE3)
38: 2-chloro-3N- (4-hydroxy-2-benzimidazolylamino) -4-methylthiophene hydrochloride	0.84(hNHE3)		0.54(hNHE3)
	0.84(hNHE3)	18: 2-bromo-3N- (2-benzimidazolyl) -4-methyl-3-thiophenylamine hydrochloride	0.12(hNHE3)
19: trans-R, R-2-bromo-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride	0.56(hNHE3)		0.12(hNHE3)
	0.56(hNHE3)	2: 2-chloro-3N- (5-fluoro-2-benzimidazolyl) -4-methyl-3-thienylamine hydrochloride	0.62(hNHE3)
44: (1H-benzimidazol-2-yl) - (2-chloro-4-methyl-thiophen-3-yl) methylamine	1.59(hNHE3)		0.62(hNHE3)

Claims

1. A compound of formula I:

wherein:

r1 and R2 are each independently H, F, Cl, Br, I or methyl;

r3 is hydrogen, F, Cl, Br or I;

r4 is hydrogen, methyl or ethyl;

r5 and R6 are hydrogen or together are a bond;

r7 and R8 together are an alkylene chain containing 3, 4 or 5 carbon atoms; or

R7 and R8 together are a group of the formula:

wherein R5 and R6 together form a bond;

r10 and R11 are each independently of the other hydrogen, fluorine, chlorine, bromine, -OH, -O-CH₃or-CF₃；

R9 and R12 are hydrogen or F; or

One of the substituents R9 and R12 is hydrogen and the other is F, Cl, Br, I, COOH, CO-NR13R14 or- (X)_n-C_qH_2q-Z；

n is 0 or 1;

x is oxygen;

q is 0 or 1;

z is hydrogen;

and pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1 wherein the pharmaceutically acceptable salt is the trifluoroacetate salt.

3. A compound as claimed in claim 1 wherein:

r1 and R2 are independently of each other F, Cl, Br or CH 3;

r3 is hydrogen;

r4 is hydrogen;

r5 and R6 are hydrogen or together are a bond;

r7 and R8 together are an alkylene chain containing 3, 4 or 5 carbon atoms; or

R7 and R8 together are a group of the formula:

wherein R5 and R6 together form a bond;

r10 and R11 are each independently of the other hydrogen, -OH, -O-CH₃Or fluorine；

R9 and R12 are hydrogen; or

n is 0 or 1;

x is oxygen;

q is 0 or 1;

z is hydrogen;

and pharmaceutically acceptable salts thereof.

4. A compound as claimed in claim 3 wherein the pharmaceutically acceptable salt is the trifluoroacetate salt.

5. A compound of formula I as claimed in claim 1 or 3, selected from:

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

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

2-bromo-4-chloro-3N- (2-benzimidazolylamino) thiophene,

2, 4-dichloro-3N- (4-methyl-2-benzimidazolylamino) thiophene,

trans-R, R-2, 4-dichloro-3N- (3a, 4, 5, 6, 7, 7 a-hexahydro-1H-2-benzimidazolyl) -3-thienylamine, and

2, 4-dichloro-3N- (4-chloro-2-benzimidazolylamino) thiophene

And pharmaceutically acceptable salts thereof.

6. The use of a compound of formula I as claimed in any one of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by NHE subtype 3.

7. The use of a compound of formula I as claimed in any one of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of a respiratory disorder; for the treatment or prevention of acute and chronic kidney disease, or bowel dysfunction; for the treatment or prevention of hypertension, central nervous system disorders; for the treatment or prevention of acute and chronic injuries and conditions of organs or tissues resulting from ischemic events or from reperfusion events and their indirect sequelae, atherosclerosis, hypercholesterolemia, diseases in which cell proliferation is a primary or secondary cause, cancer, fibrotic disorders of internal organs, cardiac insufficiency or congestive heart failure, biliary dysfunction, ectoparasitic infections; for the treatment of stroke states, diabetes and late stage diabetic injury, acute or chronic inflammation, wherein all of the above diseases or conditions are mediated by NHE subtype 3; or in the manufacture of a medicament for the preservation and storage of surgically inserted grafts, in the manufacture of a medicament for surgical and organ transplantation, in the manufacture of a medicament for the prevention of age-related tissue changes, for the maintenance of health and for prolonging life.

8. The use of a compound of the formula I as claimed in any of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof in combination with a further medicament or active compound for the preparation of a medicament for the treatment or prophylaxis of respiratory disorders; for the treatment or prevention of acute and chronic kidney disease, or bowel dysfunction; for the treatment or prevention of hypertension, central nervous system disorders; for the treatment or prevention of acute and chronic injuries and conditions of organs or tissues resulting from ischemic events or from reperfusion events and their indirect sequelae, atherosclerosis, hypercholesterolemia, diseases in which cell proliferation is a primary or secondary cause, cancer, fibrotic disorders of internal organs, cardiac insufficiency or congestive heart failure, biliary dysfunction, ectoparasitic infections; for the treatment of stroke states, diabetes and late stage diabetic injury, acute or chronic inflammation, wherein all of the above diseases or conditions are mediated by NHE subtype 3; or in the manufacture of a medicament for the preservation and storage of surgically inserted grafts, in the manufacture of a medicament for surgical and organ transplantation, in the manufacture of a medicament for the prevention of age-related tissue changes, for the maintenance of health and for prolonging life.

9. The use of a compound of the formula I as claimed in any of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof, alone or in combination with other medicaments or active compounds, for the preparation of a medicament for the treatment or prevention of sleep-related respiratory disorders mediated by NHE subtype 3.

10. The use of claim 9, wherein the sleep-related respiratory disorder mediated by NHE subtype 3 is sleep apnea.

11. The use of a compound of the formula I as claimed in any of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof, alone or in combination with other medicaments or active compounds, for the preparation of a medicament for the treatment or prevention of snoring mediated by NHE subtype 3.

12. The use of a compound of the formula I as claimed in any of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof, alone or in combination with other medicaments or active compounds, for the preparation of a medicament for the treatment or prevention of acute renal failure or chronic renal failure mediated by NHE subtype 3.

13. The use of a compound of the formula I as claimed in any of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof, alone or in combination with other medicaments or active compounds, for the preparation of a medicament for the treatment or prevention of intestinal dysfunction mediated by NHE subtype 3.

14. The use of a compound of the formula I as claimed in any of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof, alone or in combination with other medicaments or active compounds, for the preparation of a medicament for the treatment or prevention of essential hypertension mediated by NHE subtype 3.

15. A medicament for human, veterinary or plant protection, comprising an effective amount of a compound of the formula I as claimed in any of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers and additives.

16. A medicament for human, veterinary or plant protection, comprising an effective amount of a compound of the formula I as claimed in any of claims 1 to 5 and/or its pharmaceutically acceptable salts in combination with other pharmacologically active compounds or medicaments and pharmaceutically acceptable carriers and additives.