OA12827A

OA12827A - Substituted thiophenes, method for the production thereof, their use as a medicament or diagnostic reagent, and a medicament containing the same.

Info

Publication number: OA12827A
Application number: OA1200400321A
Authority: OA
Inventors: Hans-Jochen Lang; Uwe Heinelt; Armin Hofmeister; Klaus Wirth; Michael Gekle; Markus Bleich
Original assignee: Aventis Pharma Gmbh
Priority date: 2002-06-04
Filing date: 2003-05-26
Publication date: 2006-07-11
Also published as: PT1513834E; CA2488242A1; IL165519A0; KR20050005532A; NO329351B1; ZA200409095B; BR0311548A; MEP27608A; RS103804A; NO20045504L; DE50302673D1; TW200406409A; RS51141B; KR101087966B1; DK1513834T3; TNSN04240A1; TWI283675B; RU2315766C2; EP1513834A1; HK1076460A1

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

012827

Substituted thiophenes, method for the production thereof, their use as a médicamentor diagnostic reagent, and a médicament containing the same

The invention relates to compounds of the type of the substituted thiophene dérivativesof the formula I. Médicaments comprising compounds of this type are of use forpreventing or treating various disorders. Thus, the compounds can be used, inter alia,for the treatment of respiratory disorders and snoring, and for improving the respiratorydrive, for the treatment of acute and chronic disorders, disorders triggered by ischémieand/or reperfusion events and by proliférative or fibrotic events, for the treatment orprophylaxis of disorders of the central nervous System and lipid metabolism, anddiabetesablood coagulation and infection by parasites.

The invention relates to compounds of the formula I,

in which: R1 and R2 independently of one anotherare H, F, Cl, Br, I, CN, NO2, -(X)n-CqH2q-Z,cycloalkyl having 3, 4, 5 or 6 carbon atoms, alkenyl having 2, 3 or 4 carbonatoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl or alkylalkynyl having3 or 4 carbon atoms; n is zéro or 1 ; 012827 2....................... X is oxygen, NH, N-CH3, S(O)k;k is zéro, 1 or 2; q is zéro, 1,2, 3, 4, 5 or 6; Z is hydrogen or CmF2m+l ; 5 m is zéro, 1,2, 3 or 4; R3 is hydrogen, methyl, F, Cl, Br, I, CN, S(O)k-CH3, -NO2, -O-CH3; k is zéro, 1 or 2; R4 is hydrogen, cycloalkyl having 3, 4,5, or 6 carbon atoms, alkenyl having 2, 34 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl or 10 alkylalkynyl having 3 or 4 carbon atoms, -CrH2r - Y; r is zéro, 1,2,3 or 4; Y is hydrogen or trifluoromethyl; R5 and R6 are hydrogen or together are a bond;. R7 and R8 ' 15 . independently of one another are (C3-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)- alkynyl, (C3-C6)-cycloalkyl or (C4-C6)-cycloalkenyl or R7 and R8 20 together are an alkylene Chain comprising 3 to 8 carbon atoms; where none, some or ail of their hydrogen atoms maÿ bé"replaced by fluorineatoms; or R7 and R8 together are a radical where R5 and R6 together form a bond;R10 and R11

25 012827 ......................:............ ;.................................................. ......3 .............:..... ................................................ independently of one another are hydrogen, fluorine, chlorine,bromine, methyl, CN, OH, -O-CH3, NO2, NH2 or -CF3; R9 and R12 are hydrogen or F; 5 or one of the substituents R9 and R12is 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 310 or 4 carbon atoms, ethynyl, alkylalkynyl having 3 or 4 carbon atoms or -(X)n - CqH2q-Z; R13andR14 are identical or different hydrogen or alkyl having 1,2, 3 or 4carbon atoms; 15 or R13 and R14 together with the nitrogen to which they are attachedform a saturated 5-, 6- or 7-membered ring;n iszeroorl; X is oxygen, NH, N-CH3, S(O)k; 20 k is zéro, 1 or 2; ' q is zéro, 1,2, 3, 4, 5 or 6;and Z is hydrogen or CmF2m+l ;m is zéro, 1,2,3 or 4; 25 and their pharmaceutically acceptable salts, and their trifluoroacetic acid salts.

One embodiment relates to compounds of the formula I in whichR1 and R2 independently of one another are H, F, Cl, Br, I, CN, NO2, -(X)n - CqH2q - Z,cycloalkyl having 3, 4, 5 or 6 carbon atoms, alkenyl having 2, 3 or 4 carbon 30 012827 .....; ......... 7..... :...... ύτη.............:.......'........4 ................:.........;' '.............'.....~..........’.............~ ' ' 7^ atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl or alkylalkynyl having 3 or 4 carbon atoms;n iszeroorl; X is oxygen, NH, N-CH3, S(O)r: 5 k is zéro, 1 or 2; q is zéro, 1,2, 3, 4, 5 or 6; Z is hydrogen or CmF2m+i; m is zéro, 1,2, 3 or 4; R3 is hydrogen, methyl, F, Cl, Br, I, CN, S(O)k-CH3, -NO2, -O- CH3; 10 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 oralkylalkynyl having 3 or 4 carbon atoms, -CqFfcq - Z; q is zéro, 1,2, 3 or 4; Z$ K. is hydrogen or trifluoromethyl; 15 R5 and R6 are hydrogen or together are a bond; R7 and R8 independently of one another are (C3-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl or (C4-C6)-cycloalkenyl 20 or * R7 and R8 together are an alkylene chain comprising 3 to 8 carbon atoms; where none, some or ail of their hydrogen atoms may be replaced by fluorine atoms; 25 or R7 and R8 together are a radical 012827 5

10 15 20 where R5 and R6 together form a bond; R9, R10 and R11 independently of one another are hydrogen, fluorine, chlorine,bromine, methyl, CN, OH, -O-CH3, NO2, NH2 or -CF3; R9andR12 are hydrogen; or one of the substituents R9 and R12is hydrogen; < t and the other is F, Ci, 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, alkylalkynylhaving 3 or 4 carbon atoms or -(X)n - CqH2q-Z; R13and R14 are identical or different hydrogen or alkyl having 1,2, 3 or 4carbon atoms; n is zéro or 1 ; _ X is oxygen, NH, N-CH3, S(O)k! k is zéro, 1 or 2;q is zéro, 1,2, 3, 4, 5 or 6;and Z is hydrogen or CmF2m+l ; m is zéro, 1, 2, 3 or 4; 25 and their pharmaceutically acceptable salts, and their trifluoroacetic acid salts.

Preference is given to compounds of the formula I, in which: 012827 6 R1 and R2 independently of one another are H, F, Cl, Br, CH3, CF3 ,SO2CH3, SO2NH2; but where at most one of the substituents R1 and R2 is hydrogen; R3 is hydrogen, F or Cl; 5 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 comprising 3,4, 5, 6, 7 or 8 carbon atoms; 10 or R7 and R8 together are a radical R12 R11

Rio R9 15 where R5 and R6 together form a bond;R10andR11 independently of one another are hydrogen, OH, fluorine or chlorine;R9 and R12 are hydrogen; or 20 one of the substituents R9 and R12is hydrogen; and the other is F, Cl, Br, CN, COOH, CO-NR13R14, SO2-NR13R14 °r “(X)n ~ CqH2q_Z,‘ R13 and R14 are identical or different hydrogen or methyl; n iszeroorl; is oxygen, NH, N-CH3 or S(O)kîk is zéro, 1 or 2; 25

X 012827 7 q is zéro, 1,2, 3 or 4;Z is hydrogen or CF3; and their pharmaceutically acceptable salts, and their trifluoroacetic acid salts. 5 Particular preference is given to compounds of the formula I in which: R1 and R2 independently of one another are F, Cl, Br, CH3 or CF3; R3 is hydrogen; R4 is hydrogen, methyl, ethyl; 10 R5andR6 are hydrogen or together are a bond; R7 and R8 together are an alkylene Chain comprising 3,4, 5, 6, 7 or 8 carbon atoms; or 15 R7 and R8 together are a radical R12 R11

Rio R9 where R5 and R6 together form a bond; 20 R10and R11 independently of one another are hydrogen, OH or fluorine; R9 and R12 are hydrogen; or one of the substituents R9 and R12is hydrogen; and the other is F, Cl, Br or -(X)n - CqH2q-Z;n is zéro or 1 ; X is oxygen, NH, N-CH3 or S(O)k‘, 25 012827 8 k iszero,1or2;q is zéro or 1 ; Z is hydrogen or CF3; and their pharmaceuticaliy acceptable salts, and their trifluoroacetic acid salts. 5

Very particular preference is given to the following compounds of the formula I,selected from the group consisting of: trans-R,R-2-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-10 thienylamine, trans-R,R-2>bromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3- thienylamine, 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, 2-bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine, $ 15 2-chioro-3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thiénylamine,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, 20 2-chloro-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene,2-chloro-3N-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene,(m-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, 25 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,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)-3-thienylamine, 30 or 2.4- dichloro-3N-(4-chloro-2-benzimidazolylamino)thiophene and their pharmaceuticaliy acceptable salts, for example the hydrochloride or the 012827 9 hydrobromide or the methanesulfonate of each of the compounds.

The compounds of the formula I can be présent in the form of their salts. Suitable acidaddition salts are salts of ail pharmacologically acceptable acids, for example halides,in particular hydrochlorides, hydrobromides, lactates, sulfates, citrates, tartrates,acétates, phosphates, methylsulfonates, benzenesulfonates, p-toluenesulfonates,adipinates, fumarates, gluconates, glutamates, glycerolphosphates, maleates,benzoates, oxalates and pamoates. This group also corresponds to the physiologicallyacceptable anions; but also trifluoroacetates. If the compounds contain an acid group,they are capable of forming salts with bases, for example as alkali métal salts,preferably sodium or potassium salts, or as ammonium salts, for example as salts withammonia or organic amines or amino acids. They can also be présent as zwitterion.

If the corppounds of the formula I contain one or more centers of asymmetry, thecompounds can independently be both S- and R-configured. The compounds can beprésent as optical isomers, as diastereomers, as racemates or as mixtures thereof.

The compounds of the formula I can furthermore be présent as tautomers or as amixture of tautomeric structures. This refers, for example, to the following tautomers:

(if R4 » H)

Alkyl radicals can be straight-chain or branched. This also applies when they carrysubstituents or are présent as substituents of other radicals, for example in fluoroalkylradicals or alkoxy radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl,isopropyl (= 1-methylethyl), n-butyl, isobutyl (= 2-methylpropyl), sec-butyl (= 1-methyl- 012827 .....-......................... ' ϊ.............~ ~....... ........-.....10 .......... propyl), tert-butyi (= 1,1 -dïmethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl orhexyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,n-pentyl, n-hexyl. In alkyl radicals, one or more, for example 1,2, 3,4, 5, 6,7, 8 or 9,hydrogen atoms may be substituted by fluorine atoms. Examples of such fluoroalkyl 5 radicals are trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, heptafluoroisopropyl.Substituted alkyl radicals may be substituted in any positions.

Alkenyl radicals may be straight-chain or branched. This also applies when they areprésent as substituents, for example in alkenylalkylene. The alkenyl radicals can be 10 unsaturated in different positions. Examples of alkenyl radicals are ethenyl, propenyl orbutenyl.

Alkynyl radicals can be straight-chain or branched. This also applies when they areprésent as substituents, for example in alkynylalkylene. The alkynyl radicals can be 15 unsaturated in different positions. Examples of alkynyl radicals are ethynyl, propynyl orbutynyl.

Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Substituted cycloalkyl radicals can be substitued in any positions. The cycloalkyl 20 radicals may also be présent branched as alkylcycloalkyl or cycloalkylalkyl.

Also described are methods for preparing compounds according to the invention.

Thus, the substances described by formula I can be prepared in a manner known tothe person skilled in the art from the isothiocyanate II parent compounds and the 25 appropriate diamines III.

R5 R? η2νΛ >rR8 H2N R6

III 012827 ....................;....... ....................... ............ 11 .................. ......

The thiourea dérivative which is formed as an intermediate is cyclized usingmethylîodide (Synthesis, 1974, 41 -42) or carbodiimide (Synthesis, 1977, 864 - 865)or using p-toluenesulfonyl chloride to give the corresponding compound of theformula I. If the isothiocyanates II employed here are not commercially available, they 5 can be prepared in a manner known from the literature from the corresponding aminothiophene dérivatives, using methods known to the person skilled in the art, forexample by treatment with thiophosgene (J. Med. Chem., 1975, 18, 90-99) orthiocarbonyl diimidazole (Justus Liebigs Ann. Chem., 1962, 657,104).

10 In addition to the isothiocyanates II described above, it is also possible to successfullyreact the isocyanates IV

with amines of the type of formula III to give the compounds of the formula I. Here, the 15 urea dérivative which is formed as an intermediate is cyclized using phosphorusoxychloride to give the corresponding compounds of the formula I.

In the présent invention, it was surprisingly possible to demonstrate that thecompounds described are potent inhibitors of the sodium/proton exchanger (NHE), in 20 partieular the sodium/proton exchanger of subtype 3 (NHE3).

The NHE3 inhibitors known to date are derived from compounds of the acylguanidinetype (EP825178), of the norbornylamine type (DE199 60 204), of the 2-guanidino-quinazolîne type (WO 0179186) or of the benzamidine type (WO0121582, 25 WO0172742). Squalamine, which has also been described as NHE3 inhibitor (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45): C136 - C144), is, accordingto current understanding, not, unlike the compounds of the formula I, effectiveimmediately, but rather via an indirect mechanism and thus reaches its maximumpotency only after one hour. Such NHE3 inhibitors which act by a different mechanism 012827 12 are therefore suitable for use as combination partners for the présent compoundsaccording to the invention.

Clonidine, which is similar to the compounds described here, is known as a weak NHE5 inhibitor. However, its action on the NHE3 of the rat is, with a half-maximal inhibitory concentration (IC50) of 620 μΜ, extremely moderate. In contrast, it shows a certain selectivity for the NHE2 (J. Orlowski et al. J. Biol. Chem. 268, 25536). It wouldtherefore be more accurate to refer to clonidine as an NHE2 inhibitor. In addition to theweak NHE action, clonidine has a high affinity for the adrenergic alpha2 receptor and 10 the imidazoline 11 receptor, mediating a strong hypotensive action (Ernsberger et al.,Eur. J. Pharmacol. 134,1,1987).

Clonidine-like compounds having a thiophene ring instead of the phenyl ring are knownfrom DE1941761. These known compounds differfrom the structures of the formula I 15 described herëin in that they hâve considerably smaller radicals R7 and R8 and inparticular by the fact that R7 and R8 are not capable of forming a joint ring.

By these différences in the substituents R7 and R8, it is possible to eliminate theundesirable clonidine-like cardiovascular effects described above, which are mediatedby the alpha-adrenoceptor action. At the same time, owing to these différences in the 20 substituents, the NHE-inhibiting properties of the compounds described herein areenhanced to the micromolar and submicromolar range, whereas the compoundsknown from DE1941761 show only extremely weakly pronounced NHE-inhibitingeffects, if any. Thus the main représentative compound from DE1941761, thehypotensive agent thiamenidine selected as development product, has, in each case at 25 300 jt/M, no inhibiting effects on the NHE-subtypes NHE1, NHE2, NHE3 and NHE5 which were tested.

Compounds of the formula I are distinguished in that they inhibit the cellularsodium/proton exchanger, and in particular by their NHE3-inhibitory action. 30 NHE3 is found in the body of various species, preferably in the gall bladder, theintestine and the kidney (Larry Fliegel et al., Biochem. Cell. Biol. 76: 735 - 741,1998), 012827 ...... ...... 13...................... but can also be detected in the brain (E. Ma et al., Neuroscience 79: 591 - 603).

Owing to the NHE-inhibitory properties, the compounds of the formula I are suitable forthe prévention and treatment of diseases caused by an activation of NHE or by an 5 activated NHE, and of diseases which are sequelae of damage caused by NHE.

Since NHE inhibitors act predominantly via influencing cellular pH régulation, they canbe combined in a favorable manner with other compounds which also regulate theintracellular pH, suitable combination partners being inhibitors of the enzyme group of 10 the carbonate dehydratases, inhibitors of the bicarbonate-ion-transporting Systems,such as the sodium bicarbonate cotransporter (NBC) or the sodium-dependentchloride/bicarbonate exchanger (NCBE), and also NHE inhibitors having inhibitoryaction on other NHE subtypes, since they can modulate or enhance thepharmacologically relevant pH-regulating effects of the NHE inhibitors described 15 herein. 5

The use of the compounds according to the invention relates to the prévention andtreatment of acute and chronic diseases in veterinary and human medicine. 20 The pharmacological action of the compounds of the formula I is characterized in thatthey induce an improvement in the respiratory drive. They can therefore be used in thetreatment of disturbed respiratory conditions which may, for example, occûr in thefollôwing clinical conditions and diseases: disturbed central respiratory drive (e.g.central sleep apnea, sudden infant death, postoperative hypoxia), muscular-related 25 respiratory disorders, respiratory disorders after long-term ventilation, respiratorydisorders during adaptation in a high mountain area, obstructive and mixed forms ofsleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia.

The compounds additionally increase the muscle tone of the upper airways, so thatsnoring is suppressed. As a resuit, the compounds mentioned are advantageously 30 used for preparing a médicament for the prévention and treatment of sleep apnea andmuscular-related respiratory disturbances and for preparing a médicament for theprévention and treatment of snoring. 012827 14 A combination of an NHE inhibitor of the formula I with a carboanhydrase inhibitor (e.g.acetazolamide) may prove to be advantageous, the latter producing metabolic acidosis " and thereby already increasing respiratory activity, as a resuit of which an increased5 action and decreased use of active compound may be achieved.

Owing to their NHE3-inhibitory action, the compounds according to the invention sparecellular energy resources which, during toxic and pathogenic events, are rapidlydepleted, thus resulting in cell damage or cell death. Here, the high-energy ATP- 10 consuming résorption of sodium in the proximal tubulus is, under the influence of thecompounds of the formula I, temporarily switched off, and the cell is thus able tosurvive an acute pathogenic, ischémie or toxic situation. The compounds are thereforesuitable by way of example for use as drugs for treating ischémie noxa, for exampleacute kidney failure. 15 Furtherrrtore, the compounds are also suitable for treating ail chronic rénal disordersand forms of nephritis which, as a conséquence of increased élimination of protein,resuit in chronic kidney failure. Accordingly, the compounds of the formula I aresuitable for preparing a médicament for the treatment of diabetic late damage, diabeticnephropathy and chronic rénal disorders, in particular ail inflammations of the kidney 20 (nephritides) associated with increased élimination of protein/albumin.

It ha's been shown that the compounds used according to the invention hâve mildlaxative action and, accordingly, can also be used advantageously as laxatives or forthe prophylaxis of intestinal obstruction. 25

Furthermore, the compounds according to the invention can be used advantageouslyfor the prévention and therapy of acute and chronic disorders of the intestinal tracttriggered, for example, by ischémie States in the intestinal région and/or by subséquentreperfusion or by States and events of inflammation. Such complications can occur, for 30 example, by lack of intestinal peristalsis, as is frequently observed, for example, aftersurgical interventions, in the case ofbowel obstruction or in cases of strongly reducedintestinal motility. 012827

Using the compounds according to the invention, it is possible to prevent gailstoneformation.

The NHE inhibitors according to the invention are generally suitable for treatingdiseases caused by ischemia and by reperfusion.

As a resuit of their pharmacological properties, the compounds according to theinvention are suitable for use as antiarrhythmics.

Owing to their cardioprotective component, the NHE inhibitors of the formula I arehighly suitable for infarct prophylaxie and infarct treatment and for treatment of anginapectoris, and they also inhibit, or strongly reduce, in a preventative manner, thepathophysiological processes which contribute to ischemically induced damage, inparticular those which trigger ischemically induced cardiac arrhythmias. Owing to theirprotective action against pathological hypoxie and ischémie situations, the compoundsof the formula ί used according to the invention can, as inhibitors of the cellular Na+/H+ exchange mechanism, be used as médicaments for treating ail acute or chronicdamage caused by ischemia, or diseases induced primarily or secondarily by thisdamage.

This relates to their use as médicaments for surgical interventions. Thus, .thecompounds according to the invention can be used for organ transplântafions, wherethe compounds can be used both for protecting the organs in the donor before andduring removal, for protecting organs that hâve been removed, for example duringtreatment with or storage in physiological bath fluids, and also during transfer into therécipient organism pretreated with compounds of the formula 1.

The compounds are also useful médicaments with protective action during angioplastiesurgical interventions, for example on the heart, but also in peripheral organs andvessels.

Since NHE inhibitors protect human tissue and organs not only effectively against 012827 ...... .......... 16 ......" ’ damage caused by ischemia and reperfusion but aiso against the cytotoxic action ofmédicaments used in particular in cancer therapy and the therapy of autoimmunediseases, the combined administration with compounds of the formula I is suitable forsuppressing or reducing the cytotoxic effects of a therapy. By reducing the cytotoxic 5 effects, in particular cardiotoxicity, by comedication with NHE inhibitors it is furthermorepossible to increase the dose of the cytotoxic therapeutics and/or to prolongmédication with such médicaments. The therapeutic benefit of such a cytotoxic therapycan be enhanced considerably by combination with NHE inhibitors.

The compounds of the formula I are suitable in particular for improving the therapy with 10 médicaments having an undesirable cardiotoxic component.

Owing to their protective action against ischemically induced damage, the compoundsaccording to the invention are also suitable for use as médicaments for treatingischemias of the nervous System, in particular the central nervous System, where they 15 can be u^ed, for example, for treating stroke or cérébral edema.

The compounds of formula I are also suitable for the therapy and prophylaxis ofdiseases and disorders induced by overexcitability of the central nervous System, inparticular for the treatment of epileptic disorders, centrally induced clonie and tonie 20 spasms, States of psychological dépréssion, anxiety disorders and psychoses. Here,the NHE inhibitors according to the invention can be used on their own or incombination with other substances having antiepileptic action or withantipsychoticactive compounds, or carbonate dehydratase inhibitors, for example acetazolamide,and also with other inhibitors of NHE or of the sodium-dependent chloride/bicarbonate 25 exchanger (NCBE).

In addition, the compounds of the formula I according to the invention are also suitablefor treating types of shock, such as, for example, of allergie, cardiogenic, hypovolémieand bacterial shock. 30

The compounds of the formula I can also be used for the prévention and treatment ofthrombotic disorders since, as NHE inhibitors, they are also capable of inhibiting 012827 17 platelet aggregation themselves. In addition, they can prevent or inhibit excessiverelease of mediators of inflammation and coagulation, in particular of the vonWillebrand factor and thrombogenic selecting proteins which takes place followingischemia and reperfusion. It is thus possible to reduce and eliminate the pathogeniceffect of significant thrombogenic factors. Accordingly, the NHE inhibitors of theprésent invention can be combined with other compounds having anticoagulativeand/or thrombolytic action, such as, for example, recombinant or natural tissueplasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombinantagonists, factor Xa antagonists, médicaments with fibrinolytic action, thromboxanereceptor antagonists, phosphodiesterase inhibitors, factor Vlla antagonists,clopidogrel, ticlopidine, etc. Combined use of the présent NHE inhibitors with NCBEinhibitors and/or with inhibitors of carbonate dehydratase, such as, for example, withacetazolamide, is particularly bénéficiai.

Furtherrrçore, the compounds of the formula I according to the invention hâve stronginhibiting action on cell prolifération, for example on fibroblast cell prolifération andprolifération of smooth vascular muscle cells. The compounds of the formula I aretherefore useful therapeutics for diseases in which cell prolifération is a primary orsecondary cause and can therefore be used as antiatherosclerotics, as agents againstchronic kidney failure and against neoplastic diseases. Thus, they can be used fortreating organ hypertrophy and hyperplasia, for example of the heart and the prostate.Compounds of the formula I are therefore suitable for the prévention and-treatment ofcardiac insufficiency (congestive heart failure = CHF) and for the treatment andprévention of prostate hyperplasia and prostate hypertrophy.

The compounds of the formula I furthermore delay or prevent fibrotic disorders. Thus,they are excellent agents for treating fibroses of the heart, and also pulmonary fibrosis,liver fibrosis, kidney fibrosis and other fibrotic disorders.

Since there is significant élévation of NHE in essential hypertensives, the compoundsof the formula I are suitable for the prévention and treatment of high blood pressureand of cardiovascular disorders. 012827 18

Here, they can be used for the treatment of high blood pressure and of cardiovasculardisorders on their own or with a suitable combination and formulation cocomponent.Thus, it is possible, for example, to combine one or more diuretics having thiazide-likeaction, loop diuretics, aldostérone and pseudoaldosterone antagonists, such as 5 hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide,bumetanide, amiloride, triamterene, spironolactone or eplerone, with compounds of theformula I. Furthermore, the NHE inhibitors of the présent invention can be used incombination with calcium antagonists such as verapamil, diltiazem, amlodipine ornifedipine, and also with ACE inhibitors, such as, for example, ramipril, enalapril, 10 lisinopril, fosinopril or captopril. Further favorable combination partners include beta-blockers such as metoprolol, albuterol etc., antagonists of the angiotensin receptor andits receptor subtypes, such as losartan, irbesartan, valsartan, omapatrilat,gemopatrilat, endothelin antagonists, renin inhibitors, adenosine receptor agonists,inhibitors and activators of calcium channels, such as glibenclamide, glimepiride, 15 diazoxidé, cromakalim, minoxidil and its dérivatives, activators of the mitochondrialATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of other potassiumchannels, such as inhibitors of Kv1.5 etc.

Owing to their antiphlogistic action, the NHE inhibitors can be used as antiinflammatory 20 agents. Mechanistically interesting is the inhibition of the release of mediators ofinflammation. Thus, the compounds can be used alone or in combination .with anantiphlogistic agent for the prévention or treatment of chronic and acùte inflammatorydisorders. The combination partners used are advantageously stéroïdal and non-steroidal antiinflammatory agents. 25

Moreover, it has been found that compounds of the formula I exert a bénéficiaiinfluence on sérum lipoproteins. They can therefore be used for the prophylaxie andrégression of atherosclerotic changes by excluding a causal risk factor. This includesnot only primary hyperlipidemias but also certain secondary hyperlipidemias as are 30 encountered, for example, in diabètes. Additionally, the compounds of the formula Ireduce infarcts induced by metabolic anomalies considerably and, in particular, lead toa significant réduction in the size and severity of the infarct induced. 012827 19

Accordingly, the compounds mentioned are used advantageously for preparing amédicament for the treatment of hypercholesterolemia, for preparing a médicament forthe prévention of atherogenesis, for preparing a médicament for the prévention andtreatment of atherosclerosis, for preparing a médicament for the prévention andtreatment of diseases induced by elevated cholestérol levels, for preparing amédicament for the prévention and treatment of diseases induced by endothélialdysfunction, for preparing a médicament for the prévention and treatment ofhypertension induced by atherosclerosis, for preparing a médicament for theprévention and treatment of thromboses induced by atherosclerosis, for preparing amédicament for the prévention and treatment of ischémie damage and post-ischemicreperfusion damage induced by hypercholesterolemia and endothélial dysfunction, forpreparing a médicament for the prévention and treatment of cardiac hypertrophies andcardiomyopathies and congestive heart failure (CHF), for preparing a médicament forthe prévention and treatment of coronary vascospasms and myocardial infarctsinduced £y hypercholesterolemia and endothélial dysfunction, for preparing amédicament for the treatment of the conditions mentioned in combination withhypotensive substances, preferably with angiotensin converting enzyme (ACE)inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor ofthe formula I with an active compound that lowers the lipid concentration in the blood,preferably an HMG-CoA reductase inhibitor (for example lovastatin or pravastatin), thelatter having hypolipidémie action, thereby enhancing the hypolipidémie properties ofthe MHE inhibitor of the formula I, has been found to be a favorable combination withiacreased action and reduced use of active compound.

Thus, compounds of the formula I bring about effective protection against endothélialdamage of various origins. Owing to this protection of the vessels against thesyndrome of endothélial dysfunction, compounds of the formula I are usefulmédicaments for the prévention and treatment of coronary vascospasms, peripheralvascular diseases, in particular intermittent claudication, of atherogenesis andatherosclerosis, of left-ventricular hypertrophy and of dilated cardiomyopathy, and ofthrombotic disorders. 012827 20

Moreover, NHE inhibitors of the formula I are suitable for treating non-insulin-dependent diabètes (NIDDM) where, for example, insulin résistance is suppressed.Here, to enhance antidiabetic efficacy and quality of action of the compoundsaccording to the invention, it may be favorable to combine these compounds with a 5 biguanide such as metformin, with an antidiabetic sulfonylurea, such as glyburide,glimepiride, tolbutamide, etc., a glucosidase inhibitor, a PPAR agonist, such asrosiglitazone, pioglitazone, etc., with an insulin product in a different administrationform, with a DB4 inhibitor, with an insulin sensitizer or with meglitinide. 10 In addition to the acute antidiabetic effects, the compounds of the formula I counteractthe development of late complications of diabètes, and they can therefore be used asmédicaments for the prévention and treatment of diabetic late damage, such asdiabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabeticcardiomyopathy and other disorders which occur as a resuit of diabètes. In this 15 connection, they can be combined advantageously with the antidiabetic médicamentsdescribed above under the NIDDM treatment. A combination with a favorableadministration form of insulin may be of particular importance.

In addition to the protective effects against acute ischémie events and subséquent 20 likewise acute reperfusion events, the NHE inhibitors of the formula I according to theinvention also hâve direct therapeutically useful action against disorders andimpairments of the entire mammalian organism which are associated withmanifestations of the chronically progressing aging process and are also independentof acute States of hypoperfusion, and may also occur under normal, non-ischemic 25 conditions. These pathological age-related manifestations, such as disease, illnessand death, induced over the long time of aging, which are now accessible to treatmentwith NHE inhibitors, are disorders and disturbances caused to a substantial extent byage-related changes in vital organs and their function which become more and moreimportant in the aging organism. 30 Disorders associated with age-related dysfunction and age-related symptoms of wearof organs are, for example, inadéquate responsiveness and reactivity of the bloodvessels to contraction and relaxation reactions. This age-related décliné in vascular 012827 ...... ...... ............ 21......... reactivity to constricting and relaxing stimuli, which are an essential process of thecardiovascular System and thus of life and health, can be significantly diminished orabolished by NHE inhibitors. An important fonction and a measure of the maintenanceof vascular reactivity is the blocking or slowing of the age-related progression of 5 endothélial dysfunction, which can be abolished highly significantly by NHE inhibitors.The compounds of the formula I are thus outstandingly suitable for the treatment andprévention of the age-related progression of endothélial dysfunction, especially ofintermittent claudication. Moreover, the compounds of the formula I are thusoutstandingly suitable for the treatment and prévention of cardiac insufficiency, of 10 congestive heart failure (CHF), and for the treatment and in particular for theprévention of age-related types of cancer.

Considération may likewise be given to combination with hypotensive médicaments,such as with ACE inhibitors, angiotensin receptor antagoniste, diuretics, Ca2+antagoniste, etc., or with metabolism-normalizing médicaments, such as cholesterol- 15 lowerincfeagents. The compounds of the formula I are thus suitable for the prévention ofage-related tissue changes and for prolonging life while maintaining a high quality oflife.

The compounds of the invention are effective inhibitors of the cellular sodium/proton 20 antiporter (Na/H exchanger) which, in numerous disorders (essential hypertension,atherosclerosis, diabètes, etc.), is also elevated in cells which are easily amenable tomeasurements, such as, for example, in érythrocytes, platelets or leukocytes. Thecompounds used according to the invention are therefore suitable as excellent andsimple scientific tools, for example in their use as diagnostic aids for the détermination 25 and différentiation of particular types of hypertension, but also of atherosclerosis, ofdiabètes and of late complications of diabètes, of proliférative disorders, etc. NHE3 inhibitors are furthermore suitable for treating disorders (human and veterinary)caused by bacteria and by protozoa. In the case of disorders caused by protozoa, 30 particular mention may be made of malaria diseases of man and of coccidiosis inpoultry.

Moreover, the compounds are suitable as agents for controlling sucking parasites in 012827 ......... ' ...... 22 human and veterinary medicine and in crop protection. Here, the use as an agentagainst blood-sucking parasites in human and veterinary medicine is preferred.

In addition to their value as potent NHE-inhibitors, their pharmacological properties and5 the absence of undesired biological actions, the compounds of the formula I are also distinguished by favorable pharmacokinetic properties which make their use asmédicament seem particularly advantageous.

The invention thus relates to médicaments for human, veterinary or phytoprotective 10 use which comprise an effective amount of a compound of the formula I and/or apharmaceutically acceptable sait thereof alone or in combination with otherpharmacologically active compounds or médicaments. Médicaments comprising a compound I can be administered, for example, orally, 15 parenterally, iptramuscularly, intravenously, rectally, nasally, by inhalation, subcutaneously or by a suitable transcutaneous administration form, with the preferredadministration being dépendent on the particular appearance of the disorder. Here, thecompounds I can be used alone or together with pharmaceutical excipients, both inveterinary medicine and in human medicine and in crop protection. 20

Excipients suitable for the desired pharmaceutical formulation are familiar to the skilledworker on the basis of his expert knowledge. Besides solvents, gel fôrmérs,suppository bases, tablet excipients and other active ingrédient carriers, it is possibleto use, for example, antioxidants, dispersants, emulsifiers, antifoams, masking flavors, 25 preservatives, solubilizers or colorants.

For a form for oral use, the active compounds are mixed with the additives suitable forthis purpose, such as carriers, stabilizers or inert diluents, and converted byconventional methods into suitable dosage forms such as tablets, coated tablets, two- 30 piece capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers whichcan be used are gum arabic, magnesia, magnésium carbonate, potassium phosphate,lactose, glucose or starch, especially corn starch. Préparation can moreover take place 012827 ......- 23 - both as dry and as wet granules. Examples of suitable oily carriers or solvents arevegetable or animal oils such as sunflower oil or fish liver oil.

For subcutaneous, percutaneous or intravenous administration, the active compounds5 used are converted into a solution, suspension or émulsion, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or otherexcipients. Examples of suitable solvents are: water, physiological saline or alcohols,for example éthanol, propanol, glycerol, and also sugar solutions, such as glucose ormannitol solutions, or else a mixture of the various solvents mentioned. 10

Suitable as pharmaceutical formulation for administration in the form of aérosols orsprays are, for example, solutions, suspensions or émulsions of the active compoundof the formula I in a pharmaceutically acceptable solvent, such as, in particular, éthanolor water, or a mixture of such solvents. 15 The formulation may, if required, also comprise other pharmaceutical excipients suchas surfactants, emulsifiers and stabilizers, and a propellant gas. Such a préparationnormallÿ contains the active compound in a concentration of about 0.1 to 10, inparticular of about 0.3 to 3% by weight. 20 The dosage of the active compound of the formula I to be administered and thefrequency of administration dépend on the potency and duration of action of thecompounds used; also on the nature and severity of the disease to be treàted, and onthe.sex, âge, weight and individual response of the mammal to be treated? 25 On average, the daily dose of the compound of the formula I for a patient weighingabout 75 kg is at least 0.001 mg/kg, preferably 0.1 mg/kg, up to a maximum of30 mg/kg, preferably 1 mg/kg, of body weight. In acute situations, for exampleimmediately after suffering high-altitude breathing disorders, it may even becomenecessary for the dosages to be higher. Especially on i.v. use, for example for an 30 infarct patient in an intensive care unit, up to 200 mg/kg per day may be necessary.

The daily dose can be divided into one or more, for example up to 4, individual doses. 012827 24

Description of the experiments and examples:

If the compounds are enantiomerically pure, the configuration and/or the sign of theoptical rotation is given. If these data are missing, the compounds are racemates or 5 not optically active. 10

The rétention times (Rt) given below refer to LCMS measurements with the followingparameters: *

Analytical methods:

A stationary phase:mobile phase: 15

B stationary phase:mobile phase:

Merck Purospher 3μ 2 x 55 mm 95% H2O (0.1% HCOOH) 95% acetonitrile (0.1%HCOOH); 5 min -» 95% acetonitrile (0.1% HCOOH); 2 min 95% H2O (0.1 % HCOOH); 1 min; 0.45 ml/min. YMC J’sphere H80 ~4// 2.1 x 33 mm 95% H2O (0.1% HCOOH) -» 95% acetonitrile (0.08%HCOOH); 2.5 min -» 95% acetonitrile (0.08% HCOOH); 0.5min -> 95% H2O (0.1% HCOOH); 0.5 min; 1.3 ml/min.

20 C stationary phase:mobile phase:

D 25 stationary phase:mobile phase: YMC J’sphere H80, 4μ, 2.1 x 20 mm - 90% H2O (0.05% TFA) -» 95% acetonitrile; 1.9 min; -» 95% acetonitrile 0.5 min; 1 ml/min.

Merck Purospher 3μ 2 x 55 mm 95% H2O (0.1% HCOOH)-» 95% acetonitrile (0.1%HCOOH); 3.4 min -» 95% acetonitrile (0.1 % HCOOH); 1 min -» 95% H2O (0.1% HCOOH); 0.2 min; 0.75 ml/min.

E 30 stationary phase:

Merck Purospher 3μ 2 x 55 mm 012827 25 95% H2O (0.05% CF3COOH)-» 95% acetonitrile (0.05% CF3COOH); 3.4 min -> 95% acetonitrile (0.05% CF3COOH); 1 min; 0.75 ml/min. YMC J’sphere H80, 4μ, 2.1 x 20 mm 96% H2O (0.05% CF3COOH)-» 95% acetonitrile; 2 min; -»95% acetonitrile 0.4 min; 1 ml/min. mobile phase:

F 5 stationary phasemobile phase:

Préparative HPLC was carried out under the following conditions: 10 stationary phase: Merck Purospher RP18 (10//M) 250 x 25 mm mobile phase: 90% H2O (0.05% TFA)-» 90% acetonitrile; 40 min; 25 ml/min

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

a) 4-Methyl-3-thienyl isothiocyanate : is obtained by reacting equimolar amounts of 3-amino-4-methylthiophene andΝ,Ν’-thiocarbonyldiimidazole in anhydrous tetrahydrofuran (THF) by stirring the 20 reaction mixture at room température for 5 hours and then allowing the mixture tostand at room température ovemight. 4-Methyl-3-thienyl isothiocyanate is isolated bydistillative removal of the solvent under reduced pressure using a rotary evaporator,dissolving the residue in ethyl acetate and washing the organic phase repeatedly withwater. The organic phase is dried over sodium sulfate and the organic solvent is then 25 distilled off under reduced pressure using a rotary evaporator, giving 4-methyl-3-thienylisothiocyanate as a brown oily residue. 4-Methyl-3-thienyl isothiocyanate can be usedwithout further purification. 012827 ----------- -------- '·........26 “" · b) N-(2-Amino-5-fluorophenyl)-N’-(4-methyl-3-thienyl)thiourea0.02 mol of 4-fluoro-1,2-diaminobenzene is added to a solution of 0.02 mol of4-methyl-3-thienyl isothiocyanate in 60 ml of anhydrous THF. The reaction mixture isstirred at room température for 2 hours and then allowed to stand overnight, and the 5 solvent is then distilled off under reduced pressure using a rotary evaporator and theoily residue is purified on a silica gel column using a mixture of identical proportions oftoluene and ethyl acetate.

Brown crystalline solid. M.p. 180°C. 10 c) 3N-(5-Fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride A molar excess (about 1.5 to 4 mol) of methyl iodide is added to 1.5 g (0.0053 mol) ofN-(2-amino-5-fluorophenyl)-N’-(4-methyl-3-thienyl)thiourea in 50 ml of anhydrouséthanol, and the mixture is boiled at reflux for 5 hours. The mixture is allowed to stand 15 at room température overnight and the éthanol is then distilled off under reducedpressure using a rotary evaporator, water is added to the residue and the pH isadjusted to 8-9 using saturated aqueous sodium bicarbonate solution. The mixture isextracted repeatedly with ethyl acetate, the organic phase is washed with water anddried over sodium sulfate, the solvent is distilled off under reduced pressure using a 20 rotary evaporator and the residue is purified by silica gel column chromatography usinga solvent mixture of identical proportions of ethyl acetate and toluene (he/einbelowreferred to as “mixture 2”) as mobile phase. The oily product obtained after distillativeremoval of the organic solvent is dissolved in ethyl acetate and made highïy acidicusing a saturated solution of hydrogen chloride in dry diethyl ether, and the precipitate 25 that crystallizes out is, after relatively long standing, filtered off. Crystalline solid, m.p.192+/-2°C.

Example 2: 2-Chloro-3N-(5-fluoro-2-benzimidazoly,)-4-methyl-3-thienylamine hydrochloride and 2,5-dichloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl- 30 3-thienylamine hydrochloride 012827 27 x HCl

xHCI

A solution of 0.24 g (0.0018 mol) of N-chlorosuccinimide in 15 ml of glacial acetic acidis added dropwise to a solution of 0.5 g (0.0018 mol) of 3N-(5-fluoro-2-benzimidazolyl)- 5 4-methyl-3-thienylamine hydrochloride in 25 ml of glacial acetic acid, the reactionmixture is stirred at room température for about 2 to 3 hours and the solvent is distilledoff under reduced pressure using a rotary evaporator. Water is added to the residueand the mixture is then made alkaline using 2N NaOH and extracted with ethyl acetate,the organic phase is washed with water and dried over sodium sulfate and the solvent 10 is distilled off under reduced pressure using a rotary evaporator. The resulting oilyresidue is, by medium pressure column chromatography, using a solvent mixture of20 parts^of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid(hereinbelow referred to as “mixture 17”) as mobile phase, separated and treatmentwith a solution of hydrogen chloride gas gives:. 15 2-chloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride fromfraction 1 and 2: colorless to slightly yellowish crystalline product, m.p. 200-202°C, 2,5-dichloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloridefrom fraction 3: colorless to slightly yellowish crystalline product, m.p. 286-288°C. 20 Example 3: 3N-(5,6-Dichloro-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride

a) N-(2-Amino-4,5-dichlorophenyl)-N’-(4-methyl-3-thienyl)thiourea25 is obtained analogously to the reaction described in example 1 b) from 4-methyI- 012827 ............... ..........28 ' 3-thienyl isothiocyanate and 4,5-dichloro-1,2-diaminobenzene. Crystalline solid,m.p. 310-320°C. b) 3N-(5,6-Dichloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride5 is obtained analogously to the procedure described in example 1 c) from N-(2-amino- 4,5-dichlorophenyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide.

Crystalline solid, m.p. 290-294°C.

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

a) N-(2-Aminophenyl)-N’-(4-methyl-3-thienyl)thiourea % is obtained analogously to the reaction described in example 1 b) from 4-methyl- 3-thienyl isothiocyanate and 1,2-diaminobenzene. Crystalline solid having a 1st m.p. of177-182°C, followed by another crystallization and 2nd m.p. 285-290°C. b) 3N-(2-Benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the procedure described in example 1 c) from

N-(2-aminophenyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide. J

Ciystalline solid following recrystallization from ethyl acetate/ethanol, m.p.194-200°C.

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

a) 3-Fluoro-1,2-diaminobenzene is obtained as an oily amorphous product by hydrogénation of 3-fluoro-2-nitrophenyl25 hydrazine (prepared by reaction of 2,6-difluoronitrobenzene with hydrazine hydrate)

27 29 using hydrogen and 10% palladium on carbon catalyst in methanol at roomtempérature and atmospheric pressure. b) N-(2-Amino-3-fluorophenyl)-N’-(4-methyl-3-thienyl)thiourea 5 is obtained analogously to the réaction described in example 1 b) from 4-methyl- 3-thienyl isothiocyanate and 3-fluoro-1,2-diaminobenzene. Crystalline solid, point ofdécomposition > 240°C. c) 3N-(-4-Fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 10 is obtained analogously to the procedure described in example 1 c) from N-(2-amino-3-fluorophenyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide. Amorphousprecipitate which crystallizes under acetone. Crystalline solid, m.p. 220-230°C.

Example 6: 3N-(4,6-Difluoro-2-benzimidazolyl)-4-methyl-3-thienylamine 15 hydrochloride a) N-(2-Amino-3,5-difluorophenyl)-N’-(4-methyl-3-thienyl)thiourea is Obtained analogously to the réaction described in example 1 b) from 4-methyl-20 3-thienyl isothiocyanate and 3,5-difluoro-1,2-diaminobenzene. Crystalline solid, 1 st melting point: 178-182°C, another crystallization with 2nd m.p.: 299-301 °C. b) 3N-(4,6-Difluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the procedure described in example 1 c) from N-(2-amino-25 3,5-difluorophenyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide. Amorphous precipitate which crystallizes under ethyl acetate. Crystalline solid, m.p. 232-234°C. 012827 -.............................. 7'......;·..... ......; :r....... 30...........~.........................

Example 7: 3N-(4,5,6,7-Tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride

5 a) N-(2-Amino-3,4,5,6-tetrafluorophenyl)-N’-(4-methyl-3-thienyl)thioureais obtained analogously to the reaction described in example 1 b) from 4-methyl- 3-thienyl isothiocyanate and 3,4,5,6-tetrafluoro-1,2-diaminobenzene. Crystalline solid,m.p.: 286-290°C. 10 b) 3N-(3,4,5,6-Tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride S J. :. is obtained analogously to the procedure described in example 1 c) from N-(2-amino-3,4,5,6-tetrafluorophenyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide.Amorphous precipitate which crystallizes under ethyl acetate. Crystalline solid, 15 m.p. 225-228°C.

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

20 a) N-(2-Amino-3-methylphenyl)-N’-(4-methyl-3-thienyl)thiourea is obtained analogously to the reaction described in example 1 b) from 4-methyl- 3-thienyl isothiocyanate and 3-methyl-1,2-diaminobenzene. Crystalline solid, m.p.184-186°C, 25 b) 3N-(4-Methyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 012827 31 is obtained analogously to the procedure described in example 1 c) from N-(2-amino-3-methylphenyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide. Amorphousprecipitate which crystallizes under acetone. Crystalline solid, point of décomposition:320°C.

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

xHCI a) trans-N-(2-Aminocyclohexyl)-N’-(4-methyl-3-thienyl)thiou rea (racemate)is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyNsothiocyanate and racemic trans-1,2-diaminocyclohexane. Crystalline solid,m.p. 205-210°C, b) trans-3N-(3a,4,5,6,7,7a-Hexahydro-1H-2-benzimidazolyl)-4-methyI-3-thienylamine hydrochloride (racemate) 0.6 g of racemic trans-N-(2-aminocyclohexyl)-N’-(4-methyl-3-thienyl)thiourea issuspended in 60 ml of toluene and dissolved by heating at 90°C. The mixture isallpwed.to cool to 70°C, a solution of 0.376 g of dicyclohexylcarbodiimide jn 5 ml ofanhydrous toluene is added dropwise and the mixture is stirred for a total of about10 hours at 70°C and for 2-3 days at room température. The crystalline solid is filteredoff, the solvent is removed under reduced pressure using a rotary evaporator and theresulting oily residue is dissolved in a little ethyl acetate. Following addition of ananhydrous solution of hydrogen chloride in diethyl ether, a viscous precipitate isformed which, after addition of a little éthanol, crystallizes. Crystalline solid,m.p.: 261-264°C. 012827 32

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

xHCI

S 5 a) trans-R,R-N-(2-Aminocyclohexyl)-N’-(4-methyl-3-thienyl)thiourea is obtained analogously to the reaction described in example 1 b) from 4-methyl- 3- thienyl isothiocyanate and trans-R,R-1,2-diaminocyciohexane by séparation by silicagel column chromatography, eluting with a solvent mixture consisting of 10 parts ofethyl acetate, 5 parts of n-heptane, 5 parts of methylene chloride, 5 parts of methanol 10 and 1 part of 26% strength aqueous ammonia (hereinbelow referred to as “mixture 4”),as an amorphous oily product in addition to a crystalline product having a highermolecular weîght of m.p. 94-100°C.

The amorphous product is processed further without further purification. 15 trans-R,R-N-(3a,4,5,6,7,7a-Hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride is obtained analogously to the procedure described in example 1 c) by reactingR,R-N-(2-aminocyclohexyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide inahhydrous éthanol as solvent and reaction medium. Amorphous precipitate which is 20 chromatographed on silica gel using mixture 4 as mobile phase and crystallized underacetone. Crystalline solid, m.p. 235-238°C.

Example 11 : trans-S,S-3N-(3a,4,5,6,7,7a-Hexahydro-1 H-2-benzimidazolyl)- 4- methyl-3-thienylamine hydrochloride x HCl 25 012827 33 a) trans-S,S-3N-(2-Aminocyclohexyl)-N’-(4-methyl-3-thienyl)thiourea is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and trans-S,S-1,2-diaminocyclohexane by séparation by silica 5 gel column chromatography using mixture 4 as mobile phase, as an amorphous oilyproduct in addition to a product of higher molecular weight of m.p. 94-102°C.

The amorphous product is processed further without further purification. b) trans-S,S-N-(3a,4,5,6,7,7a-Hexahydro-1 H-2-benzimidazolyl)-4-methyl- 10 3-thienylamine hydrochloride is obtained analogously to the procedure described in example 1 c) by reacting S,S-N-(2-aminocyclohexyl)-N’-(4-methyl-3-thienyl)thiourea and methyl iodide inanhydrous éthanol as solvent and reaction medium. Amorphous precipitate which ischromatographed on silica gel using mixture 4 as mobile phase and crystallizes under 15 acetone^ Crystalline solid, m.p. 225-230°C.

Examplè 12: 2-Chloro-3N-(2-benzimîdazolyl)-4-methyl-3-thienylamine hydrochlorideand 2,5-dichloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

xHCI

xHCI 20 are obtained analogously to the procedure described in example 2 from3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimidein glacial acetic acid. Column chromatography on silica gel using mixture 17 as mobilephase results in the séparation of 2,5-dichloro-3N-(2-benzimidazolyl)-4-methyl- 25 3-thienylamine hydrochloride (colorless crystalline compound, m.p.: 291 °C) from2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride (colorlesscrystalline compound, m.p. 257-259°C). 012827 ............................~.....Λ~'7';............---34^ ........--

Example 13: 2-Chloro-3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride

5 is obtained analogously to the procedure described in example 2 from 3N-(4-methyl- 2- benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide inglacial acetic acid. Following column chromatography on silica gel using mixture 17 asmobile phase, 2-chloro-3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride is obtained as a colorless to slightly yellowish crystalline product. 10 M.p. 255-259°C. $

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

is obtained analogously to the procedure described in example 2: from 3N-(4,5,6,7-tetrafluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride andN-chlorosuccinimide in glacial acetic acid. Crystalline product. M.p. 233-235°C. 012827 ..... ......... ......... : ........... .......:· -...... 35 .......-................ ............. ...... .....' '

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

5 is obtained analogously to the procedure described in example 2: from3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride (racemate) and N-chlorosuccinimide in glacial acetic acid. Crystallineproduct M.p. 258-260°C. 10 Example 16: trans-R,R-2-Chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benz-imidazolyl)-4-methyl-3-thienylamine hydrochloride and trans-R,R-2,5-dichloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride

15 are obtained analogously to the procedure described in example 2: from trans- R,R-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride and N-chlorosuccinimide in glacial acetic acid following chromatographieséparation of the two crystalline products in the following order. a) trans-R,R-2,5-dichloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)- 20 4-methyl-3-thienylamine hydrochloride, décomposition with foaming starting at 80°C, b) trans-R,R-2-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)- 4-methyl-3-thienylamine hydrochloride, crystalline product. M.p. 260-262°C. 012827 36

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

xHCI

5 is obtained analogously to the procedure described in example 2: from trans-S,S-3N-(3a,4>5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride and N-chlorosuccinimide in glacial acetic acid following chromatographieséparation. Colorless crystalline product, m.p. 258-260°C. 10 Example 18: 2-Bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochlorideand 2,5-dibromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride

xHCI

Br are obtained analogously to the procedure described in example 2: fronrv3I^-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-bromosuccinimide 15 (instead of N-chlorosuccinimide) in glacial acetic acid. Following column chromatography on silica gel using a mixture of 5 parts of dichloromethane, 3 parts ofn-heptane, 1 part of glacial acetic acid and 1 part of éthanol (hereinbelow referred toas “mixture Γ) as mobile phase and treatment with a solution of hydrogen chloride gasin ether, 2-bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride, a 20 crystalline product of m.p. 228-231 °C, and 2,5-dibromo-3N-(2-benzimidazolyl)- 4-methyl-3-thienylamine hydrochloride, a crystalline product of m.p. 208-210°C, areobtained by fractional crystallization in ethyl acetate. 012827 37

Example 19: trans-R,R-2-Bromo-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benz-imidazolyl)-4-methyl-3-thienylamine hydrochloride and trans-R,R-2,5-dibromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride x HCl

xHCI

Br are obtained analogously to the procedure described in example 19: fromtrans-R,R-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thieny,aminehydrochloride and N-bromosuccinimide in glacial acetic acid. Following column 10 chromatography on silica gel using mixture 1 as mobile phase, and treatment with a solution of hydrogen ch,onde gas in ether, trans-R,R-2-bromo- « 3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylaminehydrochloride, crystalline product, m.p. 215-218°C and trans-R,R-2,5-dibromo-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazoly,)-4-methyl-3-thienylamine 15 hydrochloride, crystalline product, m.p. 218-220°C are obtained following fractionalcrystallization in ethyl acetate.

Example 20:3N-(4-Ch,oro-2-benzimidazoly,amino)-4-methylthiophene hydrochloride 20 a) N-(2-Amino-3-ch,orophenyl)-N‘-(4-methyl-3-thienyl)thioureais obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3-chloro-1,2-diaminobenzene (prepared by catalytichydrogénation of 3-chloro-2-nitroaniline using Pt on activated carbon under 25 atmospheric pressure at room température). Crystalline solid, m.p. 298-305°C, 012827 38 b) 3N-(4-Chloro-2-benzimidazolylamino)-4-methylthiophene hydrochlorideis obtained analogously to the procedure described in example 1 c) from N-(2-amino-3-chlorophenyl)-N‘-(4-methyl-3-thienyl)-thiourea and methyl iodide. Amorphous

5 precipitate which crystallizes under ethyl acetate. Crystalline solid, point ofdécomposition 240-245°C

Example 21:2-Chloro-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophenehydrochloride

is obtained analogously to the procedure described in example 2 from 3N-(4-chloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride and N-chlorosuccinimide inglacial acetic acid. Following silica gel coiumn chromatography using a mixture of 10parts of methylene chloride and 1 part of methanol as mobile phase, 2-chloro-3N- 15 (4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride is, after crystallization under ethyl acetate, obtained as a colorless to slightly yellowish solid.M.p. 270-272°C.

Exâmple 22: 2-Bromo-3N-(4-chloro-2-benzimidazolylamino)-4-methÿlthiôphene 20 hydrochloride

is obtained analogously to the procedure described in example 2 from 3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride and N-bromosuccinimide 25 (instead of N-chlorosuccinimide) in glacial acetic acid. Following silica gel coiumn chromatography using a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 012827 39 3 parts of glacial acetic acid as mobile phase and treatment with a solution of hydrogenchloride gas in ether, 2-bromo-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene hydrochloride is obtained by fractionated crystallization in ethylacetate in the presence of hydrogen-chloride-saturated ether. Crystalline product of

5 m.p. 278-280°C

Example 23: (2-Bromo-4-methylthiophene-3-yl)-(5-fluoro-1 H-benzoimidazol-2-yl)amine hydrochloride

10 (5-Fluoro-1 H-benzimidazol-2-yl)-(4-methylthiophene-3-yl)amine (300 mg) (example 1 )was dissolved in glacial acetic acid (50 ml). At room température, N-bromosuccinimide(207 mgj dissolved in glacial acetic acid (10 ml), was slowly added dropwise, withvigorous stirring. After the addition had ended, stirring was continued for another10 min and the glacial acetic acid was then distilled off under reduced pressure, and 15 the residue was dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The organic phase was dried over magnésium sulfate, filtered andconcentrated. The residue was purified by préparative chromatography and theproduct-containing fractions were combined, freed from acetonitrile, made basic andextracted three times with ethyl acetate. The organic phases were combined, dried 20 (MgSO4) and filtered. Following removal of the solvent under reduced pressure, waterand 2N hydrochloric acid were added to the residue and the mixture was freeze-dried.This gave 245 mg of the desired product. LCMS-Rt (B): 0.95 minMS (ES+, M+H+): 326.09 25 012827 40

Example 24:2-Bromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophenehydrochloride and 2,5-dibromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methyl-thiophene hydrochloride

F

xHCI

F

xHCI

Br A solution of 0.161 g of N-bromosuccinimide in 6 ml of glacial acetic acid is added to asolution of 0.214 g of 3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophenehydrochloride in 6 ml of glacial acetic acid, and the mixture is stirred at roomtempérature for 30 minutes. After removal of the solvent by distillation, water is added 10 to the residue and the mixture is made alkaline using 2N NaOH and extracted withethyl acetate. The organic phase is dried, the solvent is distilled off and the residue isseparated by silica gel column chromatography using a mixture of 20 parts of ethylacetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. The hydrochlorides ofthe two compounds are obtained by distilling off the fractionated solutions, dissolving 15 the residue in ethyl acetate and precipitating the product by addition of hydrogen-chloride-saturated diethyl ether. Crystallization was promoted by gentle warming.Example 24a: 2-Bromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophenehydrochloride: colorless crystals; m.p. 212°C (décomposition).

Example 24b: 2,5-Dibromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene 20 hydrochloride: colorless crystals; m.p. 242-244°C (décomposition).

Example 25: 3N-(5-Methoxy-2-benzimidazolylamino)-4-methylthiophene H, 25 a) N-(2-Amino-4-methoxyphenyl)-N‘-(4-methyl-3-thienyl)thiourea A mixture of 5.89 g of 4-methylthiophene 3-isothiocyanate and 5 g of 4-methoxy- 1,2-diaminobenzene in 60 ml of anhydrous THF is stirred at room température for 012827 41 2 hours, and the solvent is distilled off. Water is added to the residue, the mixture isextracted with ethyl acetate, the dark solution is treated with activated carbon and theorganic solvent is re-evaporated. With gentle warming, the residue is treatedrepeatedly with diisopropyl ether and the solid is filtered off. Brown crystalline solid, 5 m.p. 143-146°C. b) A mixture of 2.83 g of N-(2-amino-4-methoxyphenyl)-N‘-(4-methyl-3-thienyl)thiourea,8.5 g of methyl iodide , and 100 ml of anhydrous éthanol is boiled under reflux for5 hours, and the solvent is then distilled off and water is added to the residue. Using 10 2N aqueous sodium hydroxide solution, the mixture is made alkaline and thenextracted with ethyl acetate, the organic phase is treated with water and then withactivated carbon and the product is purified by silica gel column chromatography usinga mobile phase mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 partsof glacial acetic acid. This gives 3N-(5-methoxy-2-benzimidazolylamino)-4- 15 methylthiophene as an amorphous product.

Exemple 26:3N-(5-Methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

xHCI

20 isôbtained by precipitating a solution of 0.2 g of 3N-(5-methoxy-2-benzimîdazolyl-amino)-4-methylthiophene (example 25) in 10 ml of ethyl acetate using a saturatedsolution of hydrogen chloride gas and diethyl ether, giving a crystalline precipitate.M.p.: 222-225°C 012827 -7 42 -.....;.....:

Example 27:2-Chloro-3N-(5-methoxy-2-benzimidazolylamino)-4-methylthiophenehydrochloride

5 For about 2 to 2½ hours, a mixture of 0.519 g of 3N-(5-methoxy-2-benzimidazolyl-amino)-4-methylthiophene hydrochloride, 0.046g of N-chlorosuccinimide and 10-15 mlof glacial acetic acid is heated at 45°C. 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 10 is chromatographed on silica gel on a medium-pressure column using a mixture of20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. Thebase obtained after removal of the solvent by distillation is, in ethyl acetate, convertedinto the hydrochloride using saturated etheral hydrogen chloride solution, and theproduct is crystallized under ethyl acetate. Crystalline solid m.p.: 182-186°C. 15

Example 28: 2,5-Dichloro-3N-(5-methoxy-2-benzimidazolylamino)-4-methylthiophenehydrochloride

20 Analogous work-up of a reaction mixture of 3N-(5-methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride, N-chlorosuccinimide and glacial acetic acid for about 2to 2½ hours at 55°C gave 2,5-dichloro-3N-(5-methoxy-2-benzimidazolylamino)- 4-methylthiophene. Crystalline solid, m.p.: 278-282°C. 012827 ....... ........ ..........-.......-..................-....................... ........ 43 :.............- .............................

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

a) 3-Methoxy-1,2-diaminobenzene was obtained as a brown oil by hydrogénation of 2-methoxy-6-nitroaniline using5 hydrogen gas and Raney nickel as catalyst at room température and a pressure of 3 bar. The product was converted into the thiourea without further purification. b) N-(2-Amino-3-methoxyphenyl)-N‘-(4-methyl-3-thienyl)thiourea is obtained analogously to the procedure described in example 25 a) from 3-methoxy- 1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF, followed 10 by medium-pressure chromatography on silica gel using a mixture of 1 part of tolueneand 1 part of ethyl acetate. Crystalline solid, m.p.: 148-153°C. Solidification of the meltand next m.p/àt 260°C. c) 3N-(4-Methoxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride 15 is obtained analogously to the procedures described in examples 25 and 26 from N-(2-amino-3-methoxyphenyl)-N‘-(4-methyl-3-thienyl)thiourea by heating with methyliodide in THF, analogous work-up and treatment of the benzimidazole with HCl inether. :

Crystalline solid, m.p.: 230-235°C. 20

Example 30:2-Chloro-3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophenehydrochloride

0128 2 7 44 A mixture of 0.1 g of 3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophenehydrochloride, 0.046 g of N-chlorosuccinimide and 10-15 ml of glacial acetic acid isheated at 40°C for about 2 to 2½ hours. The glacial acetic acid is then distilled off,water is added to the residue and the pH is adjusted to 9-10 using 2N NaOH. The 5 mixture is extracted with ethyl acetate, the solvent is evaporated and the residue ischromatographed on silica gel on a medium-pressure column using a mixture of20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial acetic acid. Theresulting base is, in ethyl acetate, converted into the hydrochloride using saturatedetheral hydrogen chloride solution. Colorless to light-yellow crystalline solid, m.p.: 10 248-250°C.

Example 31: 3N-(4-Chloro-6-trifluoromethyl-2-benzimidazolylamino)-4-methyl-thiophene hydrochloride

Cl

xHCI 15 a) N-(2-Amino-3-chloro-5-trifluoromethylphenyl)-N‘-(4-methyl-3-thienyl)thioureais obtained analogously to the procedure described in example 25 a) by reacting3-chloro-5-trifluoromethyl-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate inanhydrous THF at room température for 3 days. The solvent is distilled off and water isadded to the residue, and the mixture is then extracted with ethyl acetate, the solvent 20 is again distilled off and the amorphous residue is crystallized under diisopropyl ether.M.p.:>310°C. b) 3N-(4-chloro-6-trifluoromethyl-2-benzimidazolylamino)-4-methylthiophenehydrochloride 25 is obtained analogously to the procedures described under examples 25 and 26 fromN-(2-amino-3-chloro-5-trifluoromethylphenyl)-N‘-(4-methyl-3-thienyl)thiourea by boilingwith methyl iodide in THF under reflux conditions for 5 hours, analogous work-up andpurification by medium-pressure silica gel column chromatography using a mixture ofidentical parts by volume of ethyl acetate and toluene. The solvent is evaporated and 012827 ......................... ......45......'........~........ the residue is then dissolved in ethyl acetate, giving, by addition of a saturated solutionof hydrogen chloride in diethyl ether, 3N-(4-chloro-6-trifluoromethyl-2-benzimidazolyl-amino)-4-methylthiophene hydrochloride as a crystalline precipitate. Solid, m.p.: 210-213°C. 5

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

A mixture of 0.34 g of 3N-(4-methoxy-2-benzimidazolylamino)-4-methylthiophene 10 hydrochloride, 0.151 g of N-chlorosuccinimide and 20 ml of glacial acetic acid is stirredat room température for H hour and heated at 60°C for one hour. The glacial aceticacid is then distilled off, water is added to the residue and the pH is adjusted to 9-10using 2N NaOH. The mixture is extracted with ethyl acetate, the solvent is evaporatedand the residue is chromatographed on silica gel on a medium-pressure column using 15 a mixture of identical parts of toluene and ethyl acetate. The solvent is distilled off andthe resulting base is then, in ethyl acetate, converted into the hydrochloride usingsaturated etheral hydrogen chloride solution,. Colorless to light-yellow crystalline solid.mp.: 247-250°C. 20 Example 33:3N-(4-Carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride

a) N-(2-Amino-3-carboxyphenyl)-N‘-(4-methyl-3-thienyl)thiourea is obtained analogously to the procedure described in example 25 a) from 3-carboxy- 1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF, followed 25 by medium-pressure chromatography on silica gel using a mixture of 12 parts ofmethylene chloride and 1 part of methanol. Amorphous product. 012827 46 b) 3N-(4-Carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochlorideis obtained by boiling a solution of 1.12 g of N-(2-amino-3-carboxyphenyl)-N‘-(4-methyl-3-thienyl)thiourea and 3.1 g of methyl iodide in 60 ml of éthanol under 5 reflux. The solvent is evaporated, water is added to the residue, the pH is adjusted to 5using 2N aqueous HCl and the precipitate is filtered off. Crystalline solid, point ofdécomposition: 265-285°C.

Example 34: 2-Chloro-3N-(4-carboxy-2-benzimidazolylamino)-4-methylthiophene 10 hydrochloride is obtainfed analogously to the procedure described in example 32 from 0.2 g of 3N-(4-carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride and 0.103 g ofN-chlorosuccinimide in 20-25 ml of glacial acetic acid and précipitation of the 15 corresponding hydrochloride using HCI-saturated diethyl ether in ethyl acetate andsubséquent crystallization under diisopropyl ether and ethyl acetate. Point ofdécomposition 170°C.

Exa'mple 35: 3N-[4-(1 -Piperidinocarbonyl)-2-benzimidazolylamino]-4-methylthiophene 20 hydrochloride 0.215g of Ν,Ν’-carbonyldiimidazole is added to a mixture of 0.330 g of 3N-(4-carboxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride, 30 ml of anhydrous THFand 5 ml of anhydrous dimethylacetamide. The mixture is stirred at room température 012827 47 for about 4 hours, when the évolution of carbon dioxide has ceased, and 0.411 g ofpiperidine is then added. The solution is stirred at room température for 2 hours and,after standing overnight, the solvent is distilled off under reduced pressure. Theresidue is triturated with water, the solid is filtered off and dissolved in ethyl acetate, 5 the insoluble fraction is removed by filtration and the solvent is distilled off underreduced pressure. Foam-like amorphous product.

Example 36: 2-Chloro-4-methyl-3N-[4-(1 -piperidinocarbonyl)-2-benzimidazolylamino]-thiophene hydrochloride 10

cr S A mixture of 0.2 g of 3N-[4-(1 -piperidinocarbonyl)-2-benzimidazolylamino]-4-methyl-thiophene hydrochloride and 0.086g of N-chlorosuccinimide in about 20 ml of glacialacetic acid is stirred at room température for 1½ hours and at 35°C for about 30 min,the solvent is distilled off and the residue is, after addition of water, made alkaline 15 using 2N NaOH. Following extraction with ethyl acetate, the solvent is evaporated and the residue is purified by medium-pressure silica gel column chromatography using amixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of jglacial aceticacid. The solvent is distilled off, the residue is dissolved in ethyl acetate and themixture is acidified using a solution of ether saturated with hydrogen chloride. The 20 amorphous residue is crystallized under a mixture of ethyl acetate with a little acetoneand a little éthanol. Amorphous solid, point of décomposition from 100°C. 012827 48

Example 37: 2-Chloro-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophenehydrochloride

cr s

xHCI 5 0.132 g of N-chlorosuccinimide is added to 0.234 g of 3N-(4-fluoro-2-benzimidazolyl- amino)-4-methylthiophene hydrochloride in about 20 ml of glacial acetic acid and themixture is stirred at room température for 30 minutes and at 50-60°C for another1½ hours. The acetic acid is distilled off under reduced pressure, water is then addedto the residue and the pH is adjusted to about 10-11 using 2N NaOH, and the mixture 10 is extracted with ethyl acetate, which is then distilled off. The residue is chromatographed on a silica gel column under medium-pressure conditions using amixture ôf 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacial aceticacid. After concentration, the residue is dissolved in a little ethyl acetate and thehydrochloride is precipitated by addition of hydrogen-chloride-saturated diethyl ether. 15 Colorless to light-yellow crystalline solid. M.p.: 268-270°C.

Example 38: 2-Ghloro-3N-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophenehydrochloride

xHCI 20 A suspension of 0.13 g of 2-chloro-3N-(4-methoxy-2-benzimidazolylamino)-4-methyl-thiophene hydrochloride in about 20 ml of anhydrous methylene chloride is added to asuspension of 0.29 g of activated anhydrous aluminum chloride in 10 ml of anhydrousmethylene chloride, and the reaction mixture is stirred at 55°C for 2 hours. After 25 cooling, the reaction mixture is poured into ice-water and extracted with ethyl acetate,the organic phase is dried over sodium sulfate and the solvent is distilled off. The 012827 .......;..... ......................................;.......'........;...........49................................... .....r.....; ..... ..... ; : residue is chromatographed on a silica gel column under medium-pressure conditionsusing a mixture of 20 parts of ethyl acetate, 10 parts of n-heptane and 3 parts of glacialacetic acid, and the eluate is concentrated under reduced pressure. The residue isdissolved in ethyl acetate and the hydrochloride is precipitated by addition of 5 hydrogen-chloride-saturated diethyl ether. Crystalline solid. M.p. 246-248°C.

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

is obtained by adding 2N NaOH to a solution of 3 g of 2-chloro-3N-(2-benzimidazolyl-10 amino)-4-methylthiophene hydrochloride in 200 ml of water until a pH of 10 is set. The crystals are filtered off and washed repeatedly with water. Yield: 2.52 g. Colorless crysta, powder. M.p. 182-185°C. s . ' J ....

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

0.25 g of 2-chloro-3N-(2-benzimidazoly,amino)-4-methylthiophene is dissolved in 10 mlof éthanol, 0.1 ml of 48% strength HBr is then added and the mixture is sfirred at roomtempérature for a little while. The solvent is distilled off and the residue is crystallizedunder ethyl acetate. Yield: 0.29 g. Colorless crystals, point of décomposition: 20 252-254°C. 012827 50

Example 41:2-Chloro-3N-(2-benzimidazolylamino)-4-methylthiophene adipic acid sait

/COOH

X HOOC is obtained analogously to the procedure described in example 40 from 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene using one équivalent of adipic acid.Colorless crystals. M.p. 155-157°C.

Example 42: 2-Chloro-3N-(2-benzimidazolylamino)-4-methylthiophene oxalic acid sait

COOH 10 is obtained analogously to the procedure described in example 40 by reacting 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene with one équivalent of oxalicacid in ethyl acetate. Colorless crystals. M.p.: 220-222°C.

Example 43: 2-Chloro-3N-(2-benzimidazolylamino)-4-methylthiophene phosphoric acid 15 sait

is obtained analogously to the procedure described in example 40 from 2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene using one équivalent of phosphoric acid.Colorless crystals. Décomposition range: 113-175°C. 20

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

Λ

Cl 012827 51

Finely powdered dry potassium carbonate (66 mg) was added to a solution of 2-ch!oro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine (125 mg, from example 39) and drymethanol (20 ml). Methyl iodide (74 mg) was then added dropwise with exclusion ofmoisture and vigorous stirring, and the mixture was kept under reflux for three days. 5 The solvent was removed under reduced pressure and the residue was then partitioned between ethyl acetate and water, the ethyl acetate phase was dried withmagnésium sulfate, the magnésium sulfate was filtered off and the filtrate wasevaporated to dryness. The product was then purified by préparative HPLC. Theproduct-containing fractions were combined and, after removing the acetonitrile under 10 reduced pressure, freeze-dried. For further purification, the product was finallychromatographed on siiica gel using ethyl acetate/heptane (1/4). The product-containing fractions were combined and then evaporated to dryness, and the residuewas taken up in HCl and freeze-dried. This gave 5 mg of a solid. LCMS-Rt (A): 2.04 min 15 MS (ESt, M+H+): 278.05

Example 45: (5,6-Difluoro-1 H-benzimidazol-2-yl)-(4-methylthiophen-3-yI)aminetrifluoroacetic acid sait

20 3-lsothiocyanato-4-methylthiophene (1.08 g), dissolved in absolute tetrahydrofuran(30 ml), was added dropwise to a solution of 1,2-diamino-4,5-difluorobenzene (1 g ) inabsolute tetrahydrofuran (20 ml). The mixture was then stirred at room température for2 hours and allowed to stand ovemight. Methyl iodide (0.44 ml) was added and the 25 mixture was then stirred for 8 hours and allowed to stand ovemight. The tetrahydro-furan was then removed under reduced pressure, the residue was partitioned betweenethyl acetate and water, the phases were separated and the ethyl acetate phase wasdried over magnésium sulfate. The residue was absorbed under siiica gel andchromatographed on siiica gel using the mobile phase n-heptane : ethyl acetate = 1:1. 012827 52

This gave 229 mg of the desired compound as the free base.

An impure fraction from the above chromatography was purified by préparative HPLC.Following freeze-drying, 42.2 mg of the desired compound were isolated astrifluoroacetic acid sait. 5 LCMS-Rt (A): 1.98 minMS (ES+, M+H+): 266.13

Example 46: (2-Chloro-4-methyithiophen-3-yl)-(5,6-difluoro-1 H-benzoimidazol-2-yl)amine hydrochloride 10

HCl

At room température, a solution of N-chlorosuccinimide (124.6 mg) in glacial aceticacid (5 ml) was added dropwise to a solution of (5,6-difluoro-1 H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine (225 mg) in glacial acetic acid (5 ml). The mixture was then 15 stirred at room température for 3.5 hours. The glacial acetic acid was then removedand the residue was taken up in water and adjusted to pH 10 using 2 M aqueoussodium hydroxide solution. The aqueous phase was extracted three times with ethylacetate, the combined organic phases were dried over magnésium sulfate and thesolvent was removed. The residue was purified by préparative chromatography and 20 thêproduct-containing fractions were combined, freed from acetonitrile, made basicand extracted three times with ethyl acetate. The organic phases were combined, dried(MgSO4), filtered and concentrated. The residue was taken up in water, acidified with10% strength hydrochloric acid and freeze-dried. This gave 81 mg of the desiredproduct as a solid. 25 LCMS-Rt (A): 2.15 minMS (ES+, M+H+): 300.11 012827 53

Example 47: (2-Bromo-4-methylthiophen-3-yl)-(5,6-difluoro-1 H-benzoimidazol-2-yl)- amine 5 At room température, a solution of N-bromosuccinimide (8 mg) in glacial acetic acid(0.5 ml) was added dropwise to a solution of (5,6-difluoro-1 H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine trifluoroacetic acid sait (15 mg, example 45) in glacialacetic acid (0.5 ml) in a ReactiVial, and the mixture was stirred at room température for0.5 h. The acetic acid was then removed under reduced pressure and saturated 10 potassium carbonate solution and ethyl acetate were added to the residue. Theorganic phase was removed and the aqueous phase was then extracted twice withethy, acetate. The combined organic phases were dried using magnésium sulfate andthe drying agent was then filtered off. The residue that remained after removal of thesolvent under reduced pressure was purified by préparative chromatography. The 15 product-containing fractions were combined and freed from acetonitrile, saturated sodium bicarbonate solution was added to the residue and the mixture was extractedthree times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. After removal of the ethyl acetate under reduced pressure, the residue wascoevaporated with toluene and then dried under high vacuum. This gave 13.1 mg of the 20 desired compound. LCMS-Rt (D): 1.45 minMS (ES+, M+H+): 343.96 012827 54

Example 48: [(2-Chloro-4-methylthiophen-3-yl)-(4,5,6,7-tetrahydro-1 H-benzimidazol-2- yl)]amine hydrochloride a) 1,4-Dioxaspiro[4.5]dec-6-ylamine

10

The amine required as precursor was prepared in accordance with GB1131191.2-Chlorocyclohexanone was reacted with phthalimide to give 2-(2-oxocyclo-hexyl)isoindole-1,3-dione, which was ketalized with ethylene glycol in the presence ofpara-toluenesulfonic acid, giving 2-(1,4-dioxaspiro[4.5]dec-6-yl)isoindole-1,3-dione.Treatment with hydrazine hydrate to remove the phthalimideradical gave the desired1,4-dioxaspiro[4.5]dec-6-ylamine. b) 1-(1,4-Dioxaspiro[4.5]dec-6-yl)-3-(4-methylthiophen-3-yl)thiourea

15 A solution of 3-isothiocyanato-4-methylthiophene (296.2 mg, see exampte 1a) inabsolute tetrahydrofuran (10 ml) was added dropwise to a solution of 1,4-dioxa-spiro[4.5]dec-6-ylamine (300 mg) in absolute tetrahydrofuran (10 ml), the mixture wasstirred at room température for 2 hours and the solvent was then removed underreduced pressure. The residue was purified by préparative chromatography and the 20 product-containing fractions were combined, freed from acetonitrile, made basic andextracted three times with ethyl acetate. The organic phases were combined, dried(MgSO4) and filtered. This gave 428 mg of the desired product. LCMS-Rt (A): 3.57 minMS (ES+, M+H+): 313.19 25 012827 - ' : -· ·? ·....... .............. ........... ......;· ..... 55.......:........ .......... ............ ......... c) 1 -(1,4-Dioxaspiro[4.5]dec-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 (393 mg) wasdissolved in absolute tetrahydrofuran (8.5 ml), and a solution of methyl iodide (179 mg) 5 in absolute tetrahydrofuran (0.5 ml) was added. The mixture was then stirred at 70°Cin sand bath for 2 days. Ethyl acetate was then added to the reaction mixture, and themixture was washed twice with water. The organic phase was dried over magnésiumsulfate and the solvent was removed after filtration. The residue was purified bypréparative chromatography and the product-containing fractions were combined, 10 freed from acetonitrîle, made basic and extracted three times with ethyl acetate. Theorganic phases were combined, dried (MgSCU) and filtered. This gave 59 mg of the desired product which was used directly for the next step. LCMS-Rt (C): 1.05 minMS (ES+, M+H+): 327.4 15 d) N-(1,4-Dioxaspiro[4.5]dec-6-yl)-N'-(4-methylthiophen-3-yl)guanidine

In a ReactiVial, a 7 M solution of ammonia in methanol (2 ml) was added to 1-(1,4-dioxaspiro[4.5]dec-6-yl)-2-methyl-3-(4-methylthiophen-3-yl)isothiourea (58.8 mg), 20 and the mixture was heated in a sand bath at about 100°C for 16 hours. Removal ofthe solvent gave a residue of 51 mg of an oily product which was directly reactedfurther. LCMS-Rt (C): 1.00 minMS (ES+, M+H+): 296.4 012827 56 e) N-(2-Chloro-4-methylthiophen-3-yl)-N'-(1,4-dioxaspiro[4.5]dec-6-yl)guanidine

N-(1,4-Dioxaspiro[4.5]dec-6-yl)-N'-(4-methylthiophen-3-yl)guanidine (49 mg) was5 dissolved in glacial acetic acid (3 ml), and a solution of N-chlorosuccinimide (20.3 mg) in glacial acetic acid (5 ml) was added slowly. The mixture was stirred for a number ofhours and then allowed to stand at room température over the weekend, after whichthe glacial acetic acid was removed under reduced pressure, the residue was taken upin water and the mixture was adjusted to pH 10 using 2N sodium hydroxide solution. 10 The basic phase was extracted three times with ethyl acetate and the combinedorganic phases were dried over magnésium sulfate, filtered and concentrated. Theresidue was purified by préparative chromatography and the product-containingfractions were combined, freed from acetonitrile, made basic and extracted three timeswith ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. 15 Removal of the solvent under reduced pressure gave 24 mg of the desired productwhich was used directly for the next step. LCMS-Rt (C): 1.09 min MS (ES+, M+H+): 330.4 20 f) ((2-Chloro-4-methylthiophen-3-yl)-(4,5,6,7-tetrahydro-1 H-benzoimidazol-2-yl))aminehydrochloride

N-(2-Chloro-4-methylthiophen-3-yl)-N'-(1,4-dioxaspiro[4.5]dec-6-yl)guanidine (24 mg)was dissolved in 2N hydrochloric acid (1 ml) and stirred at room température for 25 30 min. Concentrated hydrochloric acid (1 ml) was then added, and the mixture was 012827 57 stirred for another two hours. The mixture was then diluted with a little water andfreeze-dried. Toluene was added to the residue and then distilled off under reducedpressure. This step was repeated twice, giving 22 mg of the desired product as a solid.LCMS-Rt (B): 0.95 min 5 MS (ES+, M+H+): 268.07

Exampie 49:2-Chloro-3N-(2-benzimidazolylamino)-4-methylthiophenebenzenesulfonate

10 2-Chloro-3N-(2-benzimidazolylamino)-4-methylthiophene (250 mg) was dissolved inTHF (5 ml), and benzenesulfonic acid (150 mg), dissolved in THF (5 ml), was addedwith stirring. After 3 h, the reaction mixture was left in the fridge overnight. Theprecipitate was filtered off with suction and dried at 75°C under high vacuum, givingthe desired product. Colorless crystals. M.p.: 235°C 15 Example 50:2-Chloro-3N-(2-benzimidazolylamino)-4-methylthiophene methane-sulfonate :

was obtained analogously to the procedure described in example 49 from 2-chloro-3N-(2-benzimidazoly,amino)-4-methylthiophene using one équivalent of

20 methanesulfonic acid. Colorless crystals. M.p.: 227°C

012827 58 .........

Example 51:2-Chloro-3N-(2-benzimidazolylamino)-4-methylthiophene benzoate was obtained analogously to the procedure described in example 49 from 2-chloro-3N-(2-benzimidazolyIamino)-4-methylthiophene using one équivalent of benzoic acid. For

5 the précipitation, the reaction mixture was concentrated to half of its original volume,and ether (30 ml) was then added. Colorless crystals, m.p.: 198°C

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

10 a) Methyl 3-acetylaminothiophene 2-carboxylate

With simultaneous heating in an oil bath, 567 ml of acetic anhydride are addeddropwise to a mixture of 942 g of methyl 3-aminothiophene-2-carboxylate and 1 000 mlof toluene, and the mixture is then boiled under reflux conditions for 1 Vz hours and 15 sub'sequently cooled in an ice bath to about 0°C. The crystals are filtered off andwàshed twice with a little isopropanol and twice with diisopropyl ether. Methyl 3-acetylaminothiophene-2-carboxylate can be obtained from the filtrate by furtherconcentration and crystallization. M.p. 93-95°C. 20 b) Methyl 3-acetylamino-4,5-dichlorothiophene-2-carboxylate

With magnetic stirring at a reaction température of 20-30°C, 17.9 g of sulfuryl chlorideSO2CI2 are added dropwise to a solution of 19.9 g of methyl 3-acetylaminothiophene-2-carboxylate in 100 ml of chloroform. The mixture is then stirred at 40°C for another2 hours and boiled under reflux conditions for another 15 minutes. The solvent is 25 distilled off under reduced pressure, ethyl acetate is then added to the residue and the 012827 ..... ··· 59 crystals are, after standing, filtered off. M.p. 136-138°C. c) Methyl 3-acetylamino-4 chlorothiophene-2-carboxylate A mixture of 25 g of methyl 3-acetylamino-4,5-dichlorothiophene-2-carboxylate, about5 10 g of triethylamine, 300 ml of methanol and 1 g of palladium on carbon is, at room température and under atmospheric pressure, hydrogenated until the uptake ofhydrogen has stopped. The catalyst is filtered off and the mixture is then concentratedby distillation under reduced pressure until crystallization begins, water is then addedand the solid is filtered off. Colorless crystals from isopropanol. M.p. 142-147°C. 10 d) Methyl 3-amino-4-chlorothiophene-2-carboxy,ate

In a mixture of 50 ml of methanol and 50 ml of concentrated hydrochloric acid, 7 g ofmethyl 3-acety,amino-4-chlorothiophene-2-carboxylate are stirred at 60°C for 4 hours,under reflux for 5 hours and at room température for another 3 days. Any precipitate 15 that has formed is removed by filtration, and about 173 of the volume of the solvent isremoved by distillation under reduced pressure. Following addition of about 100 ml ofwater, the mixture is stirred at room température for another 15 minutes and thecolorless crystals are filtered off and dried in a stream of air. M.p.: 62-64°C. e) 3-Amino-4-chlorothiophene 20 18.02 g of methyl 3-amino-4-chlorothiophene-2-carboxylate are added to a solution of 11.1 g of KOH and 160 ml of water and the mixture is then boiled under reflux for3 hours and, after cooling, added dropwise to a solution, which is at 60°G, of 15 ml ofconcentrated hydrochloric acid and 30 ml of water. This resufts in a vigorous évolutionof CO2. After further stirring at 60°C for about 40 minutes, the mixture is allowed to 25 cool, a layer of 50-100 ml of methyl tert-butyl ether is added, the mixture is madealkaline using concentrated aqueous sodium hydroxide solution and the aqueousphase is extracted in a separating funnel. The aqueous phase is extracted two moretimes with methyl tert-butyl ether, and the combined organic extracts are washed once • with water in a separating funnel. The organic phase is dried, the solvent is dïstilled off 30 and the oily-amorphous residue is chromatographed on a silica gel column using amixture of 1 part of ethyl acetate and 1 part of toluene. 012827 60 f) 4-Chloro-3-thienyl isothiocyanate 1.46 g of thiocarbonyldiimidazole are added to a solution of 1.1 g of 3-amino-4-chlorothiophene in 20 ml of anhydrous THF, and the mixture is stirred at roomtempérature for one hour. The solid is distilled off under reduced pressure, the residue 5 is dissolved in ethyl acetate, the organic phase is treated twice with water in a separating funnel and then dried, and the solvent is again distilled off under reducedpressure. This gives 4-chloro-3-thienyl isothiocyanate as a dark oil which is thenreacted further without further purification steps. 10 g) N-(2-Aminophenyl)-N’-(4-chloro-3-thienyl)thiourea 0.86 g of 1,2-diaminobenzene (o-phenylenediamine) is added to a solution of 1.4 g of 4-chloro-3-thienyl isothiocyanate in 40 ml of anhydrous THF, the mixture is stirred atroom température for about 20 hours and the solvent is distilled off under reducedpressure. The residue is treated with water and extracted with ethyl acetate, the 15 solvent is distilled off again and the residue is purified using medium-pressure silica gelcolumn chromatography using a 1:1 mixture of ethyl acetate and toluene. Brown-yellow solid. h) 4-Chloro-3N-(2-benzimidazolylamino)thiophene 20 A solution of 0.169 g of sodium hydroxide in 5 ml of water, followed by a solution of0.363 g of p-toluenesulfonyl chloride in 10 ml of THF, is added to a solution of 0.5 g ofN-(2-aminophenyl)-N’-(4-chloro-3-thienyl)thiourea in 25 ml of anhydrous THF. Themixture is stirred at room température for 3 hours, the solvent is then distilled off underreduced pressure and the residue is treated with water and extracted with ethyl 25 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, a small portion of the 4-chloro-3N-(2-benzimidazolylamino)- 30 thiophene was, in ethyl acetate, using ethereal hydrogen chloride solution, convertedinto 4-chloro-3N-(2-benzimidazolylamino)thiophene hydrochloride and characterized.Colorless crystals. M.p.: 256-260°C. 012827 61 i) 2,4-Dichloro-3N-(2-benzimidazolylamino)thiophene hydrochloride A solution of 0.16 g of N-chlorosuccinimide in 5 ml of glacial acetic acid is added to asolution of 0.3 g of 4-chloro-3N-(2-benzimidazolylamino)thiophene in 10 ml of glacialacetic acid. The reaction mixture is stirred at 40°C for 15 minutes and at roomtempérature for about 4 hours, the acetic acid is then distilled off under reducedpressure and the residue is treated with water. The mixture is made alkaline usingaqueous sodium hydroxide solution and then extracted with ethyl acetate, the extract iswashed with water, the organic phase is dried and the solvent is distilled off underreduced pressure. The residue is purified under medium-pressure conditions bycolumn chromatography using a mixture of 20 parts of ethyl acetate, 10 parts ofn-heptane and 3 parts of glacial acetic acid as eluent and then precipitated from ethylacetate by addition of a solution of hydrogen chloride in diethyl ether. Colorlesscrystalline product. M.p. 264-268°C.

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

x HQ

A solution of 0.356 g of N-bromosuccinimide in 6 ml of glacial acetic acidis addeddropwise to a solution of 0.5 g of 4-chloro-3N-(2-benzimidazolylamino)thiophene in15 ml of glacial acetic acid, and the mixture is stirred at room température for another15 minutes. The solvent is distilled off and the residue is treated with water and madealkaline using aqueous sodium hydroxide solution. Following extraction with ethylacetate, the organic phase is washed with water, dried and concentrated underreduced 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-heptaneand 3 parts of glacial acetic acid as eluent. Following distillative removal of the solvent,the residue is taken up in ethyl acetate and 2-bromo-4-chloro-3N-(2-benzimidazolyl-amino)thiophene hydrochloride is precipitated by addition of a solution of hydrogen 012827 62 chloride gas in diethyi ether. Colorless crystalline product. M.p.: 264-266°C.

Example 54: (2,4-Dichlorothiophen-3-yl)(5-fluoro-1H-benzimidazol-2-yl)amÎnehydrochloride 5 a) 1 -(2-Amino-4-fluorophenyl)-3-(4-chlorothiophen-3-yl)thiourea NH2

Cl 4-Fluoro-1,2-phenylenediamine (900 mg) was dissolved in THF (25 ml), and 4-chloro-3-thienyl isothiocyanate (example 52c), dissolved in THF (15 ml), was added dropwisewith stirring. The solution was stirred at room température for about 3 hours and then 10 allowed to stand overnight. The reaction mixture was then concentrated, and theresidue was purified by préparative HPLC. The product-containing fractions werecombined, freed from acetonitrile, made basic and extracted three times with ethylacetate. The organic phases were combined, dried (MgSO4) and filtered. Removal ofthe solvent gave 625 mg of the desired product. 15 LCMS-Rt (F): 1.28 minMS (ES+, M+H+): 302.0 b) (4-Chlorothiophen-3-yl)(5-fluoro-1 H-benzimidazol-2-yl)amine 1

20 1-(2-Amino-4-fluorophenyl)-3-(4-chlorothiophen-3-yl)thiourea (625 mg) was dissolvedin THF, and a solution of NaOH (0.207 g) in water (9 ml) was added. Over a period of5 min, a solution of p-toluyl chloride (0.395 g) in THF (10 ml) was added dropwise.

After the addition had ended, the mixture was stirred at room température for one hour.For work-up, water and ethyl acetate were added to the reaction mixture, and the 25 phases were separated in a separating funnel. The aqueous phase was extracted 012827 63 three times with ethyl acetate and the combined ethyl acetate phases were dried withmagnésium sulfate, elarified with charcoal, filtered and concentrated. This gave135 mg of the desired product. LCMS-Rt (F): 0.90 min5 MS (ES+, M+H+): 268.0 c) (2,4-Dichlorothiophen-3-yl)(5-fluoro-1 H-benzimidazol-2-yl)amine hydrochloride

Cl (4-Chlorothiophen-3-yl)(5-fluoro-1 H-benzimidazol-2-yl)amine (85 mg) was dissolved in 10 glacial acetic acid (4 ml), and N-chlorosuccinimide (42 mg), dissolved in glacial aceticacid (4 rhl), wâs slowly added aî room température, with vigorous stirring. After theaddition had ended, the mixture was stirred at room température for 45 min and then at50°C for 5 h. After the addition of further N-chlorosuccinimide (4 mg) stirring at 50°Cwas continued for one hour. Toluene (20 mi) was then added to the reaction mixture, 15 and the glacial acetic acid was distilled off. The residue was dissolved in ethyl acetateand eluted using saturated potassium carbonate solution. The ethyl acetate phase wasdried over magnésium sulfate, filtered and concentrated. The residue was purified bypréparative HPLC and the product-containing fractions were combined, freed fromacetonitrile, made basic and extracted three times with ethyl acetate. The organic 20 phases were combined, dried (MgSO4) and filtered. After removal of the solvent, waterand 2N hydrochloric acid were added to the residue, which was then freeze-dried. Thisgave 17 mg of the desired product. LCMS-Rt (E): 2.65 minMS (ES+, M+H+): 301.93 25 012827 64

Example 55: (2-Bromo-4-chlorothiophen-3-yl)(5-fluoro-1 H-benzimidazol-2-yl)aminehydrochloride

(4-Çhlorothiophen-3-yl)(5-fluoro-1H-benzimidazol-2-yl)amine (50 mg, example 54b) 5 was dissolved in glacial acetic acid (4 ml), and N-bromosuccinimide (33 mg), dissolved in glacial acetic acid (4 ml), was slowly added at room température, with vigorousstirring. After the addition had ended, the mixture was stirred at room température for45 min, toluene (20 ml) was then added to the reaction mixture and the glacial aceticacid was distilled off. The residue was dissolved in ethyl acetate and washed with 10 saturated potassium carbonate solution. The ethyl acetate phase was dried over magnesiùm sulfate, filtered and concentrated. The residue was purified by préparativechromatography and the product-containing fractions were combined, freed fromacetonitrile, made basic and extracted three times with ethyl acetate. The organicphases were combined, dried (MgSO4) and filtered. After removal of the solvent, water 15 and 2 N hydrochloric acid were added to the residue, which was then freeze-dried.

This gave 27 mg of the desired product. LCMS-Rt (E): 2.29 min : MS (ES+, M+H+): 347.87 20 Example 56: (2,4-Dichlorothiophen-3-yl)(5,6-difluoro-1 H-benzimidazol-2-yl)aminehydrochloride a) 1-(2-Amino-4,5-difluorophenyl)-3-(4-chlorothiophen-3-yl)thiourea 012827 65 NH2

F

S

H 1,2-Diamino-4,5-difluorobenzene (1.02 g) was initiaily charged in abs. THF (15 ml),and 4-chloro-3-thienyl isothiocyanate (1.25 g, example 52c), dissolved in abs. THF(15 ml), was added dropwise. Further treatment analogously to example 54a) gave 5 773 mg of the desired compound. LCMS-Rt (F): 1.32 minMS (ES+, M+H+): 320.0 b) (4-Chlorothiophen-3-yl)(5,6-difluoro-1H-benzimidazol-2-yl)amine 10 1-(2-Amino-4,5-difIuorophenyl)-3-(4-chlorothiophen-3-yl)thiourea (773 mg) was initiailycharged in THF (20 ml), and a solution of NaOH (240 mg) in water (9 ml) followed by asolution of tosyl chloride (528 mg) in THF (10 ml) were added. Further treatmentanalogously to example 54b) gave 275 mg of the desired compound. — 15 LCMS-Rt (F): 0.95 minMS (ES+, M+H+): 286 c) (2,4-Dichlorothiophen-3-yl)(5,6-difiuoro-1 H-benzimidazol-2-yl)amine hydrochloride

Cl 012827 66 (4-Chlorothiophen-3-yl)(5,6-difluoro-1H-benzimidazol-2-yl)amine (125 mg) was initiallycharged in acetic acid (8 ml), and a solution of Cl-succinimide (59 mg) in acetic acid(2 ml) was added dropwise. Further treatment analogously to example 54c) gave58 mg of the desired product. 5 LCMS-Rt (E): 2.97 minMS (ES+, M+H+): 319.88

Example 57: (2-Bromo-4-chlorothiophen-3-yl)(5,6-difluoro-1 H-benzimîdazol-2-yl)aminehydrochloride

(4-Chlorothiophèn-3-yl)(5,6-difluoro-1 H-benzimidazol-2-yl)amine (125 mg,example 55b) was dissolved in glacial acetic acid (8 ml), and N-bromosuccinimide(78 mg) dissolved in glacial acetic acid (2 ml), was slowly added at room température,with vigorous stirring. Further treatment analogously to example 55c) gave 77 mg of 15 the desired product. LCMS-Rt (E): 2.39 min 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 is obtained analogously to the procedure given in example 52g) from 4-chloro-3-thienylisothiocyanate and 1,2-diamino-3-methylbenzene, using medium pressure column 012827 67 chromatography on silica gel with a mixture of 20 parts of ethyl acétate, 10 parts ofn-heptane and 1 part of ethyl acetate. Brownish-yellow solid, m.p.: 193-196°C. b) e) 4-Chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene5 is obtained analogously to the procedure given in example 52h) from N-(2-amino-3- methylphenyl)-N’-(4-chloro-3-thienyl)thiourea using medium pressure columnchromatography on silica gel with a mixture of 10 parts of dichloromethane and 1 partof methanol, as an amorphous, foam-like product. Préparation of the 4-chloro-3N-(4-méthyl-2-benzimidazolylamino)thiophene hydrochloride in ethyl acetate using diethyl 10 ether saturated with hydrogen chloride gas. Crystalline product, m.p. 325-327°C.

Example 59:2,4-Dichloro-3N-(4-methyl-2-benzimidazolylamino)thiophenehydrochloride

15 is obtained analogously to the procedure given in example 52i) from 4-chloro-3N-(4-methyl-2-benzimidazolylamino)thiophene and N-chlorosuccinimide in glacial aceticacid, with analogous work-up. Crystalline product, m.p. 296-298°C. -

Example 60: trans-(3aS,7aS)-4-Chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2- 20 benzimidazolyl)-3-thienylamine hydrochloride xHCi

CI a) trans-S,S-3N-(2-Aminocyclohexyl)-N’-(4-chloro-3-thienyl)thiourea 012827 68 is obtained analogously to the reaction given in example 1, b) from 4-chloro-3-thienylisothiocyanate and trans-S,S-1,2-diaminocycIohexane by column-chromatographicséparation on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts ofdichloromethane, 5 parts of n-heptane, 5 parts of methanol and 1 part of ammonia 5 (35-37%), as an amorphous dark product which is processed further without further work-up. b) trans-(3aS, 7aS)-4-Chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)-3-thienylamine 10 is obtained analogously to the procedure given in example 52h) from trans-S,S-3N-(2-aminocyclohexyl)-N’-(4-chloro-3-thienyl)thiourea, p-toluenesulfonyl chloride andsubséquent application of medium pressure column chromatography on silica gelusing a mixture of 10 parts of dichloromethane and 1 part of methanol, as anamorphous, foam-like product. Préparation of the trans-S,S-4-chloro-3N- 15 (3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride in ethylacetate and a little éthanol using diethyl ether saturated with hydrogen chloride gas.Crystalline product, m.p. 196-200°C.

Example 61 : trans-(3aR,7aR)-4-Chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2- 20 benzimidazolyl)-3-thienylamine hydrochloride xHCl

a) trans-(1R,2R)-3N-(2-Aminocyclohexyl)-N’-(4-chloro-3-thienyl)thioureais obtained analogously to the reaction given in example 1, b) from 4-chloro-3-thienylisothiocyanate and trans-(1 R,2R)-(-)-1,2-diaminocyclohexane by subséquent column- 25 chromatographie séparation on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part ofammonia (35-37%), as an amorphous, dark product which is processed further withoutfurther work-up. 012827 69 b) trans-(3aR, 7aR)-4-Chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)-3-thienylamine is obtained analogously to the procedure given in example 52h) from trans-R,R-3N-(2-5 aminocyclohexyl)-N’-(4-chloro-3-thienyl)thiourea, p-toluenesulfonyl chloride and subséquent application of medium pressure column chromatography on silica gelusing a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts ofdichloromethane, 5 parts of methanol and 1 part of ammonia (35-37%), as anamorphous, oily product Préparation of the trans-R,R-4-chloro-3N-(3a,4,5,6,7,7a- 10 hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochioride in ethyl acetate and alittle éthanol using diethyl ether saturated with hydrogen chloride gas. Crystallineproduct, m.p. 240-244°C.

Example 62: cis-4-Chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)-3- 15 thienylamine hydrochioride xHCl

Cl a) cis-3N-(2-Aminocyclohexyl)-N’-(4-chloro-3-thienyl)thiourea is obtained analogously to the reaction given in example 1, b) from 4-chloro-3-thienyl isothiocyanate and cis-1,2-diaminocyclohexane by subséquent column- 20 chromatographie séparation on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts of methanol and 1 part ofammonia (35-37%), as an amorphous, dark product which is processed further withoutfurther work-up. 25 b) cis-4-Chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)-3-thienyl amineis obtained analogously to the procedure given in example 52h) from 3N-(cis-2-amino-cyclohexyl)-N’-(4-chloro-3-thienyl)thiourea, p-toluenesulfonyl chloride and subséquent 012827 application of medium pressure column chromatography on silica gel using a mixtureof 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of dichloromethane, 5 parts ofmethanol and 1 part of ammonia (35-37%), as a brown, oily product. Préparation of the 4-chloro-3N-(cis-3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydro- 5 chloride in ethyl acetate and a little éthanol, using diethyl ether saturated withhydrogen chloride gas. Crystalline product, m.p. 228-231°C.

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

is obtained anâlogously to the procedure given in example 52i) by reacting trans-R,R- 4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine withN-chlorosuccinimide and analogous work-up. Crystalline product. Foaming withsublimation starting at 165°C.

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

is obtained analogousiy to the procedure given in example 52i) by reacting cis-4-20 chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)-3-thienylamine with N-chlorosuccinimide and analogous work-up. Crystalline product. M.p. 270-274°C. 012827 71

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

Cl HCl

a) 1 -N-(2-Amino-3-chlorophenyl)-3-N-(4-chloro-3-thienyl)thiourea is obtained from 3-chloro-1,2-diaminobenzene and 4-chloro-3-thieny, isothiocyanate5 analogously to the procedure described in example 1b) and crystallization under

diisopropyl ether, as a solid having two melting points: m.p. 1:152-155°C withrecrystallization; m.p. 2: >310°C b) 4-Chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene 10 is obtained ariâiogously to the procedure described in example 52h) by reacting 1-N-(2-amino-3-chlorophenyl)-3-N-(4-chloro-3-thienyl)thiourea with p-toluenesulfonylchloride and eolumn chromatography on silica gel using a mixture of 3 parts of tolueneand 1 part of ethyi acetate as mobile phase and subséquent distillative removal of thesolvent under reduced pressure, as a foam-like, amorphous product which is 15 converted further into the hydrochloride. c)4-Chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride —is obtained by treating a solution of 4-chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene in ethyi acetate with a solution in diethyl ether 20 saturated with hydrogen chloride gas, as a crystalline precipitate. M.p. 276-280°C. 72 012827

Example 66: 2,4-Dichloro-3N-(4-chloro-2-benzimidazolylamino)thiophenehydrochloride

is obtained analogously to the procedure given in example 52i) from 4-chloro-3N-(4-5 methyl-2-benzimidazolylamino)thiophene and N-chlorosuccinimide in glacial acetic acid, with analogous work-up. Crystalline product, m.p. 294-297°C.

Analogously to the compounds listed in the working examples, it is possible to préparéthe following thiophene dérivatives: 10 2-bromo-4-ch,ôro-3N-(4-methyl-2-benzimidazolylamino)thiophene hydrochloride,m.p. 284-286°C, 2- bromo-4-chloro-3N-(4-chloro-2-benzimidazolylamino)thiophene hydrochloride,m.p. 304-306°C, 15 trans-R,R-2-bromo-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1 H-2-benzimidazolyl)-3- thienylamine hydrochloride, point of décomposition: 215°C, trans-(3aS,7aS)-2-bromo-4-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)- 3- thienylamine hydrochloride 243-254°C, - 2.4- dibromo-3N-(2-benzimidazolyl)-3-thienylamine hydrochloride, 20 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 25 hydrochloride, 2-chloro-3N-(4-methylsulfonyl-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride. 012827 73

Pharmacological data:

Test description: 5 In this test, the recovery of the intracelluiar pH (pHi) after an acidification, which startswhen the NHE 1s capable of functioning, even under bicarbonate-free conditions, wasdetermined. For this purpose, the pHi was determined using the pH-sensitivefluorescent dye BCECF (Calbiochem, the precursor BCECF-AM is employed). Thecells were initially loaded with BCECF. The BCECF fluorescence was determined in a

10 "ratio fluorescence spectrometer” (Photon Technology International, South Brunswick,N.J., USA) with excitation wavelengths of 505 and 440 nm and an émissionwavelength of 535 nm, and was converted into the pHi using calibration plots. Thecells were incubated in NH4CI buffer (pH 7.4) (NH4CI buffer: 115 mM NaCI, 20 mM NH4CI, 5 mM KCI, 1 mM CaCI2, 1 mM MgSO4, 20 mM Hepes, 5 mM glucose, 1 mg/ml 15 BSA; a pH of 7.4 is established with 1 M NaOH) even during the BCECF loading. Theintracelluiar acidification was induced by addition of 975 μ\ of an NhUCI-free buffer (see below) to 25 μ\ aliquots of the cells incubated in NH4CI buffer. The subséquent rate of pH recovery was recorded in the case of NHE1 for two minutes, in the case of NHE2for five minutes and in the case of NHE3 for three minutes. To calculate the inhibitory 20 power of the tested substances, the cells were initially investigated in buffers in whichcomplété or absolutely no pH recovery took place. For complété pH recovery (100%),the cells were incubated in Na+-containing buffer (133.8 mM NaCI, 4.7 mM KCI,

1.25 mM CaCI2,1.25 mM MgCI2, 0.97 mM Na2HPC>4,0.23 mM NaH2PO4, 5 mM

Hepes, 5 mM glucose, a pH of 7.0 is established with 1 M NaOH). To détermine the 25 0% value, the cells were incubated in an Na+-free buffer (133.8 mM choline chloride, 4.7 mM KCI, 1.25 mM CaCI2, 1.25 mM MgCI2, 0.97 mM K2HPO4, 0.23 mM KH2PO4, 5 mM Hepes, 5 mM glucose, a pH of 7.0 is established with 1 Μ KOH). The substancesto be tested were made up in the Na+-containing buffer. Recovery of the intracelluiarpH at each tested concentration of a substance was expressed as a percentage of the 30 maximum recovery. Using the Sigma-Plot program, the IC50 value of the substance in 012827 74 question was calculated for the individual NHE subtypes using the percentages for pHrecovery.

Results:

Example IC50 [μΜ], 16 trans-R,R-2-chloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 0.27 (rNHE3) 12 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 0.12 (rNHE3) 54: 2-bromo^t-chloro-3N-(2-benzimidazolylamino)thiophene hydrochloride 0.22 (hNHE3) 53: 2,4-dichloro-3N-(2-benzimidazolylamino)thiophene hydrochloride 0.14 (hNHE3) 56: 2,4-dichloro-3N-(4-methyl-2-benzimidazolyl- amino)thiophene hydrochloride 0.22 (hNHE3) 60: trâôs-R,R-2,4-dichloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine hydrochloride 0.19(hNHE3) 63: 2,4-dichloro-3N-(4-chloro-2-benzimidazolyl-amino)thiophene hydrochloride 0.54 (hNHE3) 38: 2-chloro-3N-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene hydrochloride 0.84 (hNHE3) 012827 75..... -...................... 18: 2-bromo-3N-(2-benzimidazolyl)-4-rnethyl-3-thienylamine hydrochloride 0.12(hNHE3) 19: trans-R,R-2-bromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 0.56 (hNHE3) 2: 2-chloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride 0.62 (hNHE3) 44: ( 1 H-benzimidazol-2"yl)-(2-chloro-4-methylthiophen-3-yl)-methylamine 1.59 (hNHE3)

Claims

012827 76 We daim:

1. A compound of the formula I, R2 S

R1 R4 H in which:10 R1 and F 15 20 R3 R4 25 15 20 R3 R4 25 R2 independently of one another are H, F, Cl, Br, I, CN, NO2, -(X)n-CqH2q-Z,cydoalkyl having 3, 4, 5 or 6 carbon atoms, alkenyl having 2, 3 or 4 carbonatoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl or alkylalkynyl having 3 or 4 carbon atoms; n is zéro or 1 ; X is oxygen, NH, N-CH3, S(O)k’, k is zéro, 1 or 2; . J q is zéro, 1,2, 3,4, 5 or 6; — Z is hydrogen or CmF2m+1; m is zéro, 1,2, 3 or 4; is hydrogen, methyl, F, Cl, Br, I, CN, S(O)k-CH3, -NO2, -O-CH3; k is zéro, 1 or 2; is hydrogen, cydoalkyl having 3,4, 5, or 6 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl oralkylalkynyl having 3 or 4 carbon atoms, -CrH2r - Y; r is zéro, 1,2, 3 or 4; Y is hydrogen or trifluoromethyl; 012827 η R5 and R6 are hydrogen or together are a bond; R7 and R8 independently of oneanother are (C3-Cs)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-Ce)-cycloalkyl or (C4-C6)-cycloalkenyl 5 or R7 and R8 together are an alkylene chain comprising 3 to 8 carbon atoms; where none, sorne or ail of their hydrogen atoms may be replaced by fluorine atoms; 10 or R7 and R8 together are a radical

Rio 15 20 where R5 and R6 together form a bond; R10andR11 independently of one another are hydrogen, fluorine, chlorine,bromine, methyl, CN, OH, -O-CH3, NO2, NH2 or -CF3; . R9andR12 are hydrogen or F; or one of the substituents R9 and R12is 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 3or 4 carbon atoms, ethynyl, alkylalkynyl having 3 or 4 carbon atoms or-(X)n - CqH2q-Z; 25 012827 78 10 15 R13andR14 are identical or different hydrogen or alkyl having 1,2,3 or 4carbon atoms; or R13 and R14 together with the nitrogen to which they are attachedform a saturated 5-, 6- or 7-membered ring;n iszeroorl; X is oxygen, NH, N-CH3, S(O)k; k is zéro, 1 or 2;q is zéro, 1,2,3,4, 5 or 6;and Z is hydrogen or CmF2m+l ; m is zéro, 1,2, 3 or 4; and its pharmaceutically acceptable salts, and its trifluoroacetic acid salts.
2. A compound as claimed in daim 1, in which: R1 and R2 independently of one another are H, F, Cl, Br, CH3, CF3, SO2CH3, SO2NH2; but where at most one of the substituents R1 and R2 is hydrogen; 20 R3 is hydrogen, F or Cl; R4 - is hydrogen, alkyl having 1,2, 3 or 4 carbon atoms, or cyclopropÿi; RSand R6 are hydrogen or together are a bond; R7 and R8 25 together are an alkylene chain comprising 3,4, 5,6, 7 or 8 carbon atoms; or R7 and R8 together are a radical 012827 79

where R5 and R6 together form a bond; R10and R11 independently of one another are hydrogen, OH, fluorine or chlorine;R9andR12 are hydrogen;or one of the substituents R9 and R12is hydrogen; and the other is F, Cl, Br, CN, COOH, CO-NR13R14, SO2-NR13R14 5 or-(X)n — CqH2q-Z; R13andR14 are identical or different hydrogen or methyl;n is zéro or 1 ; X is oxygen, NH, N-CH3 or S(O)k; k iszero, 1 or 2;q iszero, 1,2, 3 or4; Z is hydrogen or CF3; and its pharmaceuticaily acceptable salts, and its trifluoroacetic acid saits.
3. A compound as claimed in claim 1 and/or 2, in which: R1 and R2 independently of one another are F, CI, Br, CH3 or CF3;R3 is hydrogen; R4 is hydrogen, methyl, ethyl; R5 and R6 are hydrogen or together are a bond; 012827 80 R7 and R8 together are an alkylene Chain comprising 3,4, 5, 6, 7 or 8 carbon atoms;or R7 and R8 together are a radical

10 15 20 where R5 and R6 together form a bond; R10andR11 independently of one another are hydrogen, OH or fluorine;R9and R12 are hydrogen; or / one of the substituents R9 and R12is hydrogen; and the other is F, Cl, Br or -(X)n - CqH2q-Z;n is zéro or 1 ; X is oxygen, NH, N-CH3 or S(O)k; k is zéro, 1 or 2; * q iszeroorl; Z is hydrogen or CF3; and its pharmaceutically acceptable salts, and its trifluoroacetic acid salts.
4. A compound of the formula I as claimed in one or more of daims 1,2 and 3,selected from the group consisting of: 25 trans-R,R-2-chlorine-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3- thienylamine, 012827 81 trans-R,R-2-bromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl>4-methyl-3- thienylamine, 2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamineI 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-benzimidazolylamîno)-4-rnethylthiophene, 2-chloro-3N-(4-hydroxy-2-benzimidazoiylamino)-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- dichl9ro-3N-(2-benzimidazolyiamino)thiophene, 2-bromo-4-chloro-3N-(2-benzimidazolylamino)thiophene, 2.4- dichÎoro-3N-(4-methyl-2-benzimidazolylamino)thiophene, trans-R,R-2,4-dichloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thieny,amine, and 2.4- dichloro-3N-(4-chloro-2-benzimidazolylamino)thiophene and their pharmaceutically acceptable salts.
5. A compound of the formula I and/or a pharmaceutically acceptable sait thereof asclaimed in one or more of daims 1 to 4 for use as a médicament.
6. The use of a compound of the formula I and/or a pharmaceutically acceptable saitthereof as claimed in one or more of daims 1 to 4 for preparing a médicament for thetreatment or prophylaxis of respiratory disorders, in particular respiratory dîsordersassociated with sleeping, such as sleep apnea, or of snoring, for the treatment orprophylaxis of acute and chronic rénal diseases, in particular acute kidney failure orchronic kidney failure, or of disorders of intestinal function, for the treatment or 012827 ....... ' ' ' · ........... 82 prophylaxis of high blood pressure, in particular essentiel hypertension, of disorders ofthe central nervous System, in particular disorders which are the resuit of CNSoverexcitability, such as epilepsy orcentrally induced spasms, and of disorders of thecentral nervous System, in particular States of anxiety, dépréssions and psychoses, for 5 the treatment or prophylaxis of acute and chronic damage and disorders of organs ortissue caused by ischémie events or by reperfusion events and indirect sequelaethereof, of arrhythmias, of atherosclerosis, of hypercholesterolemia, of diseases inwhich cell prolifération is a primary or secondary cause, of cancer, of prostatehypertrophy or prostate hyperplasia, of fibrotic disorders of internai organs, of cardiac 10 insufficiency or of congestive heart failure, of thromboses, of disorders of gall function,of infection by ectoparasites, of disorders which are the resuit of endothélialdysfunction, of intermittent claudication, of protozoa disorders, in particular malaria, forthe treatment of States of shock, diabètes and late diabetic damage, acute or chronicinflammatory disorders or for preparing a médicament for the préservation and storage 15 of transplants for surgical interventions, for preparing a médicament for use in surgicaloperations and organ transplantations, for preparing a médicament for preventingage-related tissue change, for maintaining health and prolonging life, for reducingcytotoxic effects or for use as diagnostics.
7. The use of a compound of the formula I and/or a pharmaceutically acceptable sait thereof as claimed in one or more of daims 1 to 4 in combination with other drugs oractive compounds for preparing a médicament for the treatment or prophylaxis ofrespiratory disorders, in particular respiratory disorders associated with sleeping, suchas sleep apnea, or of snoring, for the treatment or prophylaxis of acute and chronic 25 rénal diseases, in particular acute kidney failure or chronic kidney failure, or of disorders of intestinal function, for the treatment or prophylaxis of high blood pressure,in particular essential hypertension, of disorders of the central nervous System, inparticular disorders which are the resuit of CNS overexcitability, such as epilepsy orcentrally induced spasms, and of disorders of the central nervous System, in particular 30 States of anxiety, dépressions and psychoses, for the treatment or prophylaxis of acuteand chronic damage and disorders of organs or tissues caused by ischémie events orby reperfusion events and indirect sequelae thereof, of arrhythmias, of atherosclerosis, 012827 ....... 83...... ............ of hypercholesterolemia, of diseases in which cell prolifération is a primary orseeondary cause, of cancer, of prostate hypertrophy or prostate hyperplasia, of fibroticdisorders of internai organs, of cardiac insufficiency or of congestive heart faiiure, ofthromboses, of disorders of gall fonction, of infection by ectoparasites, of disorders 5 which are the resuit of endothélial dysfonction, of intermittent claudication, of protozoadisorders, in particular malaria, for the treatment of States of shock, diabètes and latediabetic damage, acute or chronic inflammatory disorders or for preparing amédicament for the préservation and storage of transplants for surgical interventions,for preparing a médicament for use in surgical operations and organ transplantations, 10 for preparing a médicament for preventing age-related tissue change, for maintaininghealth and prolonging life or for reducing cytotoxic effects.
8. The use of a compound of the formula I and/or a pharmaceutically acceptable saitthereof as claimed in one or more of daims 1 to 4 alone or in combination with other 15 drugs orsactive compounds for preparing a médicament for the treatment or prophylaxie of respiratory disorders, in particular respiratory disorders associated withsleeping, such as sleep apnea.
9. The use of a compound of the formula I and/or a pharmaceutically acceptable sait 20 thereof as claimed in one or more of daims 1 to 4 alone or in combination with other drugs or active compounds for preparing a médicament for the treatment ofprophylaxis or snoring.
10. The use of a compound of the formula I and/or a pharmaceutically acceptable sait 25 thereof as claimed in one or more of daims 1 to 4 alone or in combination with other drugs or active compounds for preparing a médicament for the treatment orprophylaxis of acute and chronic rénal diseases, in particular acute kidney faiiure orchronic kidney faiiure.
11. The use of a compound of the formula I and/or a pharmaceutically acceptable sait thereof as claimed in one or more of daims 1 to 4 alone or in combination with other 012827 — 7 ' - .....................-.....~.................. ; ............r............ 84.....r~;7 ..................~ ............. · ~ drugs or active compounds for preparing a médicament for the treatment orprophylaxis of disorders of intestinal fonction.
12. A médicament for human, veterinary or phytoprotective use, comprising an 5 effective amount of a compound of the formula I and/or a pharmaceutically acceptablesait thereof as daimed in one or more of daims 1 to 4, together with pharmaceuticallyacceptable carriers and additives.
13. A médicament for human, veterinary or phytoprotective use, comprising an 10 effective amount of a compound of the formula I and/or a pharmaceutically acceptable sait thereof as claimed in one or more of daims 1 to 4, together with pharmaceuticallyacceptable carriers and additives, in combination with other pharmacologically activecompounds or drugs.