NZ511167A - Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments - Google Patents

Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments

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Publication number
NZ511167A
NZ511167A NZ511167A NZ51116799A NZ511167A NZ 511167 A NZ511167 A NZ 511167A NZ 511167 A NZ511167 A NZ 511167A NZ 51116799 A NZ51116799 A NZ 51116799A NZ 511167 A NZ511167 A NZ 511167A
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New Zealand
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group
pct
preparation
compound
trifluoromethyl
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NZ511167A
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Stefan Matthias Blech
Erich Burger
Christian Eickmeier
Otto Roos
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Boehringer Ingelheim Pharma
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Publication of NZ511167A publication Critical patent/NZ511167A/en

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)
  • Furan Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

Benzoylguanidine compounds of formula (I), wherein: R1 is alkyl, optionally substituted heteroaryl, aryl, and alkylaryl. The compounds are used in the manufacture of medicaments that inhibit cellular Na+/H+ exchange for the treatment of disorders such as ischaemias.

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 511167 <br><br> 511167 <br><br> WO 00/17176 <br><br> PCT/EP99/06857 <br><br> S018-639pct.204 <br><br> New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in the production of pharmaceutical compositions <br><br> 10 <br><br> The present invention relates to novel benzoylguanidine derivatives of general formula I, processes for preparing them and their use in the preparation of pharmaceutical compositions <br><br> 15 <br><br> wherein <br><br> Rx denotes C^-alkyl, <br><br> (I) <br><br> heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C^-alkyl group, a 2 0 cycloalkyl group, a branched or unbranched C^-alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, <br><br> 25 <br><br> 30 <br><br> aryl unsubstituted or mono- or polysubstituted by a branched or unbranched C^-alkyl group, a branched or unbranched C^-alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl group, a hydroxy, cyano or nitro group or halogen or by a 5- or 6-membered heteroaryl group which may <br><br> WO 00/17176 <br><br> 2 <br><br> PCT/EP99/06857 <br><br> contain one, two, three, four or five heteroatoms selected from nitrogen, oxygen and sulphur -identical to one another or different - <br><br> 10 <br><br> 5 <br><br> alkylaryl, unsubstituted or mono- or polysubstituted in the aryl and/or alkyl partial structure by a branched or unbranched C^-alkyl group, a branched or unbranched C^-alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, <br><br> optionally in the form of the individual tautomers or optionally enantiomers and mixtures thereof and in the form of the free bases or the corresponding acid addition 15 salts with pharmacologically acceptable acids. <br><br> The preferred compounds for the purposes of the present invention are the compounds of general formula I wherein <br><br> 2 0 Rt may denote an unsubstituted phenyl ring or a phenyl ring which is substituted by fluorine or by a methyl, trifluoromethyl, methoxy group or by a pyrrolyl group, or <br><br> N <br><br> N <br><br> 25 <br><br> The following compounds are particularly preferred: <br><br> 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3- <br><br> trifluoromethyl-benzoylguanidine methanesulphonate <br><br> 30 <br><br> WO 00/17176 <br><br> - 3 - <br><br> PCT/EP99/06857 <br><br> and <br><br> 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine methanesulphonate <br><br> C^-alkyl or C^g-alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 4 or 8 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned by way of example: <br><br> methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dim^thylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2 -trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, the preferred hydrocarbon groups are <br><br> WO 00/17176 - 4 - PCT/EP99/06857 <br><br> lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl. <br><br> 5 Alkoxy generally denotes a straight-chained or branched alkyl group bound via an oxygen atom. A lower alkoxy group having 1 to 4 carbon atoms is preferred. The methoxy group is particularly preferred. <br><br> 10 Aryl generally denotes an aromatic group having 6 to 10 carbon atoms - including compositions in which the aromatic group may be substituted by one or more lower alkyl groups, trifluoromethyl groups, cyano groups, alkoxy groups, nitro groups, amino groups and/or one or more <br><br> 15 halogen atoms, which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, whilst the preferred substituents are halogen, such as fluorine, chlorine or bromine, cyano and hydroxyl; for the purposes of the present invention fluorine is the <br><br> 2 0 preferred halogen. The aryl siibstituent - preferably phenyl - may moreover be substituted with a 5- or 6-membered heteroaryl group which may contain one, two, three, four or five heteroatoms from the group comprising nitrogen, oxygen and sulphur, and again the substituents <br><br> 25 may be identical or different. <br><br> Aralkyl generally denotes an aryl group having 7 to 14 carbon atoms bound via an alkylene chain, the aromatic grotip optionally being substituted by one or more lower <br><br> 3 0 alkyl groups, alkoxy groups, nitro groups, amino groups and/or one or more halogen atoms, the substituents being identical or different. Aralkyl groups having 1 to 6 carbon atoms in the aliphatic moiety and 6 carbon atoms in the aromatic moiety are preferred. <br><br> 35 <br><br> WO 00/17176 <br><br> - 5 - <br><br> PCT/EP99/06857 <br><br> The preferred aralkyl groups - unless otherwise stated -are benzyl, phenethyl and phenylpropyl. <br><br> Halogen, unless otherwise stated - denotes fluorine, chlorine, bromine and iodine, preferably fluorine, <br><br> chlorine or bromine. <br><br> Unless otherwise specified, amino denotes an NH2 function which may optionally be substituted by one or two C^a-alkyl, aryl or aralkyl groups, which may be identical or different. <br><br> Accordingly, alkylamino denotes for example methylamino, ethylamino, propylamino, 1-methylene-ethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino. <br><br> Correspondingly, dialkylamino denotes, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di-(1-methylethyl)amino, di-(1-methylpropyl)amino, di-2-methylpropylamino, ethylmethylamino, methylpropylamino. <br><br> Cycloalkyl generally denotes a saturated or unsaturated cyclic hydrocarbon group having 5 to 9 carbon atoms which may optionally be substituted by a halogen atom or a number of halogen atoms - preferably fluorine - which may be identical to or different from one another. Cyclic hydrocarbon groups having 3 to 6 carbon atoms are preferred. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and cyclononinyl. <br><br> Heteroaryl for the purposes of the above definition generally denotes a 5- to 6-membered ring which may contain oxygen, sulphur and/or nitrogen as heteroatoms and <br><br> WO 00/17176 <br><br> - 6 - <br><br> PCT/EP99/06857 <br><br> to which another aromatic ring may be fused. 5- and 6-membered aromatic rings which contain an oxygen, a sulphur and/or up to two nitrogen atoms and which are optionally benzo-condensed are preferred. <br><br> Examples of particular heterocyclic systems include: acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, azanaphthacenyl, azanaphthalenyl, azaprenyl, azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl, benzacridinyl, benzazapinyl, benzofuryl, benzonaphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl, carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl, cumarinyl, cumaronyl, decahydroquinolinyl, decahydroquinolonyl, diazaanthracenyl, diazaphenanthrenyl, dibenzazapinyl, dibenzofuranyl, dibenzothiphenyl, dichromylenyl, dihydrofuranyl, dihydroisocumarinyl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl, diprylenyl, dioxanthylenyl, oenantholactamyl, flavanyl, flavonyl, fluoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydfofuranonyl, hydroindolyl, hydropyranyl, <br><br> hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, isoindolyl, isoquinolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, <br><br> WO 00/17176 <br><br> - 7 - <br><br> PCT/EP99/06857 <br><br> naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, phenanthraquinonyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyrandionyl, pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinethionyl, pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl, pyronyl, pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl, pyrrolizinyl, pyrrolodioazinyl, pyrrolonyl, pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinolinyl, quinolizidinyl, quinolizinyl, quinolonyl, quinuclidinyl, rhodaminyl, spirocumaranyl, succinimidyl, sulpholanyl, sulpholenyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrothipyranonyl, tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl, thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl, thiopyranyl, triazaanthracenyl, triazinoindolyl, triazolopyridinyl, tropanyl, xanthenyl, xanthonyl, xathydrolyl, adeninyl, alloxanyl, alloxazinyl, <br><br> antllranilyl, azabenzanthrenyl, azabenzonaphthenyl, azanaphthacenyl, azaphenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl; benzodioxolyl, benzopyridazinyl, benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl, <br><br> WO 00/17176 <br><br> - 8 - <br><br> PCT/EP99/06857 <br><br> depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, <br><br> dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, 5 dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glycocyamidinyl, guaninyl, hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl, 10 hydantoinyl, hydroimidazolyl, hydroparazinyl, <br><br> hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, 15 isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, 2 0 oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydrothiazinonyl, <br><br> perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenoxazonyl, phthalazinyl, piperazindionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl, 25 purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, <br><br> pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinethionyl, pyrimidinyl, 30 pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, 35 tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl, thiazepinyl, thiazinyl, <br><br> WO 00/17176 <br><br> - 9 - <br><br> PCT/EP99/06857 <br><br> thiazolidinonyl, thiazolidinyl, thiazolinonyl, <br><br> thiazolinyl, thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xanthinyl, xylitolyl, azabenzonaphththenyl, benzofuroxanyl, benzothiadiazinyl, benzotriazepinonyl, benzotriazolyl, benzoxadiazinyl, dioxadiazinyl, dithiadazolyl, dithiazolyl, furazanyl, furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxadiazolyl, oxathiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, thiadiazinyl, thiadiazolinyl, thiadiazolyl, <br><br> thiadioxazinyl, thiatriazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, <br><br> trithiadiazepinyl, trithianyl or trioxolanyl. <br><br> Compounds of this type are already known from German published application 196 01 303.8. <br><br> As a result of their effect as inhibitors of cellular Na+/H+ exchange, such compounds may be used as active ingredients of pharmaceutical compositions or they may be used as intermediate products for the preparation of such active ingredients. The compounds according to the invention are effective against arrhythmias which occur in hypoxia, for example. They can also be used for diseases connected with ischaemia (such as cardiac, cerebral, gastrointestinal - such as mesenterial thrombosis/embolism, pulmonary, renal ischaemia, ischaemia of the liver, ischaemia of the skeletal muscle). Such diseases include for example coronary heart disease, cardiac infarct, angina pectoris, stable angina pectoris, ventricular arrhythmias, sub-ventricular arrhythmias, cardiac insufficiency - and also in support of bypass <br><br> WO 00/17176 <br><br> - 10 - <br><br> PCT/EP99/06857 <br><br> operations, for supporting open heart surgery, for supporting operations which require the blood supply to the heart to be interrupted and for supporting heart transplants - embolism in the pulmonary circulation, acute 5 or chronic kidney failure, chronic kidney insufficiency, cerebral infarct, reperfusion damage caused by the resumption of blood supply to areas of the brain after the clearing of vascular occlusions and acute and chronic bleeding disorders in the brain. Here, the compounds 10 mentioned may also be used in conjunction with thrombolytic agents such as t-PA, streptokinase and urokinase. <br><br> During reperfusion of the ischaemic heart (e.g. after an 15 attack of angina pectoris or cardiac infarct) irreversible damage may occur to cardiomyocytes in the affected region. The compounds according to the invention have a cardioprotective activity, inter alia, in such cases. <br><br> 2 0 The prevention of damage to transplants must also be included under the heading of ischaemia (e.g. for protecting the transplant such as the liver, kidney, heart or lung, before, during and after implantation and during storage of the organs for transplant), which may occur in 25 connection with transplants. The compounds are also drugs with a protective effect during angioplastic surgery on the heart and on the peripheral blood vessels. <br><br> In Essential hypertension and diabetic nephropathy the <br><br> 3 0 cellular sodium proton exchange is increased. The compounds according to the invention are therefore suitable as inhibitors of this exchange in order to prevent these diseases. <br><br> 35 The compounds according to the invention are further characterised by a powerful inhibitory effect on the <br><br> WO 00/17176 <br><br> - 11 - <br><br> PCT/EP99/06857 <br><br> proliferation of cells. Consequently, the compounds are useful drugs in the treatment of diseases in which cell proliferation plays a primary or secondary role and may be used as drugs against cancers, benign tumours or for 5 example prostate hypertrophy, atherosclerosis, organ hypertrophy and hyperplasia, fibrotic diseases and late complications of diabetes. <br><br> Moreover, compounds of this type are known to have a 10 favourable effect on the blood levels of the serum lipoproteins. <br><br> It has now been found that, surprisingly, the compounds of general formula I have the advantage over the 15 benzoylguanidine derivatives already known from the prior art, of not only being unexpectedly more effective but also being suitable for oral administration. <br><br> The active substances according to general formula I may 2 0 be used as an aqueous injectable solution (e.g. for intravenous, intramuscular or subcutaneous administration), as tablets, suppositories, ointments, as plasters for transdermal application, as aerosols for inhalation through the lungs or as a nasal spray. <br><br> 25 <br><br> The content of active substance in a tablet or suppository is between 5 and 200 mg, preferably between 10 and 50 mg. For inhalation, the individual dose is between 0.05 and 2 0 rtig, preferably between 0.2 and 5 mg. For parenteral 30 injection, the single dose is between 0.1 and 50 mg, <br><br> preferably between 0.5 and 20 mg. The above doses may be administered several times a day if necessary. <br><br> The following are some examples of pharmaceutical 35 preparations containing the active substance: <br><br> WO 00/17176 <br><br> - 12 - <br><br> PCT/EP99/06857 <br><br> Tablets; <br><br> Active substance of general formula I Magnesium stearate <br><br> 2 0.0 mg 1.0 mg 62.0 mg 8 3.0 mg 1.6 mg <br><br> 5 Corn starch Lactose <br><br> Polyvinylpyrrolidone <br><br> Solution for injection <br><br> 10 <br><br> Active substance of general formula I Sodium chloride Water for injections <br><br> 0.3 g 0.9 g ad 10 0 ml <br><br> 15 The solution may be sterilised by standard methods. <br><br> Aqueous solution for nasal administration or inhalation <br><br> The above solution is suitable for nasal administration in 25 a spray or, when used in conjunction with a device which produces an aerosol having a particle size of preferably between 2 and 6 |^m, it is suitable for administration into the lungs. <br><br> 3 0 Capsules for inhalation <br><br> The compounds of general formula I are packed into hard gelatin capsules in micronised form (particle size essentially between 2 and 6 |iM) , optionally with the 35 addition of micronised carrier substances such as lactose. They are inhaled by means of conventional devices for <br><br> Active substance of general formula I <br><br> 0.3 g 0.9 g <br><br> 2 0 Sodium chloride <br><br> Benzalkonium chloride Purified water <br><br> 0.01 mg ad 100 ml <br><br> WO 00/17176 <br><br> - 13 - <br><br> PCT/EP99/06857 <br><br> powder inhalation. Between 0.2 and 2 0 mg of the active substance of general formula I and 0 to 40 mg of lactose are packed into each capsule, for example. <br><br> 5 Aerosol for inhalation <br><br> Active substance of general formula I 1 part <br><br> Soya lecithin - 0.2 parts <br><br> Propellant gas mixture ad 100 parts <br><br> 10 <br><br> The preparation is preferably transferred into aerosol containers with a metering valve, each spray delivering a dose of 0.5 mg. For other dosages in the range specified, preparations containing a larger or smaller proportion of 15 active substance are conveniently used. <br><br> Ointment (composition g/100 g of ointment) <br><br> Active substance of general formula I 2 g <br><br> 2 0 Fuming hydrochloric acid 0.011 g <br><br> Sodium pyrosulphite 0.05 g <br><br> Mixture of equal parts of cetyl alcohol and stearyl alcohol 2 0 g <br><br> White Vaseline 5 g <br><br> 25 Artificial bergamot oil 0.075 g <br><br> Distilled water ad 100 <br><br> The itigredients are processed in the usual way to form an oinCment. <br><br> 30 <br><br> The methods of producing the compounds according to the invention are generally known from the prior art; thus, the compounds according to the invention may be obtained by the following method, for example: <br><br> 35 <br><br> WO 00/17176 <br><br> - 14 - <br><br> PCT/EP99/06857 <br><br> By reacting 4-(1-piperazinyl)-3-trifluoromethylbenzoic acid esters of general formula II <br><br> 10 <br><br> 15 <br><br> H' <br><br> C1 "C4" Alkyl <br><br> (II) <br><br> with a compound of general formula III <br><br> R.CiOQ <br><br> (III) <br><br> wherein Q denotes a leaving group which may be substituted by the piperazine nitrogen, optionally in the presence of adjuvants, preferably carbonyldiimidazole, the resulting benzoic acid derivative of general formula IV <br><br> C1 " C "Alkyl <br><br> (IV) <br><br> is obtained, which is suspended in a suitable, preferably anhydrous, solvent, preferably dimethylformamide, and is 20 mixed with a mixture of a solution or suspension of a base - preferably sodium hydride in a suitable anhydrous solvent - preferably dimethylformamide - with a guanidine salt - preferably guanidine hydrochloride - and the reaction product is isolated. <br><br> WO 00/17176 <br><br> - 15 - <br><br> PCT/EP99/06857 <br><br> The present invention is illustrated by the Examples which follow: <br><br> WO 00/17176 <br><br> - 16 - <br><br> PCT/EP99/06857 <br><br> Examples: <br><br> Methyl 4-fluoro-3 -tri fluoromethyl-benzoate <br><br> 5 35.4 g (170 mmol) of 4-fluoro-3-(trifluoromethyl)-benzoic acid in 250 ml of methanol are mixed with 68 ml of S0C12( whilst .cooling with ice, at 5°C within 25 minutes. After it has all been added, the reaction mixture is refluxed for a further 3 hours. The reaction solution is cooled to 10 ambient temperature and evaporated down in vacuo. The oily residue is taken up in 2 00 ml of diethylether and extracted with water, saturated NaHC03 solution and again with water. The combined organic phases are dried over magnesium sulphate and evaporated down in vacuo. <br><br> 15 <br><br> Yield: 29.0 g (77%) <br><br> Methyl 4-(4-benzvl-l-piperazinyl)-3-trifluoromethyl-benzoate <br><br> 20 <br><br> 7 g (31.5 mmol) of methyl 4-fluoro'-3-trif luoromethyl-benzoate are dissolved in 60 ml of dry dimethylsulphoxide (DMSO) and combined with 5.55 g (31.5 mmol) of N-benzylpiperazine and 4.35 g (31.5 mmol) of potassium 25 carbonate. The mixture is stirred for 12 hours at 90°C. After cooling, the reaction mixture is poured into 200 ml of water and extracted three times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium 30 sulphate and distilled off in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate and n-heptane. <br><br> Yield: 3.93 g (33%) <br><br> 35 <br><br> WO 00/17176 <br><br> - 17 - <br><br> PCT/EP99/06857 <br><br> Methyl 4- (l-piperazinvl) -3-trif luoromethyl-benzoate <br><br> 20.2 g (53.3 mmol) of methyl 4-(4-benzyl-l-piperazinyl)-3-trifluoromethyl-benzoate are dissolved in 200 ml of 5 methanol and combined with 2 g of palladium on charcoal and hydrogenated over a period of 1.4 hours at 7 0°C under a hydrogen pressure of 5 bar. The solution is suction filtered over celite and distilled off in vacuo. <br><br> 10 Yield: 14.85 g (97%) <br><br> General method of coupling methyl 4-(1-piperazinyl)-3-trifluoromethyl-benzoate with benzoic acids: <br><br> 15 5 mmol of the corresponding carboxylic acid are dissolved in 3 0 ml of absolute tetrahydrofuran (THF) and combined under protective gas at 0°C with 810 mg (5 mmol) of carbonyldiimidazole and stirred for 2 hours at ambient temperature (about 25°C) . Then 1.44 g (5 mmol) of methyl <br><br> 20 4-(1-piperazinyl)-3-trifluoromethyl-benzoate are added and the mixture is stirred for about another 12 hours. The solution is evaporated to dryness in vacuo and taken up in ethyl acetate. After washing with saturated NaHC03 solution, saturated NaCl solution and water, the organic <br><br> 25 phases are dried over MgS04 and evaporated down in vacuo. After crystallisation in a suitable solvent or chromatography on silica gel with a suitable eluant, the following compounds are obtained. <br><br> 30 1. methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate <br><br> Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 81% <br><br> 35 <br><br> WO 00/17176 <br><br> - 18 - <br><br> PCT/EP99/06857 <br><br> 2. methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate <br><br> Crystallised from methanol <br><br> Yield: 75% <br><br> Melting point: 149°C <br><br> 3. methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)-3 -trifluoromethyl-benzoate <br><br> Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 77% <br><br> 4. methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate <br><br> Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 79% <br><br> 5. methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate <br><br> Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 83% <br><br> 6. methyl 4-(4-phenylcarbonyl-1-piperazinyl)-3-trifluoromethyl-benzoate <br><br> * Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 87% ;7. methyl 4-(4-(2-furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate ;Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 75% ;WO 00/17176 ;- 19 - ;PCT/EP99/068 57 ;8. methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate ;5 Column chromatography: ethyl acetate/n-heptane (2:1) ;Yield: 79% ;9. methyl 4 -(4 -(4-(1-pyrry1)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate ;10 ;Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 87% ;10. methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3-15 trifluoromethyl-benzoate ;Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 73% ;2 0 General method for preparing aeyl guanidines from the corresponding methyl carbonates: ;5.09 g (127.2 mmol) of 60% NaH in white oil is washed twice with ether and decanted off. 200 ml of absolute DMF 25 are added and 12.15 g (127.2 mmol) of guanidine hydrochloride are added in small amounts with stirring under protective gas. After stirring for 1 hour, ;21.2 Tnmol of the corresponding methyl ester are added and the'solution is stirred for a further 2 hours at a ;3 0 temperature of about 12 0°C. The reaction mixture is then allowed to cool to ambient temperature, filtered and the filtrate is evaporated down in vacuo. After chromatography on silica gel with a suitable eluant and conversion with ethereal hydrochloric acid or other 35 pharmacologically acceptable acids into the corresponding salts, the following compounds are obtained (in the ;WO 00/17176 ;- 20 - ;PCT/EP99/06857 ;10 ;15 ;structural formulae which follow, the hydrogen atoms have been omitted in the interests of clarity, provided that they are bound to a carbon or nitrogen atom and are not required for the understanding of the invention): ;1st Example ;4-(4-(3-Methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride o NH, ;II ;o rV ' ;xHCl from methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl) 3-trifluoromethyl-benzoate ;Column chromatography: ethyl acetate/methanol (5:1) ;Yield: 71% ;20 Melting point: &gt;200°C ;MS: (M+HK = 450 (free base) ;2nd Example ;25 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3- ;trifluoromethyl-benzoylguanidine-methanesulphonate ;WO 00/17176 ;- 21 - ;PCT/EP99/06857 ;from methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate ;Column chromatography: ethyl acetate/methanol (5:1) ;Yield: 66% ;Melting point: 246°C ;MS: (M+HK = 409 (free base) ;3rd Example ;4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate from methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)- ;3-trifluoromethyl-benzoate ;Column chromatography: ethyl acetate/methanol (5:1) ;Yield: 40% ;Melting point: 140°C ;MS: (M+H)" = 438 (free base) ;4th Example ;4-(4-(2-Methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride ;O NH, ;O NH. ;O ;xHCl ;WO 00/17176 ;- 22 - ;PCT/EP99/06857 ;from methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)- ;3-trifluoromethyl-benzoate ;Column chromatography: ethyl acetate/methanol (5:1) ;Yield: 71% ;Melting point: 219°C (decomposition) ;MS: (M+H)+ = 450 (free base) ;5th Example ;4-(4-(3-Trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride from methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperaz inyl)-3 -trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 25% ;Melting point: 140°C (decomposition) ;MS: (M+H)+ = 488 (free base) ;6th Example ;4-(4-Phenylcarbonyl-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride ;O NHj x HCI ;F ;O ;o ish2 ;WO 00/17176 ;- 23 - ;PCT/EP99/068 57 ;from methyl 4-(4-phenylcarbonyl-1-piperazinyl)-3-trifluoromethyl-benzoate ;Column chromatography: ethyl acetate/methanol (5:1) Yield: 64% ;Melting point: 214°C ;MS: (M+H)* = 420 (free base) <br><br> 7th Example <br><br> 4-(4-(2-Furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate x CH,SO,H <br><br> from methyl 4-(4-(2-furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Crystallisation from ether Yield: 19% <br><br> Melting point: 190°C (decomposition) <br><br> MS: (M+H)+ = 410 (free base) <br><br> 8th Example <br><br> 4-(4-(3-Methylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate x CH,SO,H <br><br> WO 00/17176 <br><br> 24 <br><br> PCT/EP99/06857 <br><br> from methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl)-3 -trifluoromethyl-benzoate <br><br> Crystallisation from methanol/ethyl acetate Yield: 76% <br><br> Melting point: 199°C <br><br> MS: (M+H)+ = 434 (free base) <br><br> 9th Example <br><br> 4-(4-(4-(1-Pyrrolyl)phenylcarbonyl)-1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-dimethylsulphonate from methyl 4-(4-(4-(1-pyrryl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Crystallisation from methanol Yield: 48% <br><br> Melting point: 150°C (decomposition) <br><br> MS: (M+H) • = 485 (free base) <br><br> 10th Example <br><br> F <br><br> O NHj <br><br> 4-(4-(2-Pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-dimethanesulphonate <br><br> WO 00/17176 <br><br> - 25 - <br><br> PCT/EP99/068 57 <br><br> 10 from methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate <br><br> Column chromatography: ethyl acetate/methanol (5:1) <br><br> Yield: 34% <br><br> Melting point: 115°C (decomposition) <br><br> 15 MS: (M+H)+ = 421 (free base) <br><br> Pharmacological data <br><br> Inhibition of the Na+/H+ exchanger in human intestinal 20 cancer cells (HT-29): <br><br> HT-29 cells are incubated in growth medium at 37°C with 5% C02. After 3-5 days the growth medium was removed, the cells were washed and charged with 7.5 fiM of BCECF-AM (pH-25 sensitive fluorescent dye) at 37°C without C02. After 30 minutes the cells were washed and acidified with the following medium: 7 0 mM choline chloride, 20 mM NH4C1, 1 mM MgCl2, 1.8 mM CaCl2, 5 mM glucose and 15 mM HEPES, pH 7.5. <br><br> 30 <br><br> After 6 minutes' incubation at 3 7°C without C02 the cells are washed, and incubated for 5 minutes with wash medium: 12 0 mM choline chloride, 5 mM KC1, 1 mM MgCl2, 1.8 mM CaCl2, 5 mM glucose and 15 mM MOPS, pH 7.0. <br><br> 35 <br><br> WO 00/17176 <br><br> - 26 - <br><br> PCT/EP99/06857 <br><br> The wash medium is removed and control medium is added with or without the test compound: 120 mM NaCl, 5 mM KC1, 1 mM MgCl2, 1.8 mM CaCl2; 5mM glucose, 15 mM MOPS, pH 7.0. <br><br> 5 The cells are incubated for 4 minutes at 37°C without C02 and measured fluorimetrically (CytoFluor 2350). The fluorescence of the dye BCECF is measured at the excitation wavelengths 485 nm (pH sensitive) and 440 nm (non-pH sensitive) and at the emission wavelength 530 nm. <br><br> 10 The cytoplasmic pH is calculated from the ratio of fluorescences at 485 and 440 nm. The fluorescence ratio is calibrated by measuring the fluorescent signal after equilibration of external and internal pH with nigericin. <br><br> Example <br><br> IC50/10"6 mol l"1 <br><br> 1 <br><br> 0.076 <br><br> 3 <br><br> 0.038 <br><br> 4 <br><br> 0.084 <br><br> 5 <br><br> 0.023 <br><br> 7 <br><br> 0.084 <br><br> 8 <br><br> 0.061 <br><br> 10 <br><br> 0.079 <br><br> 15 <br><br> The compounds according to the invention also surprisingly have very good bioavailability and long half-lives after oral administration - properties which make them exceptionally suitable for oral use. <br><br> 20 <br><br> Pharmacokinetic data: <br><br> Male rats weighing about 2 00 g (not starved) were used for the tests. For intravenous and oral administration the 25 substances are dissolved in an acidified aqueous solution (pH 3). Individual bolus injections (0.5 mg/kg i.v., 2.5 mg/kg p.o.) are injected into the caudal vein (0.2 ml/200 g) or administered through a cannula into the <br><br></p> </div>

Claims (1)

  1. <div class="application article clearfix printTableText" id="claims"> <p lang="en"> WO 00/17176<br><br> - 27 -<br><br> PCT/EP99/06857<br><br> stomach (1 ml/200 g). The solutions administered are analysed to confirm the dosage given. 0.5 ml aliquots of blood are taken from the retroorbital venous plexus under brief halothane anaesthesia with heparinised glass 5 capillaries according to the following plan:<br><br> after i.v. administration: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h;<br><br> after oral administration: 15 min, 1 h, 2 h, 4 h, 6 h, 10 8 h, 24 h, 32 h.<br><br> The samples are centrifuged and the plasma is stored at -20°C until ready to be analysed. Preparation of the samples is carried out by liquid-liquid extraction with an 15 internal standard. The plasma extracts are analysed by reversed phase HPLC, coupled with an electrospray tandem mass spectrometer.<br><br> The pharmacokinetic data is determined from the 20 corresponding plasma concentrations by compartment-free analysis using the TopFit program (Heinzel, G.,<br><br> Woloszczak, R., Thomann, P. TopFit 2.0 - Pharmacokinetic and pharmacodynamic data analysis, system for the PC, Gustav Fischer Verlag, Stuttgart, Jena, New York, 1993).<br><br> 25<br><br> Example<br><br> F<br><br> t1/2 (i.v.)<br><br> 11/2 (P • O • )<br><br> 2<br><br> 63<br><br> 1.3<br><br> 5.0<br><br> 3<br><br> 71<br><br> 3.1<br><br> 5.4<br><br> 5 *<br><br> 58<br><br> 5.4<br><br> 7.5<br><br> Reference is hereby made to the entire contents of the disclosure of German Patent Application No. 198 43 489, from which the present Patent Application claims priority.<br><br> WO 00/17176<br><br> 28<br><br> PCT/EP99/06857<br><br> Patent Claims<br><br> 1. A benzoylguanidine derivative of general formula I,<br><br> wherein<br><br> Ri denotes Ci-8-alkyl,<br><br> heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched Ci-4-alkyl group, a cycloalkyl group, a branched or unbranched Ci-4-alkoxy group, an NH2 group which may be optionally substituted by one or two Ci-s alkyl, aryl or aralkyl groups which may be identical or different, a trifluoromethyl group, a cyano or nitro group or halogen,<br><br> aryl unsubstituted or mono- or polysubstituted by a branched or unbranched Ci-4-alkyl group, a branched or unbranched Ci_4-alkoxy group, an NH2 group which may be optionally substituted by one or two Ci-8 alkyl, aryl or aralkyl groups which may be identical or different, a trifluoromethyl group, a hydroxy cyano or nitro group or halogen or by a 5- or 6-membered heteroaryl group which may contain one, two, three, four or five heteroatoms selected from nitrogen,<br><br> O<br><br> (I)<br><br> IPONZ<br><br> ' I AUb 2003<br><br> WO 00/17176<br><br> - 29 -<br><br> PCT/EP99/06857<br><br> oxygen and sulphur - identical to one another or different -<br><br> alkylaryl, unsubstituted or mono- or polysubstituted in the aryl and/or alkyl partial structure by a branched or unbranched Ci_4-alkyl group, a branched or unbranched Ci-4-alkoxy group, an NH2 group which may be optionally substituted by one or two Ci_8 alkyl, aryl or aralkyl groups which may be identical or different, a trifluoromethyl group, a cyano or nitro group or halogen,<br><br> optionally in the form of the individual tautomers or optionally enantiomers and mixtures thereof and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.<br><br> 2. A compound of general formula I according to claim 1, wherein<br><br> Ri denotes an unsubstituted phenyl ring or a phenyl ring which is substituted by fluorine or by a methyl, trifluoromethyl, methoxy group or by a pyrrolyl group, or<br><br> 3 . 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethy1-benzoylguanidine-methanesulphonate<br><br> O NH.<br><br> IPONZ<br><br> 0<br><br> 1 1 AUG 2003<br><br> WO 00/17176<br><br> - 30 -<br><br> PCT/EP99/06857<br><br> 4. 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate<br><br> 0 NH,<br><br> A<br><br> N NH<br><br> CH3SO3H<br><br> 5. Process for preparing a compound of general formula I<br><br> N<br><br> N<br><br> NH„<br><br> NH,<br><br> R«|\ ^ N<br><br> O<br><br> (I)<br><br> in which 4-(l-piperazinyl-3-trifluoromethylbenzoic acid ester of general formula II<br><br> O<br><br> N<br><br> H'<br><br> N<br><br> C1 -C4 -Alkyl<br><br> (II)<br><br> is reacted with a compound of general formula III<br><br> RiC(0)Q<br><br> (III)<br><br> IPONZ<br><br> 11 AUB 2003<br><br> WO 00/17176<br><br> - 31 -<br><br> PCT/EP99/06857<br><br> in which R is as defined in claim 1 and Q denotes a leaving group which may be substituted by the secondary piperazine nitrogen, optionally in the presence of adjuvants and the resulting benzoic acid derivative of general formula IV<br><br> O<br><br> (IV)<br><br> is suspended in a suitable solvent and is mixed with a mixture of a solution or suspension of a base in the presence of a guanidine salt and the reaction product is isolated and, optionally, the desired acid addition salt is formed with a pharmacologically acceptable acid.<br><br> 6. Process according to claim 5 wherein said adjuvant is carbonyldiimidazole.<br><br> 7. Process according to claim 5 or 6 wherein said solvent is anhydrous.<br><br> 8. Process according to any one of claims 5 to 7 wherein said solvent is dimethylformamide.<br><br> 9. Process according to any one of claims 5 to 8 wherein said mixture of a solution or suspension of a base is sodium hydride in a suitable anhydrous solvent.<br><br> 10. Process according to claim 9 wherein said anhydrous solvent is dimethylformamide.<br><br> WO 00/17176<br><br> - 32 -<br><br> PCT/EP99/06857<br><br> 11. Process according to any one of claims 5 to 10 wherein said guanidine salt is guanidine hydrochloride.<br><br> 12. Pharmaceutical preparation containing a compound<br><br> 5 according to one of claims 1 to 4 and the acid addition salts thereof together with conventional excipients and carriers.<br><br> 13. A compound according to one of claims 1 to 4 or a 10 preparation according to claim 12 for use in therapy.<br><br> 14. A compound according to one of claims 1 to 4 or a preparation according to claim 12 for use in the inhibition of cellular Na+/H+ exchange.<br><br> 15<br><br> 15. A compound according to one of claims 1 to 4 or a preparation according to claim 12 for use in the therapeutic treatment of ischaemias.<br><br> 20 16. A compound according to one of claims 1 to 4 or a preparation according to claim 12 for use in the treatment of coronary heart disease, cardiac infarct, angina pectoris, stable angina pectoris, ventricular arrhythmias, sub-ventricular arrhythmias, cardiac insufficiency, 25 embolism in the pulmonary circulation, acute or chronic kidney failure, chronic kidney insufficiency, cerebral infarct, reperfusion damage caused by the resumption of blood supply to areas of the brain after the clearing of vascular occlusions and acute and chronic bleeding 30 disorders in the brain; for use in support of operations which require the blood supply to the heart to be interrupted; for use as a cardioprotectant during reperfusion of the ischaemic heart; or for use in prevention of damage to transplants during and after 35 implantation and during storage of the organs for transplant. - •<br><br> 5 O. '<br><br> pro<br><br> V*<br><br> WO 00/17176 - 33 - PCT/EP99/06857<br><br> 17. A compound according to one of claims 1 to 4 or a preparation according to claim 12 for use in the treatment of arrhythmias, essential hypertension or diabetic nephropathy.<br><br> 5<br><br> 18. Use of a compounds of general formula I as defined in any one of claims 1 to 4 or a preparation according to claim 12 for the preparation of a medicament for the therapeutic treatment of ischaemias.<br><br> 10<br><br> 19. Use of a compound according to one of claims 1 to 4 or a preparation according to claim 12 in the preparation of a medicament for the treatment of coronary heart disease, cardiac infarct, angina pectoris, stable angina<br><br> 15 pectoris, ventricular arrhythmias, sub-ventricular arrhythmias, cardiac insufficiency, embolism in the pulmonary circulation, acute or chronic kidney failure, chronic kidney insufficiency, cerebral infarct,<br><br> reperfusion damage caused by the resumption of blood<br><br> 20 supply to areas of the brain after the clearing.of vascular occlusions and acute and chronic bleeding disorders in the brain; for use in support of operations which require the blood supply to the heart to be interrupted; for use as a cardioprotectant during<br><br> 25 reperfusion of the ischaemic heart; or for use in prevention of damage to transplants during and after implantation and during storage of the organs for transplant.<br><br> 30 20. Use of a compound according to one of claims 1 to 4 or a preparation according to claim 12 in the preparation of a medicament for the treatment of arrhythmias,<br><br> essential hypertension or diabetic nephropathy.<br><br> WO 00/17176<br><br> 34<br><br> PCT/EP99/06857<br><br> 21. A compound of formula I as defined in claim 1 substantially as hereinbefore described and in reference to the Examples.<br><br> 5 22. A process for the preparation of a compound of formula I as defined in claim 1 substantially as hereinbefore described and in reference to the Examples.<br><br> 23. A pharmaceutical preparation comprising a compound of 10 formula I as defined in claim 1 substantially as hereinbefore described and in reference to the Examples.<br><br> 15 B<br><br> BALDWIN SHELSTON WATERS<br><br> O<br><br> *<br><br> -.3<br><br> r<br><br> </p> </div>
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