AU6465999A - 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 Download PDFInfo
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- AU6465999A AU6465999A AU64659/99A AU6465999A AU6465999A AU 6465999 A AU6465999 A AU 6465999A AU 64659/99 A AU64659/99 A AU 64659/99A AU 6465999 A AU6465999 A AU 6465999A AU 6465999 A AU6465999 A AU 6465999A
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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
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- C07D207/02—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
- 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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- C07D213/02—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
- 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
- C07D213/78—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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- C07D295/00—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
- 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
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description
WO 00/17176 - 1 - PCT/EP99/06857 S018-639pct .204 New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in 5 the production of pharmaceutical compositions The present invention relates to novel benzoylguanidine derivatives of general formula I, processes for preparing them and their use in the preparation of pharmaceutical 10 compositions F N NH2 N2 R N 0 (I) wherein 15 Ri denotes C 18 -alkyl, heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C -alkyl group, a 20 cycloalkyl group, a branched or unbranched C 14 -alkoxy group, an NH 2 group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, 25 aryl unsubstituted or mono- or polysubstituted by a branched or unbranched C 14 -alkyl group, a branched or unbranched C 1 4 -alkoxy group, an NH 2 group or a primary or secondary amino group, a trifluoromethyl group, a hydroxy, cyano or nitro group or halogen or 30 by a 5- or 6-membered heteroaryl group which may WO 00/17176 - 2 - PCT/EP99/06857 contain one, two, three, four or five heteroatoms selected from nitrogen, oxygen and sulphur identical to one another or different 5 alkylaryl, unsubstituted or mono- or polysubstituted in the aryl and/or alkyl partial structure by a branched or unbranched C 1 4 -alkyl group, a branched or unbranched C 1 4 -alkoxy group, an NH 2 group or a primary or secondary amino group, a trifluoromethyl 10 group, a cyano or nitro group or halogen, 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. The preferred compounds for the purposes of the present invention are the compounds of general formula I wherein 20 RI 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 N N 25 The following compounds are particularly preferred: 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoylguanidine methanesulphonate 30 WO 00/17176 - 3 - PCT/EP99/06857 0
NH
2 H F oF 5 0 X CH 3
SO
3 H and 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3 10 trifluoromethyl-benzoylguanidine methanesulphonate o NH, N NH F NX CH 3
SO
3 H 15 N F F F 0
C
1 4 -alkyl or Cl- alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 4 or 8 carbon 20 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: 25 methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1 dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1 ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3 30 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-l-methylpropyl and 1-ethyl-2-methylpropyl. Unless 35 otherwise stated, the preferred hydrocarbon groups are WO 00/17176 - 4 - PCT/EP99/06857 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. 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. 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 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 20 preferred halogen. The aryl substituent - 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 25 may be identical or different. Aralkyl generally denotes an aryl group having 7 to 14 carbon atoms bound via an alkylene chain, the aromatic grodip optionally being substituted by one or more lower 30 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. 35 WO 00/17176 - 5 - PCT/EP99/06857 The preferred aralkyl groups - unless otherwise stated are benzyl, phenethyl and phenylpropyl. Halogen, unless otherwise stated - denotes fluorine, 5 chlorine, bromine and iodine, preferably fluorine, chlorine or bromine. Unless otherwise specified, amino denotes an NH 2 function which may optionally be substituted by one or two 10 C 18 -alkyl, aryl or aralkyl groups, which may be identical or different. Accordingly, alkylamino denotes for example methylamino, ethylamino, propylamino, 1-methylene-ethylamino, 15 butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino. Correspondingly, dialkylamino denotes, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, 20 di-(1-methylethyl)amino, di- (1-methylpropyl)amino, di-2 methylpropylamino, ethylmethylamino, methylpropylamino. Cycloalkyl generally denotes a saturated or unsaturated cyclic hydrocarbon group having 5 to 9 carbon atoms which 25 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, 30 cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and cyclononinyl. Heteroaryl for the purposes of the above definition 35 generally denotes a 5- to 6-membered ring which may contain oxygen, sulphur and/or nitrogen as heteroatoms and WO 00/17176 - 6 - PCT/EP99/06857 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. 5 Examples of particular heterocyclic systems include: acridiuyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, 10 azanaphthacenyl, azanaphthalenyl, azaprenyl, azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl, benzacridinyl, benzazapinyl, benzofuryl, benzonaphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, 15 benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl, carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl, cumarinyl, cumaronyl, decahydroquinolinyl, decahydroquinolonyl, diazaanthracenyl, diazaphenanthrenyl, 20 dibenzazapinyl, dibenzofuranyl-, dibenzothiphenyl, dichromylenyl, dihydrofuranyl, dihydroisocumarinyl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl, diprylenyl, dioxanthylenyl, oenantholactamyl, flavanyl, 25 flavonyl, fluoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydtofuranonyl, hydroindolyl, hydropyranyl, 30 hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, 35 isoindolyl, isoquinolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, WO 00/17176 - 7 - PCT/EP99/06857 naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, 5 phenanthraquinonyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyrandionyl, pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinethionyl, 10 pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl, pyronyl, pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl, pyrrolizinyl, pyrrolodioazinyl, pyrrolonyl, 15 pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinolinyl, quinolizidinyl, quinolizinyl, quinolonyl, quinuclidinyl, rhodaminyl, spirocumaranyl, succinimidyl, sulpholanyl, sulpholenyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, 20 tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrothipyranonyl, tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl, thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, 25 thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl, thiopyranyl, triazaanthracenyl, triazinoindolyl, triazolopyridinyl, tropanyl, xanthenyl, xanthonyl, xathydrolyl, adeninyl, alloxanyl, alloxazinyl, antliranilyl, azabenzanthrenyl, azabenzonaphthenyl, 30 azanaphthacenyl, azaphenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl; benzodioxolyl, benzopyridazinyl, 35 benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl, WO 00/17176 - 8 - PCT/EP99/06857 depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, 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, 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, 20 oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenoxazonyl, phthalazinyl, piperazindionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl, 25 purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, 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, WO 00/17176 - 9 - PCT/EP99/06857 thiazolidinonyl, thiazolidinyl, thiazolinonyl, thiazolinyl, thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xanthinyl, xylitolyl, 5 azabenzonaphththenyl, benzofuroxanyl, benzothiadiazinyl, benzotriazepinonyl, benzotriazolyl, benzoxadiazinyl, dioxadiazinyl, dithiadazolyl, dithiazolyl, furazanyl, furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxadiazolyl, oxathiazinonyl, oxatriazolyl, pentazinyl, 10 pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, thiadiazinyl, thiadiazolinyl, thiadiazolyl, thiadioxazinyl, thiatriazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, 15 triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadiazepinyl, trithianyl or trioxolanyl. Compounds of this type are already known from German 20 published application 196 01 303.8. As a result of their effect as inhibitors of cellular Na*/I* exchange, such compounds may be used as active ingredients of pharmaceutical compositions or they may be 25 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, 30 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, 35 ventricular arrhythmias, sub-ventricular arrhythmias, cardiac insufficiency - and also in support of bypass WO 00/17176 - 10 - PCT/EP99/06857 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. 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. 20 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. In essential hypertension and diabetic nephropathy the 30 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. 35 The compounds according to the invention are further characterised by a powerful inhibitory effect on the WO 00/17176 - 11 - PCT/EP99/06857 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. Moreover, compounds of this type are known to have a 10 favourable effect on the blood levels of the serum lipoproteins. 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. The active substances according to general formula I may 20 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. 25 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 20 itg, preferably between 0.2 and 5 mg. For parenteral 30 injection, the single dose is between 0.1 and 50 mg, preferably between 0.5 and 20 mg. The above doses may be administered several times a day if necessary. The following are some examples of pharmaceutical 35 preparations containing the active substance: WO 00/17176 - 12 - PCT/EP99/06857 Tablets: Active substance of general formula I 20.0 mg Magnesium stearate 1.0 mg 5 Corn starch 62.0 mg Lactose 83.0 mg Polyvinylpyrrolidone 1.6 mg Solution for injection 10 Active substance of general formula I 0.3 g Sodium chloride 0.9 g Water for injections ad 100 ml 15 The solution may be sterilised by standard methods. Aqueous solution for nasal administration or inhalation Active substance of general formula I 0.3 g 20 Sodium chloride 0.9 g Benzalkonium chloride 0.01 mg Purified water ad 100 ml 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 pm, it is suitable for administration into the lungs. 30 Capsules for inhalation The compounds of general formula I are packed into hard gelatin capsules in micronised form (particle size essentially between 2 and 6 pM), optionally with the 35 addition of micronised carrier substances such as lactose. They are inhaled by means of conventional devices for WO 00/17176 - 13 - PCT/EP99/06857 powder inhalation. Between 0.2 and 20 mg of the active substance of general formula I and 0 to 40 mg of lactose are packed into each capsule, for example. 5 Aerosol for inhalation Active -substance of general formula I 1 part Soya lecithin . 0.2 parts Propellant gas mixture ad 100 parts 10 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. Ointment (composition g/100 g of ointment) Active substance of general formula I 2 g 20 Fuming hydrochloric acid 0.011 g Sodium pyrosulphite 0.05 g Mixture of equal parts of cetyl alcohol and stearyl alcohol 20 g White Vaseline 5 g 25 Artificial bergamot oil 0.075 g Distilled water ad 100 The ingredients are processed in the usual way to form an ointment. 30 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: 35 WO 00/17176 - 14 - PCT/EP99/06857 By reacting 4-(1-piperazinyl)-3-trifluoromethylbenzoic acid esters of general formula II FF 0 F 0
-C
4 -Alkyl H'N 5 (II) with a compound of general formula III RiC(0)Q (III) 10 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 15 FF 0 F 0 1 I N - C4 -Alkyl R1I N 0 (IV) 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.
WO 00/17176 - 15 - PCT/EP99/06857 The present invention is illustrated by the Examples which follow: WO 00/17176 - 16 - PCT/EP99/06857 Examples: Methyl 4-fluoro-3-trifluoromethyl-henzoate 5 35.4 g (170 mmol) of 4-fluoro-3-(trifluoromethyl)-benzoic acid in 250 ml of methanol are mixed with 68 ml of SOCl 2 , whilst .cooling with ice, at 5 0 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 200 ml of diethylether and extracted with water, saturated NaHCO, solution and again with water. The combined organic phases are dried over magnesium sulphate and evaporated down in vacuo. 15 Yield: 29.0 g (77%) Methyl 4- (4-henzyl-1-piperazinyl)-3-trifluoromethyl henzoate 20 7 g (31.5 mmol) of methyl 4-fluoro-3-trifluoromethyl 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 0 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. Yield: 3.93 g (33%) 35 WO 00/17176 - 17 - PCT/EP99/06857 Methyl 4-(1-piperazinyl')-3-trifluoromethyl-henzoate 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 70 0 C under a hydrogen pressure of 5 bar. The solution is suction filtered over celite and distilled off in vacuo. 10 Yield: 14.85 g (97%) General method of coupling methyl 4-(1-piperazinyl)-3 trifluoromethyl-benzoate with benzoic acids: 15 5 mmol of the corresponding carboxylic acid are dissolved in 30 ml of absolute tetrahydrofuran (THF) and combined under protective gas at 0 0 C with 810 mg (5 mmol) of carbonyldiimidazole and stirred for 2 hours at ambient temperature (about 25 0 C). Then 1.44 g (5 mmol) of methyl 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 NaHCO 3 solution, saturated NaCl solution and water, the organic 25 phases are dried over MgSO 4 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. 30 1. methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl) 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 81% 35 WO 00/17176 - 18 - PCT/EP99/06857 2. methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoate Crystallised from methanol 5 Yield: 75% Melting point: 149 0 C 3. methyl 4-(4-'(4-fluorophenylcarbonyl)-1-piperazinyl) 3-trifluoromethyl-benzoate 10 Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 77% 4. methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl) 15 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 79% 20 5. methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1 piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 83% 25 6. methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3 trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) 30 Yield: 87% 7. methyl 4-(4-(2-furylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoate 35 Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 75% WO 00/17176 - 19 - PCT/EP99/06857 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-(l-pyrryl)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% 20 General method for preparing acyl 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 wmol of the corresponding methyl ester are added and the'solution is stirred for a further 2 hours at a 30 temperature of about 120 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 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): 5 1st Example 4-(4-(3-Methoxyphenylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoylguanidine-hydrochloride 10 0 NH H Hx HCI 0 15 from methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl) 3 -trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 71% 20 Melting point: >200 0 C MS: (M+H)* = 450 (free base) 2nd Example 25 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoylguanidine-methanesulphonate 0
NH
2 S N NH 30 N x CH 3
SO
3 H N N F F F 0 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% 5 Melting point: 246 0 C MS: (M+H)* = 409 (free base) 3rd Example 10 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3 trifluoromethyl -benzoylguanidine-methanesulphonate 0 NH 2 SN NH 15 F N N F x CH 3
SO
3 H F 0 from methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl) 20 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 40% Melting point: 140 0 C MS: (M+H)* = 438 (free base) 25 4th Example 4- (4- (2-Methoxyphenylcarbonyl) -1-piperazinyl) -3 trifluoromethyl-benzoylguanidine-hydrochloride 30 0 NH 2 N NH N X HCI NJ F F
H
3 C' O
F
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% 5 Melting point: 219 0 C (decomposition) MS: (M+H)* = 450 (free base) 5th Example 10 4-(4-(3-Trifluoromethylphenylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoylguanidine-hydrochloride 0 NH 2 11 N NH 15 N ' F N F F x HCI F 0 from methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1 piperazinyl) -3 -trifluoromethyl-benzoate 20 Column chromatography: ethyl acetate/methanol (5:1) Yield: 25% Melting point: 140*C (decomposition) MS: (M+H)* = 488 (free base) 25 6th Example 4- (4-Phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl bentoylguanidine -hydrochloride 0 NH 30 N NH N NF F o F x HCI 0 WO 00/17176 - 23 - PCT/EP99/06857 from methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3 trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 64% 5 Melting point: 214 0 C MS: (M+H)* = 420 (free base) 7th Example 10 4-(4-(2-Furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl benzoylguanidine-methanesulphonate 0 NH 2 I N NH 15 N F NJ F o x CH 3
SO
3 H from methyl 4-(4-(2-furylcarbonyl)-1-piperazinyl)-3 20 trifluoromethyl-benzoate Crystallisation from ether Yield: 19% Melting point: 190'C (decomposition) MS: (M+H)* = 410 (free base) 25 8th Example 4- (4- (3-Methylphenylcarbonyl) -1-piperazinyl) -3 trifluoromethyl-benzoylguanidine -methanesulphonate 30 N NH NTN N
H
3 C F F F x CH 3
SO
3 H 0 WO 00/17176 - 24 - PCT/EP99/06857 from methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl) 3-trifluoromethyl-benzoate Crystallisation from methanol/ethyl acetate Yield: 76% 5 Melting point: 199 0 C MS: (M+H)* = 434 (free base) 9th Example 10 4
-(
4 -(4-(l-Pyrrolyl)phenylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoylguanidine-dimethylsulphonate N 15 o N x 2 CH 3
SO
3 H N F ~N NH F 0 NH 2 20 from methyl 4- (4- (4- (l-pyrryl)phenylcarbonyl) -1 piperazinyl)-3-trifluoromethyl-benzoate Crystallisation from methanol Yield: 48% 25 Melting point: 150 0 C (decomposition) MS: (M+H)* = 485 (free base) 10th Example 30 4-(4-(2-Pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl benzoylguanidine- dimethanesulphonate WO 00/17176 - 25 - PCT/EP99/06857 N 0 N 5 N F ; N NH F 0 NH 2 x 2 CHISO 3 H 10 from methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3 trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 34% Melting point: 115*C (decomposition) 15 MS: (M+H)* = 421 (free base) Pharmacological data Inhibition of the Na*/H* exchanger in human intestinal 20 cancer cells (HT-29): HT-29 cells are incubated in growth medium at 37 0 C with 5%
CO
2 - After 3-5 days the growth medium was removed, the cells were washed and charged with 7.5 pM of BCECF-AM (pH 25 sensitive fluorescent dye) at 37 0 C without CO 2 - After 30 minutes the cells were washed and acidified with the following medium: 70 mM choline chloride, 20 mM NH 4 C1, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 5 mM glucose and 15 mM HEPES, pH 7.5. 30 After 6 minutes' incubation at 37 0 C without CO 2 the cells are washed, and incubated for 5 minutes with wash medium: 120 mM choline chloride, 5 mM KCl, 1 mM MgCl 2 , 1-8 mM CaCl 2 , 5 mM glucose and 15 mM MOPS, pH 7. 0. 35 WO 00/17176 - 26 - PCT/EP99/06857 The wash medium is removed and control medium is added with or without the test compound: 120 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 5mM glucose, 15 mM MOPS, pH 7.0. 5 The cells are incubated for 4 minutes at 37 0 C without CO 2 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. 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. Example
IC
0 /10- 6 mol 11 1 0.076 3 0.038 4 0.084 5 0.023 7 0.084 8 0.061 10 0.079 15 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. 20 Pharmacokinetic data: Male rats weighing about 200 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 WO 00/17176 - 27 - PCT/EP99/06857 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: - after i.v. administration: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h; - after oral administration: 15 min, 1 h, 2 h, 4 h, 6 h, 10 8 h, 24 h, 32 h. 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. The pharmacokinetic data is determined from the 20 corresponding plasma concentrations by compartment-free analysis using the TopFit program (Heinzel, G., Woloszczak, R., Thomann, P. TopFit 2.0 - Pharmacokinetic and pharmacodynamic data analysis, system for the PC, Gustav Fischer Verlag, Stuttgart, Jena, New York, 1993). 25 Example F t 1
/
2 (iv.) t 1 2 (p.o.) 2 63 1.3 5.0 3 71 3.1 5.4 5 58 5.4 7.5 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.
Claims (4)
1. Benzoylguanidine derivatives of general formula I, FF NH 2 F F O NH 2 F N~ -r N NH 2 R N 0 5 wherein R 1 denotes C,_--alkyl, 10 heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched Ci--alkyl group, a cycloalkyl group, a branched or unbranched C -- alkoxy group, an NH 2 group or a primary or secondary amino 15 group, a trifluoromethyl group, a cyano or nitro group or halogen, aryl unsubstituted or mono- or polysubstituted by a branched or unbranched C, 4 - alkyl group, a branched or 20 unbranched C 1 4 -alkoxy group, an NH 2 group or a primary or secondary amino group, a trifluoromethyl group, 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 25 nitrogen, oxygen and sulphur - identical to one another or different alkylaryl, unsubstituted or mono- or polysubstituted in the aryl and/or alkyl partial structure by a WO 00/17176 - 29 - PCT/EP99/06857 branched or unbranched C 1 4 -alkyl group, a branched or unbranched C 1 4 -alkoxy group, an NH 2 group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, 5 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. 10 2. Compounds of general formula I according to claim 1, characterised in that R 1 may denote an unsubstituted phenyl ring or a phenyl 15 ring which is substituted by fluorine or by a methyl, trifluoromethyl, methoxy group or by a pyrrolyl group, or N N 20 3. 4 -( 4 -(2-Pyrrolylcarbonyl)-l-piperazinyl)-3 trifluoromethyl-benzoylguanidine-methanesulphonate 0 NH N NH 25 * N S N F F XCH 3 SO 3 H F 0 4. 4- (4- (4-Fluorophenylcarbonyl) -1-piperazinyl) -3 30 trifluoromethyl-benzoylguanidine-methanesulphonate WO 00/17176 - 30 - PCT/EP99/06857 N NH SNNH F F F X CHSO 3 H 0 5 5. Process for preparing compounds of general formula I F NH 2 NH 2 R 1 N 0 (I) 10 characterised in that 4-(l-piperazinyl-3-trifluoromethyl benzoic acid ester of general formula II F F 0 F O N C- C 4 -Alkyl H'N 15 is reacted with a compound of general formula III R 1 C(O)Q (III) 20 wherein Q denotes a leaving group which may be substituted by the piperazine nitrogen, optionally in the presence of adjuvants, preferably carbonyldiimidazole, and the resulting benzoic acid derivative of general formula IV WO 00/17176 - 31 - PCT/EP99/06857 F F O F 0' 0 NC - C 4 - Alkyl R1 N 0 (IV) is suspended in a suitable, preferably anhydrous, solvent, 5 preferably dimethylformamide, and is 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 10 isolated and, optionally, the desired acid addition salt is formed with a pharmacologically acceptable acid. 6. Pharmaceutical preparation, characterised in that it contains a compound according to one of claims 1 to 4 and 15 the acid addition salts thereof together with conventional excipients and carriers.
7. Use of compounds according to one of claims 1 to 4 as pharmaceutical compositions. 20
8. Use of compounds after use of compounds according to claim 7 as pharmaceutical compositions having an inhibitory effect on the Na*/H* exchange. 25 9. Use of compounds of general formula I, the acid addition salts thereof for preparing a medicament for the therapeutic treatment of ischaemias.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843489A DE19843489B4 (en) | 1998-09-22 | 1998-09-22 | Benzoylguanidine derivatives having advantageous properties, processes for their preparation and their use in the preparation of medicaments, and pharmaceutical compositions containing them |
| DE19843489 | 1998-09-22 | ||
| PCT/EP1999/006857 WO2000017176A2 (en) | 1998-09-22 | 1999-09-16 | Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU6465999A true AU6465999A (en) | 2000-04-10 |
| AU764819B2 AU764819B2 (en) | 2003-08-28 |
| AU764819C AU764819C (en) | 2004-12-16 |
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|---|---|---|---|
| AU64659/99A Ceased AU764819C (en) | 1998-09-22 | 1999-09-16 | Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments |
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|---|---|
| EP (1) | EP1165534B1 (en) |
| JP (1) | JP3817425B2 (en) |
| KR (1) | KR100621821B1 (en) |
| CN (1) | CN1166654C (en) |
| AR (1) | AR023668A1 (en) |
| AT (1) | ATE288425T1 (en) |
| AU (1) | AU764819C (en) |
| BG (1) | BG64985B1 (en) |
| BR (1) | BR9913107A (en) |
| CA (1) | CA2345006C (en) |
| CO (1) | CO5150207A1 (en) |
| CZ (1) | CZ300158B6 (en) |
| DE (2) | DE19843489B4 (en) |
| EA (1) | EA004687B1 (en) |
| EE (1) | EE04749B1 (en) |
| EG (1) | EG23757A (en) |
| ES (1) | ES2237951T3 (en) |
| HK (1) | HK1043367B (en) |
| HR (1) | HRP20010194B1 (en) |
| HU (1) | HU228955B1 (en) |
| ID (1) | ID27759A (en) |
| IL (1) | IL141805A (en) |
| MY (1) | MY121362A (en) |
| NO (1) | NO317993B1 (en) |
| NZ (1) | NZ511167A (en) |
| PE (1) | PE20001085A1 (en) |
| PL (1) | PL195291B1 (en) |
| PT (1) | PT1165534E (en) |
| RS (1) | RS49971B (en) |
| SA (1) | SA99200474B1 (en) |
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| TR (1) | TR200100801T2 (en) |
| TW (1) | TWI221841B (en) |
| WO (1) | WO2000017176A2 (en) |
| ZA (1) | ZA200101212B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10106970A1 (en) * | 2001-02-15 | 2002-08-29 | Boehringer Ingelheim Pharma | New benzoylguanidine salt |
| US6730678B2 (en) * | 2001-02-15 | 2004-05-04 | Boehringer Ingelheim Pharma Kg | Benzoylguanidine salt and hydrates thereof |
| DE10144030A1 (en) * | 2001-09-07 | 2003-03-27 | Boehringer Ingelheim Pharma | Composition containing 4-piperazino-benzoylguanidine derivative, useful e.g. for treating cardiac infarction, containing component to improve local tolerance, e.g. beta-cyclodextrin derivative or polymer |
| US6982256B2 (en) | 2001-09-07 | 2006-01-03 | Boehringer Ingelheim Pharma Kg | Tolerance of 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine in intravenous administration |
| FR2871157A1 (en) * | 2004-06-04 | 2005-12-09 | Aventis Pharma Sa | BIARYL AROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF |
| JP2011527677A (en) * | 2008-07-08 | 2011-11-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Pyrrolidinyl and piperidinyl compounds useful as NHE-1 inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19601303A1 (en) * | 1996-01-16 | 1997-07-17 | Boehringer Ingelheim Kg | Novel benzoylguanidine derivatives, process for their preparation and their use in the manufacture of medicaments |
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1998
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- 1999-09-16 WO PCT/EP1999/006857 patent/WO2000017176A2/en active IP Right Grant
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- 1999-09-16 AU AU64659/99A patent/AU764819C/en not_active Ceased
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- 1999-09-16 EE EEP200100178A patent/EE04749B1/en not_active IP Right Cessation
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2001
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