CA2345006C - New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in the production of pharmaceutical compositions - Google Patents
New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in the production of pharmaceutical compositions Download PDFInfo
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- 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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- C07D295/18—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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Abstract
The invention relates to novel benzoylguanidine derivatives of general formula (I), to a method for producing them and to their use in the production of medicaments.
Description
+ , .
S018-639pct.204 New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in 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 compositions F O
F / N =~
N
O
(I) wherein R1 denotes C1 .-alkyl, heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C1_4-alkyl group, a cycloalkyl group, a branched or unbranched C1_4-alkoxy group, an NHZ group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, aryl unsubstituted or mono- or polysubstituted by a branched or unbranched C1_4-alkyl group, a branched or unbranched C1_4-alkoxy group, an NHz 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 contain one, two, three, four or: five heteroatoms selected from 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 branched or unbranched C1_4-alkyl group, a branched or unbranched C1_, -alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl 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 salts with pharmacologically acceptable acids.
The preferred compounds for the purposes of the present invention are the compounds of general formula I wherein R1 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 O
The following compounds are particularly preferred:
4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine methanesulphonate O NHz N NH
N
fl N
FFF
O
X CiH3SO3H
and 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine methanesulphonate l~ Z
'-N~ 1~NH
F'I'~F
F
O
C1_4-alkyl or C1_B-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:
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-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 i-ethyl-2-methylpropyl. Unless otherwise stated, the preferred hydrocarbon groups are 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.
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.
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 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 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 may be identical or different.
Aralkyl generally denotes an aryl group having 7 to 14 carbon atoms bound via an alkylene chain, the aromatic group optionally being substituted by one or more lower 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.
S018-639pct.204 New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in 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 compositions F O
F / N =~
N
O
(I) wherein R1 denotes C1 .-alkyl, heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C1_4-alkyl group, a cycloalkyl group, a branched or unbranched C1_4-alkoxy group, an NHZ group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, aryl unsubstituted or mono- or polysubstituted by a branched or unbranched C1_4-alkyl group, a branched or unbranched C1_4-alkoxy group, an NHz 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 contain one, two, three, four or: five heteroatoms selected from 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 branched or unbranched C1_4-alkyl group, a branched or unbranched C1_, -alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl 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 salts with pharmacologically acceptable acids.
The preferred compounds for the purposes of the present invention are the compounds of general formula I wherein R1 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 O
The following compounds are particularly preferred:
4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine methanesulphonate O NHz N NH
N
fl N
FFF
O
X CiH3SO3H
and 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine methanesulphonate l~ Z
'-N~ 1~NH
F'I'~F
F
O
C1_4-alkyl or C1_B-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:
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-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 i-ethyl-2-methylpropyl. Unless otherwise stated, the preferred hydrocarbon groups are 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.
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.
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 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 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 may be identical or different.
Aralkyl generally denotes an aryl group having 7 to 14 carbon atoms bound via an alkylene chain, the aromatic group optionally being substituted by one or more lower 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.
The preferred aralkyl groups - unless otherwise stated -are benzyl, phenethyl and phenylpropyl.
Halogen, unless otherwise stated - denotes fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
Unless otherwise specified, amino denotes an NH2 function which may optionally be substituted by one or two C1_8-alkyl, aryl or aralkyl groups, which may be identical or different.
Accordingly, alkylamino denotes for example methylamino, ethylamino, propylamino, 1-methylene--ethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.
Correspondingly, dialkylamino denotes, for example, dimethylamino, diet:hylamino, dipropylamino, dibutylamino, 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 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.
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 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.
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, decahydroquino:linyl, decahydroquinolonyl, diazaanthraceny:l, 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, hydrofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, isoindolyl, isoquiriolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihyd:ropyranyl, 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, all.oxazinyl, anthranilyl, azabenzanthrenyl, azaberizonaphthenyl, 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, depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glycocyamidinyl, guaninyl, hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl, hydantoinyl, hydroimidazolyl, hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenoxazonyl, phthalazinyl, piperazindionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinethionyl, pyrimidinyl, pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl., thiazepinyl, thiazinyl, thiazolidinonyl, thiazolidinyl, thiazolinonyl, 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, thiadioxazinyl, thiatriazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadiazepinyl, trithianyl or trioxolanyl.
Compounds of this type are already known from German published application 196 01 303.8.
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 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 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 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 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.
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 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 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.
The compounds according to the invention are further characterised by a powerful inhibitory effect on the 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, benigri tumours or for 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 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 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 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.
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 mg, preferably between 0.2 and 5 mg. For parenteral 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 preparations containing the active substance:
Halogen, unless otherwise stated - denotes fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
Unless otherwise specified, amino denotes an NH2 function which may optionally be substituted by one or two C1_8-alkyl, aryl or aralkyl groups, which may be identical or different.
Accordingly, alkylamino denotes for example methylamino, ethylamino, propylamino, 1-methylene--ethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.
Correspondingly, dialkylamino denotes, for example, dimethylamino, diet:hylamino, dipropylamino, dibutylamino, 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 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.
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 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.
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, decahydroquino:linyl, decahydroquinolonyl, diazaanthraceny:l, 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, hydrofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, isoindolyl, isoquiriolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihyd:ropyranyl, 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, all.oxazinyl, anthranilyl, azabenzanthrenyl, azaberizonaphthenyl, 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, depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glycocyamidinyl, guaninyl, hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl, hydantoinyl, hydroimidazolyl, hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl, imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydrothiazinonyl, perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenoxazonyl, phthalazinyl, piperazindionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinethionyl, pyrimidinyl, pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl., thiazepinyl, thiazinyl, thiazolidinonyl, thiazolidinyl, thiazolinonyl, 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, thiadioxazinyl, thiatriazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadiazepinyl, trithianyl or trioxolanyl.
Compounds of this type are already known from German published application 196 01 303.8.
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 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 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 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 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.
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 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 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.
The compounds according to the invention are further characterised by a powerful inhibitory effect on the 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, benigri tumours or for 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 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 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 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.
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 mg, preferably between 0.2 and 5 mg. For parenteral 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 preparations containing the active substance:
Tablets:
Active substance of general formula I 20.0 mg Magnesium stearate 1.0 mg Corn starch 62.0 mg Lactose 83.0 mg Polyvinylpyrrolidone 1.6 mg Sol iti on for i nj .__i on Active substance of general formula 1 0.3 g Sodium chloride 0.9 g Water for injections ad 100 ml The solution may be sterilised by standard methods.
AQueQUS sol u i on for nasal admi ni st-rat- i nn or i nhal at- i nn Active substance of general formula 1 0.3 g Sodium chloride 0.9 g Benzalkonium chloride 0.01 mg Purified water ad 100 ml The above solution is suitable for nasal administration in 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.
Cap,mul .-, for i nhal a i on The compounds of general formula I are packed into hard gelatin capsules in micronised form (particle size essentially between 2 and 6 M), optionally with the addition of micronised carrier substances such as lactose.
They are inhaled by means of conventional devices for 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.
A_rosol for 'nhala.ion Active substance of general formula I 1 part Soya lecithin 0.2 parts Propellant gas mixture ad 100 parts The preparation is preferably transferred into aerosol containers with a metering valve, each spray delivering a dose of 0.5 mg. For other dosages iri the range specified, preparations containing a larger or smaller proportion of active substance are conveniently used.
O;n-m t(composition g/100 g of ointment) Active substance of general formula I 2 g 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 Artificial bergamot oil 0.075 g Distilled water ad 100 The ingredients are processed in the usual way to form an ointment.
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:
Active substance of general formula I 20.0 mg Magnesium stearate 1.0 mg Corn starch 62.0 mg Lactose 83.0 mg Polyvinylpyrrolidone 1.6 mg Sol iti on for i nj .__i on Active substance of general formula 1 0.3 g Sodium chloride 0.9 g Water for injections ad 100 ml The solution may be sterilised by standard methods.
AQueQUS sol u i on for nasal admi ni st-rat- i nn or i nhal at- i nn Active substance of general formula 1 0.3 g Sodium chloride 0.9 g Benzalkonium chloride 0.01 mg Purified water ad 100 ml The above solution is suitable for nasal administration in 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.
Cap,mul .-, for i nhal a i on The compounds of general formula I are packed into hard gelatin capsules in micronised form (particle size essentially between 2 and 6 M), optionally with the addition of micronised carrier substances such as lactose.
They are inhaled by means of conventional devices for 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.
A_rosol for 'nhala.ion Active substance of general formula I 1 part Soya lecithin 0.2 parts Propellant gas mixture ad 100 parts The preparation is preferably transferred into aerosol containers with a metering valve, each spray delivering a dose of 0.5 mg. For other dosages iri the range specified, preparations containing a larger or smaller proportion of active substance are conveniently used.
O;n-m t(composition g/100 g of ointment) Active substance of general formula I 2 g 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 Artificial bergamot oil 0.075 g Distilled water ad 100 The ingredients are processed in the usual way to form an ointment.
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:
By reacting 4-(1-piperazinyl)-3-trifluoromethylbenzoic acid esters of general formula II
F O
N 1 'C4Alkyl H"N
(II) with a compound of general formula III
R1C(O)Q (III) 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
F I O
- Alkyl r N C1 - C4 ~ ~ N
O
(IV) is obtained, which is suspended in a suitable, preferably anhydrous, solvent, 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 isolated.
F O
N 1 'C4Alkyl H"N
(II) with a compound of general formula III
R1C(O)Q (III) 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
F I O
- Alkyl r N C1 - C4 ~ ~ N
O
(IV) is obtained, which is suspended in a suitable, preferably anhydrous, solvent, 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 isolated.
The present invention is illustrated by the Examples which follow:
Examples:
Methyl 4-fluoro-3- .ri flliorom +-hyl -bPn oatP
35.4 g (170 mmol) of 4-fluoro-3-(trifluoromethyl)-benzoic acid in 250 ml of methanol are mixed with 68 ml of SOC12, 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 ambient temperature and evaporated down in vacuo. The oily residue is taken up in 200 ml of diethylether and extracted with water, saturated NaHCO3 solution and again with water. The combined organic phases are dried over magnesium sulphate and evaporated down in vacuo.
Yield: 29.0 g (77%) Methyl 4- (4-~yl -l -ipinerazinyl ) -3- ri fl uoromPt-hyl -b -n .oa 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 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 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%) Methy1 4_ (l -~)in rPyl )-3- r; fl uo nrnPt-hyl -hPnznat-a 20.2 g (53.3 mmol) of methyl 4-(4-benzyl-l-piperazinyl)-3-trifluoromethyl-benzoate are dissolved in 200 ml of methanol and combiiZed with 2 g of palladium on charcoal and hydrogenated over a period of 1.4 hours at 70 C under a hydrogen pressure of 5 bar. The solution is suction filtered over celite and distilled off in vacuo.
Yield: 14.85 g (97%) General method of coupling methyl 4-(1-piperazinyl)-3-trifluoromethyl-benzoate with benzoic acids:
5 mmol of the corresponding carboxylic acid are dissolved in 30 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 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 NaHCO3 solution, saturated NaCl solution and water, the organic phases are dried over MgSO4 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.
1. methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 81%
Methyl 4-fluoro-3- .ri flliorom +-hyl -bPn oatP
35.4 g (170 mmol) of 4-fluoro-3-(trifluoromethyl)-benzoic acid in 250 ml of methanol are mixed with 68 ml of SOC12, 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 ambient temperature and evaporated down in vacuo. The oily residue is taken up in 200 ml of diethylether and extracted with water, saturated NaHCO3 solution and again with water. The combined organic phases are dried over magnesium sulphate and evaporated down in vacuo.
Yield: 29.0 g (77%) Methyl 4- (4-~yl -l -ipinerazinyl ) -3- ri fl uoromPt-hyl -b -n .oa 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 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 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%) Methy1 4_ (l -~)in rPyl )-3- r; fl uo nrnPt-hyl -hPnznat-a 20.2 g (53.3 mmol) of methyl 4-(4-benzyl-l-piperazinyl)-3-trifluoromethyl-benzoate are dissolved in 200 ml of methanol and combiiZed with 2 g of palladium on charcoal and hydrogenated over a period of 1.4 hours at 70 C under a hydrogen pressure of 5 bar. The solution is suction filtered over celite and distilled off in vacuo.
Yield: 14.85 g (97%) General method of coupling methyl 4-(1-piperazinyl)-3-trifluoromethyl-benzoate with benzoic acids:
5 mmol of the corresponding carboxylic acid are dissolved in 30 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 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 NaHCO3 solution, saturated NaCl solution and water, the organic phases are dried over MgSO4 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.
1. methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 81%
2. methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Crystallised from methanol Yield: 75%
Melting point: 149 C
3. methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 77%
4. methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 79%
5. methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 83%
6. methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3-trifluoromethyl-benzoate 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%
Melting point: 149 C
3. methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 77%
4. methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 79%
5. methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 83%
6. methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3-trifluoromethyl-benzoate 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%
8. methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 79%
9. methyl 4-(4-(4-(l-pyrryl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 87%
10. methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 73%
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
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 mmol of the corresponding methyl ester are added and the solution is stirred for a further 2 hours at a temperature of about 120 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 pharmacologically acceptable acids into the corresponding salts, the following compounds are obtained (in the 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):
lst Example 4-(4-(4-Methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride O NHZ
~N "~'NH
~+
N
I X H 'iI
H~ "~ H.
~ F F
F
from methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 71%
Melting point: >200 C
MS: (M+H)' = 450 (free base) 2nd Example 4-(4-(2-PyrrOlylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate NNH
ti /. ~+
L. x 1~H3~7O3H
(I ~ ~
N F .~, F
9. methyl 4-(4-(4-(l-pyrryl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 87%
10. methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 73%
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
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 mmol of the corresponding methyl ester are added and the solution is stirred for a further 2 hours at a temperature of about 120 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 pharmacologically acceptable acids into the corresponding salts, the following compounds are obtained (in the 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):
lst Example 4-(4-(4-Methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride O NHZ
~N "~'NH
~+
N
I X H 'iI
H~ "~ H.
~ F F
F
from methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 71%
Melting point: >200 C
MS: (M+H)' = 450 (free base) 2nd Example 4-(4-(2-PyrrOlylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate NNH
ti /. ~+
L. x 1~H3~7O3H
(I ~ ~
N F .~, F
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+H)' = 409 (free base) 3rd Example 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate UN"-t~NH
F
N
I~ I N J x CH3HO3H
~I F
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 NHZ
N '~NH
N%~
x HCI
~
F ~
O O
Melting point: 246"C
MS: (M+H)' = 409 (free base) 3rd Example 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate UN"-t~NH
F
N
I~ I N J x CH3HO3H
~I F
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 NHZ
N '~NH
N%~
x HCI
~
F ~
O O
from methyl 4-(4-(2-methoxyphenylcarbonyl)-l-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-hydr.ochloride O NFil ' ~ ~.
N' NH
N
F
N
F~~ FFx HCI
from methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-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-l-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride O NHZ
N,NH
J! ,r F
F
II F X HCI
Melting point: 219 C (decomposition) MS: (M+H)' = 450 (free base) 5th Example 4-(4-(3-Trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydr.ochloride O NFil ' ~ ~.
N' NH
N
F
N
F~~ FFx HCI
from methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-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-l-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride O NHZ
N,NH
J! ,r F
F
II F X HCI
from methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 64%
Melting point: 214 C
MS: (M+H)' = 420 (free base) 7th Example 4-(4-(2-Furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate O NHZ
N ~~NH
[- i1 J ' O N
F " F F
0 x CH3SO3H
from methyl 4- (4- (2-furylcarbonyl) -1--piperazinyl) -3-trifluoromethyl-benzoate Crystallisation from ether Yield: 19%
Melting point: 190"C (decomposition) MS: (M+H)' = 410 (free base) 8th Example 4-(4-(3-Methylphenylcarbonyl)-1-piper.azinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate 0 NHz ~ 11 N~NH
N:
F
F
F x CH3SO3H
Melting point: 214 C
MS: (M+H)' = 420 (free base) 7th Example 4-(4-(2-Furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate O NHZ
N ~~NH
[- i1 J ' O N
F " F F
0 x CH3SO3H
from methyl 4- (4- (2-furylcarbonyl) -1--piperazinyl) -3-trifluoromethyl-benzoate Crystallisation from ether Yield: 19%
Melting point: 190"C (decomposition) MS: (M+H)' = 410 (free base) 8th Example 4-(4-(3-Methylphenylcarbonyl)-1-piper.azinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate 0 NHz ~ 11 N~NH
N:
F
F
F x CH3SO3H
from methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Crystallisation from methanol/ethyl acetate Yield: 76%
Melting point: 199 C
MS: (M+H)' = 434 (free base) 9th Example 4-(4-(4-(l-Pyrrolyl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-dimethylsulphonate N
J, o~ N,~ X 2 CH3SO3H
N
F, N; ~NH
FT ; ~;
from methyl 4-(4-(4-(l-pyrryl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Crystallisation from methanol Yield: 48%
Melting point: 150 C (decomposition) MS: (M+H)' = 485 (free base) 10th Example 4-(4-(2-Pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-dimethanesulphonate O N
~
F. N NH
F"
F O NHz from methyl 4-(4-(2-pyridylcarbonyl)-l-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 34%
Melting point: 115 C (decomposition) MS: (M+H)' = 421 (free base) Pharmacological data Inhibition of the Na'/H' exchanger in human intestinal cancer cells (HT-29):
HT-29 cells are incubated in growth medium at 37 C with 5%
COz. After 3-5 days the growth medium was removed, the cells were washed and charged with 7.5 M of BCECF-AM (pH-sensitive fluorescent dye) at 37 C without CO2. After 30 minutes the cells were washed and acidified with the following medium: 70 mM choline chloride, 20 mM NH4C1, 1 mM MgCl2, 1.8 mM CaClz, 5 mM glucose and 15 mM HEPES, pH
7.5.
After 6 minutes' incubation at 37 C without C02 the cells are washed, and incubated for 5 minutes with wash medium:
120 mM choline chloride, 5 mM KC1, 1 mM MgC12, 1.8 mM
CaC17, 5 mM glucose and 15 mM MOPS, pH 7Ø
Melting point: 199 C
MS: (M+H)' = 434 (free base) 9th Example 4-(4-(4-(l-Pyrrolyl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-dimethylsulphonate N
J, o~ N,~ X 2 CH3SO3H
N
F, N; ~NH
FT ; ~;
from methyl 4-(4-(4-(l-pyrryl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Crystallisation from methanol Yield: 48%
Melting point: 150 C (decomposition) MS: (M+H)' = 485 (free base) 10th Example 4-(4-(2-Pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-dimethanesulphonate O N
~
F. N NH
F"
F O NHz from methyl 4-(4-(2-pyridylcarbonyl)-l-piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 34%
Melting point: 115 C (decomposition) MS: (M+H)' = 421 (free base) Pharmacological data Inhibition of the Na'/H' exchanger in human intestinal cancer cells (HT-29):
HT-29 cells are incubated in growth medium at 37 C with 5%
COz. After 3-5 days the growth medium was removed, the cells were washed and charged with 7.5 M of BCECF-AM (pH-sensitive fluorescent dye) at 37 C without CO2. After 30 minutes the cells were washed and acidified with the following medium: 70 mM choline chloride, 20 mM NH4C1, 1 mM MgCl2, 1.8 mM CaClz, 5 mM glucose and 15 mM HEPES, pH
7.5.
After 6 minutes' incubation at 37 C without C02 the cells are washed, and incubated for 5 minutes with wash medium:
120 mM choline chloride, 5 mM KC1, 1 mM MgC12, 1.8 mM
CaC17, 5 mM glucose and 15 mM MOPS, pH 7Ø
The wash medium is removed and control medium is added with or without the test compound: 120 mM NaCl, 5 mM KC1, 1 mM MgClz, 1.8 mM CaCl2, 5mM glucose, 15 mM MOPS, pH 7Ø
The cells are incubated for 4 minutes at 37 C without COz 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.
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 IC50/10-" mol 1-1 1 0.076 3 0.038 4 0.084 5 0.023 7 0.084 8 0.061 10 0.079 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.
Pharmacokinetic data:
Male rats weighing about 200 g (not starved) were used for the tests. For intravenous and oral administration the 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 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 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, 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 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 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).
Example F t12 (i.v.) t12 (p.o.) 2 63 1.3 5.0 3 71 3.1 5.4 5 58 5.4 7.5
The cells are incubated for 4 minutes at 37 C without COz 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.
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 IC50/10-" mol 1-1 1 0.076 3 0.038 4 0.084 5 0.023 7 0.084 8 0.061 10 0.079 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.
Pharmacokinetic data:
Male rats weighing about 200 g (not starved) were used for the tests. For intravenous and oral administration the 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 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 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, 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 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 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).
Example F t12 (i.v.) t12 (p.o.) 2 63 1.3 5.0 3 71 3.1 5.4 5 58 5.4 7.5
Claims (23)
1. A compound of general formula I, wherein R1 denotes C1-8-alkyl, heteroaryl wherein the heteroaryl is a one or two ringed structure wherein each ring is 5- or 6-membered having one or more heteroatoms selected from S, N and O and the remaining ring atoms are carbon and wherein the heteroaryl is unsubstituted, mono-substituted or polysubstituted by a branched or unbranched C1-4-alkyl group, a cycloalkyl group, a branched or unbranched C1-4-alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, C6-10-aryl wherein the aryl is unsubstituted, mono-substituted or polysubstituted by a branched or unbranched C1-4-alkyl group, a branched or unbranched C1-4-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 contain one, two, three, four or five heteroatoms selected from nitrogen, oxygen and sulphur - identical to one another or different -C7-14-alkylaryl, unsubstituted or mono- or polysubstituted in the aryl and/or alkyl partial structure by a branched or unbranched C1-4-alkyl group, a branched or unbranched C1-4-alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, or a tautomer, enantiomer or pharmaceutically acceptable salt thereof.
2. A compound, tautomer, enantiomer or salt according to claim 1, wherein R1 is 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 R1 is a group selected from
3. 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate
4. 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate
5. Process for preparing a compound of general formula I
wherein R1 is as defined in claim 1, comprising reacting 4-(1-piperazinyl)-3-trifluoromethyl-benzoic acid ester of the general formula II
with a compound of general formula III
R1C(O)Q (III) wherein Q denotes a leaving group which may be substituted by the piperazine nitrogen, and the resulting benzoic acid derivative of general formula IV
is suspended in a suitable solvent, and is mixed with a mixture of a solution or suspension of a base with a guanidine salt and the reaction product is isolated.
wherein R1 is as defined in claim 1, comprising reacting 4-(1-piperazinyl)-3-trifluoromethyl-benzoic acid ester of the general formula II
with a compound of general formula III
R1C(O)Q (III) wherein Q denotes a leaving group which may be substituted by the piperazine nitrogen, and the resulting benzoic acid derivative of general formula IV
is suspended in a suitable solvent, and is mixed with a mixture of a solution or suspension of a base with a guanidine salt and the reaction product is isolated.
6. The process according to claim 5, wherein the reaction of 4-(1-piperazinyl)-3-trifluoromethyl-benzoic acid ester of general formula II with a compound of general formula III is performed in the presence of an adjuvant.
7. The process according to claim 6, wherein the adjuvant is carbonyldiimidazole.
8. The process according to any one of claims 5 to 7, wherein the benzoic acid derivative of general formula IV is suspended in anhydrous dimethylformamide.
9. The process according to any one of claims 5 to 8, wherein the base is sodium hydride.
10. The process according to any one of claims 5 to 9, wherein the base is in a suitable anhydrous solvent.
11. The process according to claim 10, wherein the base is in anhydrous dimethylformamide.
12. The process according to any one of claims 5 to 11, wherein the guanidine salt is guanidine hydrochloride.
13. The process according to any one of claims 5 to 12, further comprising converting the reaction product to an acid addition salt with a pharmacologically acceptable acid.
14. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable excipient or carrier.
15. A pharmaceutical composition according to claim 14 for inhibiting Na+/H+ exchange.
16. A pharmaceutical composition according to claim 14 for treatment of an ischaemia.
17. Use of a compound as defined in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof for inhibiting Na+/H+ exchange.
18. Use of a compound as defined in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof for therapeutic treatment of an ischaemia.
19. Use of a compound as defined in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof in manufacture of a medicament for inhibiting Na+/H+
exchange.
exchange.
20. Use of a compound as defined in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof in manufacture of a medicament for therapeutic treatment of an ischaemia.
21. Use according to any one of claims 17 to 20, wherein the acid addition salt is present.
22. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof for inhibiting Na+/H+ exchange.
23. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof for therapeutic treatment of an ischaemia.
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 |
| DE19843489.8 | 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 (2)
| Publication Number | Publication Date |
|---|---|
| CA2345006A1 CA2345006A1 (en) | 2000-03-30 |
| CA2345006C true CA2345006C (en) | 2007-11-13 |
Family
ID=7881872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002345006A Expired - Fee Related CA2345006C (en) | 1998-09-22 | 1999-09-16 | New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in the production of pharmaceutical compositions |
Country Status (35)
| Country | Link |
|---|---|
| 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) |
| SK (1) | SK285578B6 (en) |
| 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 |
|---|---|---|---|---|
| US6730678B2 (en) * | 2001-02-15 | 2004-05-04 | Boehringer Ingelheim Pharma Kg | Benzoylguanidine salt and hydrates thereof |
| DE10106970A1 (en) * | 2001-02-15 | 2002-08-29 | Boehringer Ingelheim Pharma | New benzoylguanidine salt |
| 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 |
| EP2321274A1 (en) * | 2008-07-08 | 2011-05-18 | Boehringer Ingelheim International GmbH | 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 |
-
1998
- 1998-09-22 DE DE19843489A patent/DE19843489B4/en not_active Expired - Fee Related
-
1999
- 1999-08-17 SA SA99200474A patent/SA99200474B1/en unknown
- 1999-09-16 TR TR2001/00801T patent/TR200100801T2/en unknown
- 1999-09-16 HU HU0200225A patent/HU228955B1/en not_active IP Right Cessation
- 1999-09-16 ES ES99952453T patent/ES2237951T3/en not_active Expired - Lifetime
- 1999-09-16 NZ NZ511167A patent/NZ511167A/en not_active IP Right Cessation
- 1999-09-16 CZ CZ20011047A patent/CZ300158B6/en not_active IP Right Cessation
- 1999-09-16 RS YUP-215/01A patent/RS49971B/en unknown
- 1999-09-16 ID IDW20010663A patent/ID27759A/en unknown
- 1999-09-16 JP JP2000574086A patent/JP3817425B2/en not_active Expired - Fee Related
- 1999-09-16 PL PL99347234A patent/PL195291B1/en unknown
- 1999-09-16 SK SK396-2001A patent/SK285578B6/en not_active IP Right Cessation
- 1999-09-16 IL IL14180599A patent/IL141805A/en not_active IP Right Cessation
- 1999-09-16 EP EP99952453A patent/EP1165534B1/en not_active Expired - Lifetime
- 1999-09-16 CN CNB998111430A patent/CN1166654C/en not_active Expired - Fee Related
- 1999-09-16 BR BR9913107-2A patent/BR9913107A/en not_active IP Right Cessation
- 1999-09-16 DE DE59911568T patent/DE59911568D1/en not_active Expired - Lifetime
- 1999-09-16 KR KR1020017003627A patent/KR100621821B1/en not_active IP Right Cessation
- 1999-09-16 EE EEP200100178A patent/EE04749B1/en not_active IP Right Cessation
- 1999-09-16 EA EA200100317A patent/EA004687B1/en not_active IP Right Cessation
- 1999-09-16 CA CA002345006A patent/CA2345006C/en not_active Expired - Fee Related
- 1999-09-16 AT AT99952453T patent/ATE288425T1/en active
- 1999-09-16 WO PCT/EP1999/006857 patent/WO2000017176A2/en active IP Right Grant
- 1999-09-16 AU AU64659/99A patent/AU764819C/en not_active Ceased
- 1999-09-16 PT PT99952453T patent/PT1165534E/en unknown
- 1999-09-20 PE PE1999000949A patent/PE20001085A1/en not_active Application Discontinuation
- 1999-09-20 MY MYPI99004064A patent/MY121362A/en unknown
- 1999-09-21 CO CO99059852A patent/CO5150207A1/en unknown
- 1999-09-22 AR ARP990104775A patent/AR023668A1/en not_active Ceased/Invalidation/Refusal/Rejection/Nullification
- 1999-09-22 TW TW088116279A patent/TWI221841B/en not_active IP Right Cessation
- 1999-09-22 EG EG118099A patent/EG23757A/en active
-
2001
- 2001-02-13 ZA ZA200101212A patent/ZA200101212B/en unknown
- 2001-03-09 BG BG105326A patent/BG64985B1/en active Active
- 2001-03-15 HR HR20010194A patent/HRP20010194B1/en not_active IP Right Cessation
- 2001-03-21 NO NO20011428A patent/NO317993B1/en not_active IP Right Cessation
-
2002
- 2002-07-08 HK HK02105065.7A patent/HK1043367B/en not_active IP Right Cessation
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| MKLA | Lapsed |
Effective date: 20170918 |