AU764819B2 - 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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- 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
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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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 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 FF NH 2 F F I NH 2
N
0
(I)
wherein R, denotes C 8 alkyl, heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C 1 4 -alkyl group, a cycloalkyl group, a branched or unbranched C, 1 -alkoxy group, an NH 2 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 C, 1 -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 by a 5- or 6-membered heteroaryl group which may
U
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 alkylaryl, unsubstituted or mono- or polysubstituted in the aryl and/or alkyl partial structure by a branched or unbranched C 4 -alkyl group, a branched or unbranched C 1 alkoxy group, an NH, 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 R, 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
NN
The following compounds are particularly preferred: 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3trifluoromethyl-benzoylguanidine methanesulphonate WO 00/17176 PCT/EP99/06857 0 NH 2
F
F
X CH 3
SO
3
H
and 4-(4-(4-Fluorophenyicarbonyl)-l-piperazinyl)-3trifluoromethyl-benzoylguanidine methanesuiphonate 0 NH F N N HX CH 3
SO
3
H
F
F
0
CI-
4 -alkyl or Cl-,-alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 4 or 8 carbon atoms, which may optionally be sub stituted 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-methyipropyl, 2-methyipropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1dim;thylpropyl, 1,2-dimethylpropyl, 2,2-dimethyipropyl, 1ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1,2dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-l-methylpropyl and l-ethyl-2-methylpropyl. Unless otherwise stated, the preferred hydrocarbon groups are WO 00/17176 4 PCT/E299/06857 lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, iso-propyl, n-butyl, 1methylpropyl, 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 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 6membered 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 grodp 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.
I 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, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
Unless otherwise specified, amino denotes an NH, function which may optionally be substituted by one or two
C,
1 -alkyl, aryl or aralkyl groups, which may be identical or different.
Accordingly, alkylamino denotes for example methylamino, ethylamino, propylamino, 1-methylene-ethylamino, butylamino, l-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.
Correspondingly, dialkylamino denotes, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di-(1-methylethyl)amino, di-(1-methylpropyl)amino, di-2methylpropylamino, 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 WO 00/17176 6 WO 001717 -6-PCT/EP99/06 857 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: acridiuy1, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazul'emyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl, azanaphthacenyl, azanaphthalenyl, azaprenyl, azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl, benzacridinyl, benzazapinyl, benzofuryl, benzonaphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl, carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl, cumarinyl, cumaronyl, decahydroquinolinyl, decahydroquinolonyl, diazaanthracenyl, diazaphenanthrenyl, dibenzazapinyl, dibenzofuranyl-, dibenzothiphenyl, dichromylenyl, dihydrofuranyl, dihydroisocumarinyl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl, diprylenyl, dioxanthylenyl, oenantholactamyl, flavanyl, flavonyl, fluoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydtofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl, indolizinyl, indolonyl, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, isoindolyl, isoquinolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, WO 00/17176 7 WO 001717 -7-PCT/EP99/06857 naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, phenanthraquinonyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyrandionyl, pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyr idinyl, 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, suipholanyl, suipholenyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrothipyranonyl, tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl, thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl, thiopyranyl, triazaanthracenyl, triaz inoindolyl, triazolopyridinyl, tropanyl, xanthenyl, xanthonyl, xathydrolyl, adeninyl, alloxanyl, alloxazinyl, antitranilyl, azabenzanthrenyl, azabenzonaphthenyl, azanaphthacenyl, azaphenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl; benzodioxolyl, benzopyridazinyl, benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl, WO 00/17176 8 WO 001717 -8-PCT/EP99/06857 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, methyithyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl, oxazolyl, perhydrocinnolinyl, -perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhyd'rothiazinonyl, perimidinyl, phenazinyl, phenothiaz inyl, phenoxathilnyl, 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, pyrroiobenzodiazepinyl, pyrrolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl, thiazepinyl, thiazinyl, 'l WO 00/17176 9 PCT/EP99/06857 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 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 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 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 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 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 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 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 ixhalation, the individual dose is between 0.05 and itg, 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: WO 00/17176 12 PCT/EP99/06857 Tablets: Active substance of general formula I Magnesium stearate Corn starch Lactose Polyvinylpyrrolidone Solution for injection .0 Active substance of general formula I Sodium chloride Water for injections 20.0 mg 1.0 mg 62.0 mg 83.0 mg 1.6 mg 0.3 g 0.9 g ad 100 ml The solution may be sterilised by standard methods.
Aaueous solution for nasal administration or inhalation Active substance of general formula I Sodium chloride Benzalkonium chloride Purified water 0.3 g 0.9 g 0.01 mg 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 utm, it is suitable for administration into the 1ungs.
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 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.
Aerosol for inhalation Active-substance of general formula I Soya lecithin Propellant gas mixture 1 part 0.2 parts 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 in the range specified, preparations containing a larger or smaller proportion of active substance are conveniently used.
Ointment (composition g/100 g of ointment) Active substance of general formula I Fuming hydrochloric acid Sodium pyrosulphite Mixture of equal parts of cetyl alcohol and stearyl alcohol White Vaseline Artificial bergamot oil Distilled water ad The ingredients are processed in the usual ointment.
2g 0.011 g 0.05 g 20 g 5 g 0.075 g 100 way to form an 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: WO 00/17176 14 PCT/EP99/06857 By reacting 4-(1-piperazinyl)-3-trifluoromethylbenzoic acid esters of general formula II FF 0 F 0O N C1 -C 4 -Alkyl
HN
with a compound of general formula III RC(0)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
:N
0
C
1
C
4 -Alkyl 1 4
(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.
WO 00/17176 -15 PCT/EP99/06857 The present invention is illustrated by the Examples which follow: t r WO 00/17176 16 PCT/EP99/06857 Examples: Methyl 4-fluoro-3-trifluoromethyl-benzoate 35.4 g (170 mmol) of 4-fluoro-3-(trifluoromethyl)-benzoic acid in 250 ml of methanol are mixed with 68 ml of SOC1,, whilst .cooling with ice, at 50C 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-henzyl-1-piperazinyl)-3-trifluornmethylbenzoate 7 g (31.5 mmol) of methyl 4-fluoro-3-trifluoromethylbenzoate are dissolved in 60 ml of dry dimethylsulphoxide (DMSO) and combined with 5.55 g (31.5 mmol) of Nbenzylpiperazine and 4.35 g (31.5 mmol) of potassium 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 satdrated 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%) WO 00/17176 17 PCT/EP99/06857 Methyl 4-(1-piperazinyl) -3-trifluoromethyl-henzoat 20.2 g (53.3 mmol) of methyl 4-(4-benzyl-l-piperazinyl)-3trifluoromethyl-benzoate are dissolved in 200 ml of 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.
Yield: 14.85 g (97%) General method of coupling methyl 4-(l-piperazinyl)-3trifluoromethyl-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 0 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 NaHCO, solution, saturated NaCl solution and water, the organic phases are dried over MgSO, 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)-l-piperazinyl)- 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 81% WO 00/17176 18 PCT/EP99/06857 2. methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3trifluoromethyl-benzoate Crystallised from methanol Yield: Melting point: 149 0
C
3. methyl 4- (4-fluorophenylcarbonyl) -1-piperazinyl) 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 77% 4. methyl 4-(4-(2-methoxyphenylcarbonyl)-l-piperazinyl)- 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 79% 5. methyl 4- (3-trifluoromethylphenylcarbonyl) -1piperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 83% 6. methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 87% 7. methyl 4 4 2 -furylcarbonyl)-l-piperazinyl)-3trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: WO 00/17176 19 PCT/EP99/06857 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-(1-pyrryl)phenylcarbonyl)-lpiperazinyl)-3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 87% methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3trifluoromethyl-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 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 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): 1st Example 4-(4-(3-Methoxyphenylcarbonyl)-1-piperazinyl)-3trifluoromethyl-benzoylguanidine-hydrochloride 0 NH Sx HCI 0 from methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)- 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 71% Melting point: >200 0
C
MS: 450 (free base) 2nd Example 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3trifluoromethyl-benzoylguanidine-methanesulphonate 0 NH 2 3 NHX xCH 3
SO
3
H
WO 00/17176 21 PCT/EP99/06857 from methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 66% Melting point: 246 0
C
MS: 409 (free base) 3rd Example 4- (4-Fluorophenylcarbonyl) -1-piperazinyl) -3trifluoromethyl-benzoylguanidine-methanesuiphonate 0 NH 2 F N NJ FN x CH 3
SO
3
H
F
0 from methyl 4- (4-f luorophenylcarbonyl) -1-piperazinyl) 3-trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: Melting point: 140 0
C
MS: 438 (free base) 4th Example 4-(4-(2-Methoxyphenylcarbonyl)-1-piperazinyl)-3trifluoromethyl-benzoylguanidine-hydrochloride 0 NH 2 SNl NH N x HCI y NJ F
F
,0 0 WO 00/17176 -22 PCT/EP99/06857 from methyl 4- (2-methoxyphenylcarbonyl) -1-piperazinyl) 3 -trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 71% Melting point: 219'C (decomposition) MS: 450 (free base) Example 4- (3-Trifluoromethylphenylcarbonyl) -1-piperazinyl) -3trifluoromethyl -benzoylguanidine-hydrochloride 0 NH r FV]) JF F F x HCI F 0 from methyl 4- (3-trifluoromethylphenylcarbonyl) -1piperazinyl) -3 -trifluoromethyl--benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: Melting point: 140'C (decomposition) MS: 488 (free base) 6th Example 4- (4-Phenylcarbonyl-l-piperazinyl) -3-trifluoromethylbentoylguanidine -hydrochloride 0 N 11 x HCI WO 00/17176 23 WO 0/1716 3 -PCT/EP99/06857 from methyl 4- (4-phenylcarbonyl-1-piperazinyl) -3trifluoromethyl -benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 64% Melting point: 214 0
C
MS: 420 (free base) 7th Example 4- (2-Furylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine-methanesulphonate 0 NH S NTNH N r F
NJ
0F F 0 x CHSO 3
H
from methyl 4- (2-furylcarbonyl) -1-piperazinyl) -3trifluoromethyl-benzoate Crystallisation from ether Yield: 19% Melting point: 190'C (decomposition) MS: 410 (free base) 8th Example 4- (3-Methyiphenylcarbonyl) -1-piperazinyl) -3trifluoromethyl -benzoylguanidine-methanesulphonate 0 N N
N
F a J FFF x CHSO 3
H
WO 00/17176 24 WO 0/1716 4 -PCT/EP99/06 857 from methyl 4- (3-methylphenylcarbonyl) -1-piperazinyl) 3 -trifluoromethyl-benzoate Crystallisation from methanol/ethyl acetate Yield: 76% Melting point: 199 0
C
MS: 434 (free base) 9th Example 4-(4-(4-(l-Pyrrolyl)phenylcarbonyl) -l-piperazinyl)-3trifluoromethyl -benzoylguanidine -dimethylsuiphonate
N
0 N x 2 CH 3
SO
3
H
N
F N NH
FF
from methyl 4- (l-pyrryl)phenylcarbonyl) -1piperazinyl) -3-trifluoromethyl-benzoate Crystallisation from methanol Yield: 48% Melting point: 150 0 C (decomposition) MS: 485 (free base) Example 4- (2-Pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine -dimethanesulphonate WO 00/17176 25 PCT/EP99/06857
NN
F N NH
F
F 0 NH 2 x 2 CH 3
SO
3
H
from methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3trifluoromethyl-benzoate Column chromatography: ethyl acetate/methanol (5:1) Yield: 34% Melting point: 115 0 C (decomposition) MS: 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 0 C with CO,. After 3-5 days the growth medium was removed, the cells were washed and charged with 7.5 .M of BCECF-AM (pHsensitive fluorescent dye) at 37 0 C without CO 2 After minutes the cells were washed and acidified with the following medium: 70 mM choline chloride, 20 mM NH 4 C1, 1 mM MgC2,, 1.8 mM CaCI 2 5 mM glucose and 15 mM HEPES, pH 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 KC1, 1 mM MgCl 2 1.8 mM CaCl 2 5 mM glucose and 15 mM MOPS, pH 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 NaC1, 5 mM KC1, 1 mM MgCl 2 1.8 mM CaCl 2 5mM glucose, 15 mM MOPS, pH 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.
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 ICso/10 6 mol 1-1 1 0.076 3 0.038 4 0.084 0.023 7 0.084 8 0.061 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 Individual bolus injections (0.5 mg/kg i.v., mg/kg 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 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; Safter 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 0 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, Thomann, P. TopFit 2.0 Pharmacokinetic and pharmacodynamic data analysis, system for the PC, Gustav Fischer Verlag, Stuttgart, Jena, New York, 1993).
Example F t 1 /2 t 1 /2 2 63 1.3 3 71 3.1 5.4 58 5.4 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.
P:\OPERUgc\2407586 s.dc-01)7/0)3 -27A- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
*o* *oo
Claims (28)
1. Denzoylguanidile derivatives of general f ormula I, FF NH 2 N NH 2 0 wherein R. denotes C 1 alkyl, heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C 1 4 -alkyl group, a cycloalkyl group, a branched or unbranched C 1 alkcoxy group, an N'H, group which may optionally be substituted by one or two C,..-alkyl, aryl or aralkyl groups which may. be identical or different; a trif luoromethyl group, a cyano or nitro group or halogen, 20 aryl. unsubstituted or mono- or polysubstituted by a branched or unbranched C,,,-alkyl group, a branched or unbranched C,--alkoxy group, an NH, group which may optionally be substituted by one or two C,-alkyl, aryl or aralkyl groups which may be identical or different; a trifluoromethyl group, a hydroxy, cyano or nitro group or halogen or by a 5- or 6-tnerbered heteroary. group which may contain one, two, three, four or five heteroatoms selected from nitrogen, 29 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 C,. 4 -alkyl group, a branched or unbranched Cl- -alkoxy group, an NH, group which may optionally be substituted by one or two C,- 9 -alkyl, aryl or aralkyl groups which may be identical or different; a trifluoromethy. group, a cyano or nitro group or halogen, optionally in the form of the individual tautomerp or optionally enantiomers and mixtures thereof and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
2. Compounds of general formula I accordinlg to claim 1, wherein R, denotes an unsubstituted phenyl ring or a phenyl ring which is substituted by fluorine or by a methyl, trifluoromethyl, methoxy group or by a pyrrolyl group, or
3. 4- (2-Pyrrolylcarbanyl) -i-piperazilyl) -3- trifluoromethyl -benzoylguanidifle-Iethanesulphonate 30 o NH 2 N- N N F F 0 xCH 3 SO 3 jH
4. 4- (4-FluorophlCarbOflYl) -i-piperazinyl) -3- trifluoromfethYl -benzoylgualidifle methanesulphOflate NJ 'r F o F xCH 3 SO 3 H 0 0 0a 0@*0 Process for preparing compounds of general formula I F CH F NH 2 F -yN in which a 4 (l-piperaZifyl3trif1lUOrOmtthYlbenzoic acid ester of general formula 11 0 0 0000 00 00 31 F N C 1 -C 4 -IkyI is reacted with a compound of general formula III RIC(0) Q (111) in which R, is as defined in claim I. and Q denotes a leaving group which may be substituted by the secondary piperazile nitrogen, optionally in the presence of auxiliaries, and the resulting benzoic acid derivative of general formula IV F0 N 1 -C 4 'Alkyl 0 (IV) is suspended in a solvent, and is mixed with a mixture of a solution or suspension of a base in the presence of a 20 guanidine salt and the reaction product is isolated and, optionally, the desired acid addition salt is formed with a pharmacologically acceptable acid. .55 55~5 P:\OPER\gc\2407586 cl.doc-)2A)7A)3 -32-
6. Process according to claim 5 wherein said auxiliary is carbonyldiimidazole.
7. Process according to claim 5 or claim 6 wherein said solvent is anhydrous.
8. Process according to any one of claims 5 to 7 wherein said solvent is dimethylformamide.
9. Process according to any one of claims 5 to 8 wherein said mixture of a solution or suspension of a base is sodium hydride in an anhydrous solvent. Process according to claim 9 wherein said anhydrous solvent is dimethylformamide.
11. Process according to any one of claims 5 to 10 wherein said guanidine salt is guanidine hydrochloride.
12. Pharmaceutical preparation wherein it contains a compound according to one of claims 1 to 4 and the acid addition salts thereof together with conventional excipients and carriers. 25 13. A compound according to any one of claims 1 to 4 or a preparation according to claim 12 for use in therapy.
14. A compound according to any one of claims 1 to 4 or a preparation according to claim 12 for use in inhibition of 30 cellular Na'/H exchange. 4
15. A compound according to any one of claims 1 to 4 or a preparation according to claim 12 for use in the therapeutic treatment of ischaemias.
16. A compound according to any one of claims 1 to 4 or a P:\OPERUgc2407586 cl.doc.02/07/03 -33- preparation according to claim 12 for use in the treatment of coronary heart disease, cardiac infarct, angina pectoris, stable angina pectoris, ventricular arrhythmias, sub- ventricular arrhythmias, cardiac insufficiency, 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; for use in support of operations which require the blood supply to the heart to be interrupted; for use as a cardioprotectant during reperfusion of the ischaemic heart; or for use in prevention of damage to transplants during and after implantation and during storage of the organs for transplant.
17. A compound according to any one of claims 1 to 4 or a preparation according to claim 12 for use in the treatment of arrhythmias, essential hypertension or diabetic nephropathy.
18. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 in the preparation of a medicament for the therapeutic treatment of ischaemias.
19. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 in the preparation of a medicament for the treatment of coronary heart disease, cardiac infarct, angina pectoris, stable angina pectoris, 30 ventricular arrhythmias, sub-ventricular arrhythmias, cardiac insufficiency, embolism in the pulmonary circulation, acute or chronic kidney failure, chronic kidney insufficiency,* *cerebral infarct, ~insufficiency, cerebral infarct, 34 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; for use in support of operations which require the blood supply to the heart to be interrupted; for use as a cardioprotectant during reperfusion of the ischaemic heart; or for use in prevention of damage to transplants during and after implantaion and during storage of the organs for transplant. Use of a compound according to one of claims 1 to 4 or a preparation according to claim 12 in the preparation of a medicament for the treatment of arrythmias, essential hypertension or diabetic nephropathy in the preparation of a medicament.
21. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 to inhibit Na'/H' exchange.
22. A compound of formula I as defined in claim 1 substantially as hereinbefore described and in reference to the Examples.
23. A process for the preparation of a compound of formula I as defined in claim 1 substantially as hereinbefore described and in reference to the Examples.
24. A pharmaceutical preparation comprising a compound of formula I as defined in claim 1 substantially as hereinbefore described and in reference to the Examples.
25. Method of treating ischaemias in a subject which :35 comprises administering to said subject an effective P:\OPERUgc\2407586 c.doc-02/07A03 amount of a compound according to any one of claims 1 to 4, or a preparation according to claim 12.
26. Method of treatment using a compound of formula I as defined in claim 1 substantially as hereinbefore described and in reference to the Examples.
27. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 in therapy.
28. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 in the inhibition of cellular Na'/H' exchange.
29. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 in the therapeutic treatment of ischaemias. Use of a compound according to any one of claims 1 to 4 S 20 or a preparation according to claim 12 in the treatment of coronary heart disease, cardiac infarct, angina pectoris, stable angina pectoris, ventricular arrhythmias, sub- ventricular arrhythmias, cardiac insufficiency, 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; for use in support of operations which require the blood supply to the heart to be interrupted; for use as a cardioprotectant during reperfusion of the ischaemic heart; or for use in prevention of damage to transplants during and after implantation and during storage of the organs for transplant.
31. Use of a compound according to any one of claims 1 to 4 P:\OPERJgc\2407586 c.doc.- )713 -36- or a preparation according to claim 12 in the treatment of arrhythmias, essential hypertension or diabetic nephropathy.
32. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 in the preparation of a medicament for the therapeutic treatment of ischaemias.
33. Use of a compound according to any one of claims 1 to 4 or a preparation according to claim 12 in the preparation of a medicament for the treatment of coronary heart disease, cardiac infarct, angina pectoris, stable angina pectoris, ventricular arrhythmias, sub-ventricular arrhythmias, cardiac insufficiency, 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 occlusion and acute and chronic bleeding disorders in the brain; for use in support of operations which require the blood supply to the heart to 20 be interrupted; for use as a cardioprotectant during reperfusion of the ischaemic heart; or for use in prevention of damage to transplants during and after implantation and during storage of the organs for transplant. DATED: 2 July, 2003 S: 30 by DAVIES COLLISON CAVE Patent Attorneys for the Applicant(s): BOEHRINGER INGELHEIM PHAMRA KG
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 AU6465999A (en) | 2000-04-10 |
| AU764819B2 true AU764819B2 (en) | 2003-08-28 |
| AU764819C AU764819C (en) | 2004-12-16 |
Family
ID=7881872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002250939B2 (en) * | 2001-02-15 | 2007-09-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel benzoylguanidine salt |
Families Citing this family (5)
| 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 |
| 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 |
Citations (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
Patent Citations (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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002250939B2 (en) * | 2001-02-15 | 2007-09-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel benzoylguanidine salt |
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