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ZA200101212B - 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 PDF

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Publication number
ZA200101212B
ZA200101212B ZA200101212A ZA200101212A ZA200101212B ZA 200101212 B ZA200101212 B ZA 200101212B ZA 200101212 A ZA200101212 A ZA 200101212A ZA 200101212 A ZA200101212 A ZA 200101212A ZA 200101212 B ZA200101212 B ZA 200101212B
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South Africa
Prior art keywords
group
general formula
trifluoromethyl
compounds
branched
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ZA200101212A
Inventor
Christian Eickmeier
Erich Buerger
Blech Stefan Matthias
Otto Roos
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Boehringer Ingelheim Pharma
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Publication of ZA200101212B publication Critical patent/ZA200101212B/en

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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Description

Pa " 3 ® LI 4
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 NH,
F N=(
NH,
FON
Ris NJ rt
O
(I) wherein
R, denotes C, ;-alkyl, heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C, .,-alkyl group, a cycloalkyl group, a branched or unbranched C, , -alkoxy group, an NH, 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, ,-alkyl group, a branched or unbranched C,,-alkoxy group, an NH, 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 C, , -alkyl group, a branched or unbranched C, ,-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
RR, 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 0 Na
J + J PZ
The following compounds are particularly preferred: 4-(4-(2-Pyrrolylcarbonyl) -l-piperazinyl)-3- trifluoromethyl -benzoylguanidine methanesulphonate
0 NH,
DE rf Tu
JA
J F
X CH,SO;H and 4-(4- (4-Fluorophenylcarbonyl) -1-piperazinyl)-3- trifluoromethyl-benzoylguanidine methanesulphonate oN,
Ne
F FN Z X CH;SO;H ne J ~~ F I oO
C,.,-alkyl or C, -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, l-methylethyl (isopropyl), n-butyl, ) 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1l-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1- dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1- ethylpropyl, hexyl, l-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, 1l-ethylbutyl, 2- ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-1l-methylpropyl and 1l-ethyl-2-methylpropyl. Unless otherwise stated, the preferred hydrocarbon groups are
Ce 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
E 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.
Ce
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,,-alkyl, aryl or aralkyl groups, which may be identical oo or different.
Accordingly, alkylamino denotes for example methylamino, ethylamino, propylamino, 1l-methylene-ethylamino, butylamino, l-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.
Correspondingly, dialkylamino denotes, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di-(l-wethylethyl)amino, di- (l-methylpropyl)amino, di-2- methylpropylamino, ethylmethylamino, methylpropylamino.
Cycloalkyl generally denotes a saturated or unsaturated
E 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
. oe 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, oo 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, hydrofuranonyl, 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,
SS @ naphthalenyl, naphthimidazopyridindionyl, naphthindolizinedionyl, naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl, phenanthraquinonyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyrandionyl, pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinethionyl, pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl, pyronyl, pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl, pyrrolizinyl, pyrrolodiocazinyl, pyrrolonyl, pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinolinyl, quinolizidinyl, quinolizinyl, guinolonyl, quinuclidinyl, rhodaminyl, spirocumaranyl, succinimidyl, sulpholanyl, sulpholenyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrothipyranonyl, tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl, thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl, } thiopyranyl, triazaanthracenyl, triazinoindolyl, triazolopyridinyl, tropanyl, xanthenyl, xanthonyl, xathydrolyl, adeninyl, alloxanyl, alloxazinyl, anthranilyl, azabenzanthrenyl, azabenzonaphthenyl, azanaphthacenyl, azaphenoxazinyl, azapurinyl, azinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl, benzodioxolanyl; benzodioxolyl, benzopyridazinyl,
Dbenzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl,
oC @
WC 00/17176 - 8 - PCT/EP95/06857 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, isocalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl, morpholinyl, naphthimidazolyl, oroticyl, oxathianyl, oxathiolanvyl, 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,
oe 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
Ce 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
S 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, 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
Dbenzoylguanidine 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.
N
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:
Ce
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
Solut Co .
Active substance of general formula I 0.3 g
Sodium chloride 0.9 g
Water for injections ad 100 ml
The solution may be sterilised by standard methods.
Lut; : 1 min; . nhalati
Active substance of general formula I 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 um, it is suitable for administration into the lungs.
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 uM), optionally with the addition of micronised carrier substances such as lactose.
They are inhaled by means of conventional devices for
Co - ® 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. 1 halat
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 in the range specified, preparations containing a larger or smaller proportion of active substance are conveniently used.
Qintment (composition g/100 g of ointment)
Active substance of general formula I 2g
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 59g
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-(l-piperazinyl)-3-trifluoromethylbenzoic acid esters of general formula II
F F O
SOB:
CY C, “C, ~ Alkyl .N
H
(1) with a compound of general formula III
R,C(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
Sen
ON Cy C, -Alkyl
Rin Ne } 0 (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:
- oo ®
Examples:
Methyl 4-fluoro-3-trifluoromethyl-henzoate 35.4 g (170 mmol) of 4-fluoro-3- (trifluoromethyl) -benzoic acid in 250 ml of methanol are mixed with 68 ml of SOCl,, 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 NaHCO, 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-benzyl-l-piperazinyl)-3-trifluoromethyl- benzoate 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%)
: .- ® 20.2 g (53.3 mmol) of methyl 4-(4-benzyl-l-piperazinyl)-3- trifluoromethyl-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°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)-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-(l-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)-1-piperazinyl) - 3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 81%

Claims (13)

Patent Claims
1. Benzoylguanidine derivatives of general formula I, F O F NH, F N=( NH ON 2 Ring No Ny Po 0 (h wherein R, denotes C, ,-alkyl, heteroaryl unsubstituted or mono- or polysubstituted by a branched or unbranched C,,-alkyl group, a cycloalkyl group, a branched or unbranched C, ,-alkoxy group, an NH, group or a primary or secondary amino group, a trifluoromethyl group, a cyano or nitro group or halogen, oo aryl unsubstituted or mono- or polysubstituted by a _ branched or unbranched C, ,-alkyl group, a branched or unbranched C, ,-alkoxy group, an NH, group or a primary or secondary amino group, a trifluoromethyl group, cyano or nitro group or halogen or by a 5- or 6-membered heteroaryl group which may contain one, two, three, four or five heteroatoms selected from 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,.,-alkyl group, a branched or unbranched C, ,-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.
2. Compounds of general formula I according to claim 1, characterised in that 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 N N 0 AN +7 J _
3. 4-(4-(2-Pyrrolylcarbonyl)-1l-piperazinyl)-3- trifluoromethyl-benzoylguanidine-methanesulphonate O NH, oo T NNT SN La
No . . NP xCH,SO,H a so. o}
4. 4-(4- (4-Fluorophenylcarbonyl)-1-piperazinyl) -3- trifluoromethyl -benzoylguanidine-methanesulphonate oe oN, SN F ON A NJ Pe x CH,SO,H 0}
5. Process for preparing compounds of general formula I F 0) F NH, F N= Co AN NH, 0) (1) characterised in that 4-(l-piperazinyl-3-trifluoromethyl- benzoic acid ester of general formula II FF 0 Sen Fy C, -C, ~ Alkyl a. .N H (1h) is reacted with a compound of general formula III R,C(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, and the resulting benzoic acid derivative of general formula IV
F F O S80 - - ON Cy = C, ~Alky RL Oo (IV) 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 and, optionally, the desired acid addition salt is formed with a pharmacologically acceptable acid.
6. Pharmaceutical preparation, characterised in that it contains a compound according to one of claims 1 to 4 and the acid addition salts thereof together with conventional excipients and carriers.
7. Use of compounds according to one of claims 1 to 4 as Co pharmaceutical compositions. I 20 oo
8. Use of compounds after use of compounds according to claim 7 as pharmaceutical compositions having an inhibitory effect on the Na'/H exchange.
9. Use of compounds of general formula I, the acid addition salts thereof for preparing a medicament for the therapeutic treatment of ischaemias.
10. Compounds of general formula I according to claim 1, substantially as herein described and exemplified.
11. Process according to claim 5, substantially as herein described and exemplified.
12. Pharmaceutical preparation according to claim 6, substantially as herein described and exemplified.
13. Use according to claim 7, 8 or 9, substantially as herein described and exemplified. AMENDED SHEE”
ZA200101212A 1998-09-22 2001-02-13 Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments. ZA200101212B (en)

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