BG64985B1 - Benzoylguanadine derivatives with advantageous properties, method for producing them and their use in the production of medicaments - Google Patents

Abstract

The invention relates to novel benzoylguanadine derivatives of general formula to a method for producing them and to their use in the production of medicaments.

Description

Technical field

The present invention relates to a new type of benzoylguanidine derivatives of general formula I, a method for their preparation and their use for the manufacture of pharmaceuticals

(I) in which

R 1 means: C ₍ -C ₈ -alkyl, heteroaryl, unsubstituted or mono- or polysubstituted or branched C ₍ -C ₄ -alkyl, cycloalkyl, branched or unbranched C 1 -C ₄ alkoxy group, NH ₂ - rpyna or a primary or secondary amino group, with a trifluoromethyl group, with a cyano or with a nitro group or with a halogen, aryl, unsubstituted or mono- or polysubstituted with a branched or unbranched C 1 -C 6 -alkyl group, branched or unbranched C 1 -C 6 alkoxy group , NH ₂ - group or a primary or secondary amino group, a trifluoromethyl d upa, hydroxy, cyano or nitro or halogen or having a 5 or 6 membered heteroalkyl group which may contain one, two, three or five heteroatoms in the nitrogen, oxygen or sulfur group - identical or different, alkylaryl, unsubstituted or mono- or polysubstituted in the aryl and / or alkylpartial structure, branched or unbranched C ₁ -C ₄ -alkyl group, branched or unbranched C 1 -C ₄ -alkoxy group, NH ₂ group or primary or secondary amino group, trifluoromethyl a group, cyano or nitro group or halogen, optionally in the form and the individual tautomers or enantiomers and mixtures thereof, as well as in the form of free bases or the corresponding acid addition salts with pharmacologically reliable acids.

Preferred compounds of the present invention are the general formula I wherein

R 1 may mean an unsubstituted phenyl ring or a phenyl ring which is substituted with fluorine or with a methyl, trifluoromethyl, methoxy group or pyrrolyl group, or may mean:

The following compounds are particularly preferred:

4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate

4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-fluoromethyl-benzoylguanidine-methanesulfonate

Oh

Fr.

C 1 -C ₄ -alkyl, respectively. C ₍ -C ₈ -alkyl) generally means a branched or unbranched hydrocarbon moiety of 1 to 4 or 8 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be the same or different. Examples include:

methyl, ethyl, propyl, 1-methylethyl (isopropyl), normal-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methyl2-pentyl, 3-methylpentyl. 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Preferably, unless otherwise indicated, lower alkyl radicals having 1 to 4 carbon atoms, such as methyl; ethyl, propyl, isopropyl, normal-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, "alkoxy" generally means a straight or branched alkyl group linked through an oxygen atom. A lower alkoxy moiety of 1 to 4 carbon atoms is preferred, especially a methoxy group.

"Aryl" generally means an aromatic moiety of 6 to 10 and carbon atoms, also in compositions, wherein the aromatic moiety may be substituted by one or more lower alkyl group (s), trifluoromethyl group (s), cyano group (s) i), alkoxy group (s), nitro group (s), amino group (s) and / or with one or more halogen atoms (s) identical or different; the preferred aryl moiety is optionally substituted phenyl moiety wherein halogens such as fluorine, chlorine or bromo-cyano as well as a hydroxyl group are preferred as substituents, in particular within the meaning of the present invention, chlorine is preferred as chlorine. The aryl group, preferably phenyl, may be further substituted by a 5 or 6 membered heteroaryl group which may contain one, two, three, four or five heteroatoms from the nitrogen, oxygen or sulfur group.

"Aralkyl" generally means an aryl group linked by an alkylene chain of 7 to 14 carbon atoms, wherein the aromatic moiety may be substituted by one or more lower alkyl group (s), alkoxy group (s), nitro group (s) , amino group (s) and / or one or more halogen atoms (s) are the same or different. Aralkyl groups having 1 to 6 carbon atoms (s) in the aliphatic moiety and 6 carbon atoms in the aromatic moiety are preferred.

Preferred aralkyl residues, unless otherwise indicated, are benzyl, phenethyl and phenylpropyl.

"Halogen" means, unless otherwise specified, fluorine, chlorine, bromine, iodine, and preferably fluorine, chlorine or bromine.

"Amino" means, unless otherwise stated, NIL, a function which may in this case be substituted by one or two C ₁ -C ₈ alkyl, aryl, or aralkyl groups, identical or different.

Accordingly, "alkylamino", for example, means methylamino, ethylamino, propylamino, 1methyleneethylamino, boogylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1 dimethylethyl amino.

Accordingly, "dialkylamino", for example, means dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (1-methylethyl) amino, di- (1-methylpropyl) amino, di-2-methylpropylamino, ethylmethylamino, methylpropylamino.

"Cycloalkyl" means generally a saturated or unsaturated cyclic hydrocarbon moiety of 5 to 9 carbon atoms, which may in this case be substituted by one halogen atom or more halogen atoms, preferably chlorine, which may be the same or different. Cyclic hydrocarbons having 3 to 6 carbon atoms are preferred. As an example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and cyclononinyl could be enumerated.

"Heteroaryl" means generally a 5 to 6 membered ring which, such as heteroatoms, may contain oxygen, sulfur and / or nitrogen and which may be fused to another aromatic ring. Preferred are 5 and 6 membered aromatic rings which contain oxygen, sulfur and / or up to two nitrogen atoms and which in this case are benzocondensed.

As a specific heterocyclic systems could be listed, for example acridinyl, akridonil, alkilpiridinil, anthraquinone, ascorbyl, azaazulenil, azabenzantratsenil, azabenzantrenil, azahrizenil, azatsiklazinil, azaindolyl, azanaftatsenil, azanaftalenil, azaprenil, azatrifenilenil, azepinyl, azinoindolil, azinopirolil, benzakridinil, benzazapinil, benzofuryl, benzonaphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, benzothiopinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl , Caprolactamyl, carbazolyl, carbolinyl, Catechin, hromenopironil, hromonopiranil, coumarinyl kumaronil, decahydroquinolinyl, dekahidrohinolonil, diazaantratsenil, diazafenantrenil, dibenzazapenil, dibenzofuranyl, dibenzotifenil, dihromilenil, dihydrofuranyl, dihidroizokumarinil, dihidriizohinolinil, dihydropyranyl, dihydropyridinyl, dihidropiridonil, dihidropironil, dihydrothiopyranyl, diprilenil , dioxanthenyl, oenantolactamyl, flavanil, flavonyl, fluoroanil, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopiranil, furopironil, hetoroazulenil, heksahidropirazinoizokvinolinil, tetrahydrofuranyl, hidrofuranonil, hidroindonil, hidropiranil, hidropiridinil, hidropirolil, hidrohinolinil, hidrotiohromenil, hidrotiofenil, indolizidinil, indolizinyl, indolonyl, izatinil, izatogenil, izobenzofurandionil, izobenzfuranil, isochromanyl, isoflavone, isoindolinyl, izoindolobenzazapinil, isoivdolyl, isoquinolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, monoazabenzonaphthenyl, naphthalenyl, naphtimidazopyridinedinyl, naphtindolizinedio yl, naftodihidropiranil, naftofuranil, nafgiridinil, oxepinyl, oxindolyl, oksolenil, perhidroazolopiridinil, perhidroindolil, fenantrahinonil, ftalideizokvinolinil, phthalimidyl, ftalonil, piperidinyl, piperidonyl, prolinyl, parazinil, piranoazinil, piranoazolil, piranopirandionil, pyranopyridinyl, piranohinolinil, piranopirazinil, pyranyl, pyrazolopyridinyl, pyridinethionyl, pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl, pyronyl, irokolinil, pyrrolidinyl, pirolizidiyukil, pirolizikil, pirolodioazinil, pirolonil, pyrrolopyrimidinyl pirolohinolonil, pyrrolyl, hinakridonil, quinolinyl, hinolizidinil, quinolizinyl, quinolone, quinuclidinyl, rodaminil, spirokumaranil, sukinimidil, sulfolanyl, sulfolenil, tetrahydrofuranyl, tetrahydroisoquinolinyl, tegrahidropiranil, tetrahydropyridinyl, tetrahidrotiapiranil, tetra hydrothiophenyl, tetrahydrothypyranonyl, tetrahydrothyranyl, tetronyl, thiophenyl, thiachromanyl, thiadecalinyl, thiaphenyl, thiapyranyl, thiapyronyl, thiazolopyrid ynyl, thienopyridinyl, tienopirolil, tienotiofenil, thiepinyl tiohromenil, tiokumarinil, thiopyranyl, triazaantratsenil, triazinoindolil, triazolopiridinil, tropanyl, xanthenyl, ksantonil, ksantidrolil, Adenine, aloksanil, aloksazinil, anthranilyl, azabenzatrenil, azabenzonaftenil, azanaftatsenil, azafenoksazinil, azapurinil, piperazinyl, azoloazinyl, azolyl, barbituric acid, benzazinyl, binzimidazolethionyl, benzimidazolonyl, benzisothiazolyl, benzisoxazolyl, benzocinolinyl, benzodiazocinyl, benzodioxolanyl, benzodioxolyl, benzopioxolyl, benzopyridoxyl , Benzothiazepine, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl, depsidinil, diazafenantrenil, diazepinyl, diazinyl, dibenzoksazepinil, dihidrobenzimidazolil, dihidrobenzotiazinil, dihidrooksazolil, dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, dioxanyl, dioksenil, dioxepinyl, dioksinonil, dioxolanyl, dioksolonil, dioksopiperazinil , dipyrimidopyrazinyl, difiolanil, difiolvinyl, difiolyl, flavinyl, furopyrimidinyl, glycocamidinyl, guaninyl, hexahydropyrazinoisquinolinyl, hexahydropyridazinyl, hydantoinyl, hidroimidazolil, hidroparazinil, hidropirazolil, hidropiridazinil, hidropirimidinil, imidazolinyl, imidazolyl, imidazokvinazolinil, imidazothiazolyl, indazolebenzopirazolil, indoksazenil, inosinate, izoaloksazinil, isothiazolyl, isoxazolidinyl, izoksazolinonil, isoxazolinyl, izoksazolonil, isoxazolyl, lumazinil, metilfiminil, methyluracilic, morpholinyl, naphtimidazolyl, oroticyl, oxathianyl, oxathiolanil, oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidinyl, oxazolinonyl, oxazolinyl, ox zolonil, oksazolopirimidinil, oxazolyl, perhidrotsinolinil, perhidropiroloazinil, perhidropirolotiazinil, perhidrotiazinonil, perimidinil, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, fenoksazonil, phthalazinyl, piperazindionil, piperazinodionil, polikvnoksalinil, pteridinyl, pterinil, purinyl, pyrazinyl, pyrazolidinyl, pirazolidonil, pyrazolinonyl, parazolinil, pyrazolobenzodiazepinyl, pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyridylidinyl, pyrimidine thionyl, pyrimidinyl, pirimidionil, pirimidoazepinil, pirimidopteridinil, pirolobenzodiazepinil, pirolodiazinil, pyrrolopyrimidinyl hinazolidinil, hinazolinonil, quinazolinyl, quinoxalinyl, sultamil, sultinil, sultonil, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahidropiridazinil, tetrahidrokvinoksalinil, tetrahydrothiazolyl, thiazepinyl, thiazinyl, thiazolidinone, thiazolidinyl, tiazolinonil, thiazolinyl, thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xanthinyl, xylitol , Azabenzonaftenil, benzofuraksanil, benzotiadiazinil, benzotriazepinonil, benzotriazolyl, benzoksadiazinil, dioksadiazinil, ditiadazolil, dithiazolyl, furazanyl, furoksanil, hidrotriazolil, hidroksitrizinil, oxadiazinyl, oxadiazolyl, oksatiazinonil, oksagriazolil, pentazinil, pentazolil, polioksadiazolil, sidonil, tetraoksanil, tetrazepinil, tetrazinyl, tetrazolyl , thiadiazinyl, thiadiazolinyl, thiadiazolyl, thiadioxazinyl, hyatriazinyl, thiatriazolyl, triazepenyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl, trithiadiazinpinyl, trithanyl or trioxolanyl.

Compounds of this type are known from Deutschen Offenlegungsschrift 196 01 303.8.

Compounds of this type, due to their action as inhibitors of cellular Na + / H / + equilibrium, are useful as active substances in drugs, or may be used as intermediates for the production of such active substances. The compounds of the invention act against the arrhythmia that occurs, for example, in hypoxia. In addition, they are applicable to diseases that are associated with ischemia (for example: cardiac, cerebral, gastrointestinal, such as menstrual thrombosis / embolism, pulmonary, renal ischemia, ischemia of the lung, skeletal muscle ischemia). Relevant diseases are, for example, coronary heart disease, heart attack, angina pectoris, persistent angina pectoris, ventricular arrhythmias, subventricular arrhythmias, heart failure, in addition assistance with bypass surgery, assistance with open heart surgery, assistance with surgery, blood supply to the heart and assistance with cardiac transplant embolism in the small pulmonary cycle, acute and chronic renal failure, chronic renal failure, cerebral infarction, reperfusion injury Nia in restoring blood supply to the brain areas after removal of vascular occlusions and acute and chronic disorders in kravosnabdavaneto brain. The compounds mentioned are also used in combination with thrombolytic agents such as t-PA, streptokinase and urokinase.

Reperfusion of ischemic heart, (for example, with an attack of angina or heart attack), irreversible damage to the cardiomyocytes in the affected area can occur. The compounds of the invention act in this case in a cardioprotective manner.

In the field of application - ischemia, the reduction of graft damage (eg as transplant protection, eg liver, kidney, heart or lung, before, during and after implantation, and during transplant storage) should also be included. that may occur in connection with the transplant. The compounds are extremely protective drugs in the implementation of anginoplastic interventions in the heart and peripheral vessels.

In essential hypertension and diabetic neuropathy, cellular sodium-proton metabolism is increased. The compounds of the invention are suitable as inhibitors of this exchange for the prophylactic treatment of these diseases.

The compounds of the invention are also distinguished by having a strong inhibitory effect on cell proliferation. Therefore, the compounds are of interest as drugs in diseases in which cell proliferation plays a primary or secondary role and can be used as anti-cancer agents, benign tumors, or for example 5 prostate hypertrophy, atherosclerosis, hypertrophy and organ hyperplasia, fibrotic diseases and diabetic complications in degradation.

Furthermore, compounds of this type are known to have a beneficial effect on the blood levels of serum lipoproteins.

Surprisingly, it has been found that the compounds of the general Formula I, in comparison with the prior art benzoylguanidines, 15 have the advantage that they have an unexpectedly high efficacy for the advantage of oral use.

The active substances of formula I can be used as injectable solutions (eg, for example intravenous, intramuscular or subcutaneous administration), such as tablets, suppositories, creams, patches for transdermal administration, aerosols for inhalation administration or nasal sprays. 25

The active substance content of one tablet or suppository is between 5 and 200 mg, preferably between 10 and 50 mg. For inhalation, the single dose is between 0.05 and 20 mg. For parenteral injection, the single dose is between 30 and 0.1 and 5 mg, preferably between 0.5 and 20 mg. Said doses may, if necessary, be given several times a day.

The following are examples of pharmaceutical preparations with the active substance: 3 5

Tablets active ingredient of general formula I magnesium stearate corn starch lactose polyvinylpyrrolidone Injectable solutions active substance of general formula I sodium chloride injection water

20,0 mg

1.0 mg

62.0 mg 40

83.0 mg

1.6 mg

0.3 g 45

0.9g supplementation to 100 ml

The solution can be sterilized using standard methods. 50

Aqueous solutions for nasal or inhalation administration.

active substance of general formula I sodium chloride benzoalkonium chloride purified water

0.3 g

0.9 g

0.01 mg supplement to 100 ml

The above solution is suitable for use in the nose as a spray or in combination with a droplet-sized aerosol device, preferably between 2 and 6µm for administration through the lungs.

Inhalation capsules

The compounds of general formula I in micronized form (particle size substantially between 2 and 6 pm), optionally added with micronized substances as carrier, in this case lactose, are filled into hard gelatin capsules. Inhalation is the usual device. Each capsule is loaded with between 0.2 and 20 mg of the active substance of general formula I and 0 to 40 mg of lactose.

Aerosols for inhalation of an active substance of the general Formula I soya lecithin working gas part

0.2 parts addition to

100 pieces

The dosage form is preferably filled into aerosol dispensers, closed with a metering valve, adjusting the single stroke so that a single dose is 5 mg. For other dosages of the indicated area, administration forms with a greater or less amount of the active substance are used.

Creams (composition g / 100 g cream) active substance of general formula I2 g fuming hydrochloric acid 0.011 g sodium pyrosulphite 0.05 g mixture of equal parts cetyl alcohol and stearyl alcohol20 g white petrolatum5 g synthetic bergamon oil 0,075g distilled water ml

The ingredients are processed into creams by commonly known methods.

Methods for preparing the compounds of the invention are known in the art. For example, compounds of the invention can be prepared in the following ways:

With the reaction of 4- (1-piperazinyl) -3-fluoromethyl-benzoic acid ester of the general formula II

with a compound of general formula III

R, C (O) Q (III) in which Q represents a leaving group which may be substituted by piperizine nitrogen, optionally in the presence of auxiliaries, preferably carboniddiimidazole, and the benzoic acid derivative of general formula IV obtained

O is suspended in a suitable, preferably anhydrous solvent, preferably dimethylformamide and mixed with a mixture of solution or suspension based, preferably sodium hydride in a suitable anhydrous solvent, preferably dimethylformamide is a guanidine salt, preferably guanidine hydrochloride product isolate.

The present invention is illustrated by the following examples:

Examples:

4-Fluoro-3-trifluoromethyl-benzoic acid methyl ester

35.4 g (170 mmol) of 4-fluoro-3- (trifluoromethyl) -benzoic acid in 250 ml of methanol under ice-cooling for 25 min are mixed with 68 ml of SOCl ₂ . The reaction mixture was then refluxed for 3 h. The reaction solution was cooled to room temperature and evaporated in vacuo. The oily residue was taken up in 200 ml of diethyl ether and extracted with water, saturated NaHCO ₃ solution and again water. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo.

Yield: 29.0 g (77%)

4- (4-Benzyl-1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester.

g (31.5 mmol) of 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester was dissolved in 60 ml of dry dimethyl sulfoxide (DMSO) and mixed with 5.55 g (31.5 mmol-1 N-benzylpiperazine and 4.35 g (31.5 mmol) of potassium The mixture was stirred for 12 hours at 90 [deg.] C. After cooling, the reaction mixture was poured into 200 ml of water and extracted three times with acetic acid ethyl ester (acetic ester). The combined organic phases were washed with water and brine. sodium chloride, dried over magnesium sulphate and distilled off in vacuo The residue was chromatographed with a mixture of acetic ester / norm allen-heptane over silica gel.

Yield 3.93 g (33%)

4- (1-Piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

20.2 g (53.3 mmol) of 4- (4-benzyl-1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester was dissolved in 200 ml of methanol and mixed with charcoal with 2 g of palladium, hydrogenated for 1.4 h at 70 ° C at a water pressure of 5 bar. The solution was filtered through celite and distilled off in vacuo.

Yield: 14.85 g (97%)

Coupling of 4- (1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester with benzoic acids.

mmol of the corresponding carboxylic acid was dissolved in 30 ml of absolute tetrahydrofuran (THF) and mixed with protected gas at 0 ° C with 810 ml (5 mmol) of carbonyldimidazole and stirred for 2 h at room temperature (about 25 ° C). Thereafter, 1.44 g (5 mmol) of 4- (1-piperazinyl) -3-trifluoromethyl-benzoic acid ethyl ester was added and stirred for more than 12 hours. The solution was evaporated in vacuo to dryness and taken up with acetic ester.

After washing with saturated NaHCO ₃ solution, saturated NaCl solution and water, the organic phases are dried over MgSO ₄ and concentrated in vacuo. After crystallization in a suitable solvent or chromatography on silica gel with a suitable solvent, the following compounds are obtained:

1. 4- (4- (3-Methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 81%

2. 4- (4- (2-Pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Crystallization in methanol Yield: 75%

Melting point: 149 ° C

3. 4- (4- (4-Fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 77%

4. 4- (4- (2methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 79%

5. 4- (4- (3-Trifluoromethylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester.

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 83%

6. 4- (4-Phenylcarbonyl) 1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester.

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 87%

7. 4- (4- (2-Furylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester.

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 75%

8. 4- (4- (3-Methylphenyl carbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester.

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield; 79%

9. 4- (4- (4- (1-Pyryl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester.

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 87%

10. 4- (4- (2-Pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester.

Column chromatography: acetic ester / normal-heptane (2: 1)

Yield: 73%

Preparation of acylguanidines from the corresponding carboxylic acid methyl esters.

5.09 g (127.2 mmol) of 60% NaH in light oil was washed twice with ether and decanted. 200 ml of absolute dimethylformamide are added and 12.15 g (127.2 mmol) of guanidine hydrochloride are added in small portions under stirring and protective gas. After one hour of stirring, 21.2 mmol of the corresponding methyl ester was added and the solution was stirred for another 2 hours at 120 ° C. The mixture was then allowed to cool to room temperature, filtered and evaporated in vacuo. After chromatography on silica gel with a suitable solvent and conversion to the corresponding salts with ethereal hydrochloric acid or other pharmacologically acceptable acids, the following compounds are obtained (in the following structural formulas, the hydrogen atoms are omitted for reasons of transparency, insofar as they are linked to a carbon or nitrogen atom and insofar as they are not necessary to understand the invention):

1. Example 4- (4- (3-methoxyphenylcarbonyl) -1-piperazinyl) trifluoromethyl-benzoylguanidine hydrochloride

4- (4- (3-Methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Column chromatography: acetic ester / methanol (5: 1)

Yield: 71%

Melting point:> 200 ° C

MS: (M + H) ⁺ = 450 (free base)

2. Example 4- (4- (2-Pyrrolylcarbonyl) -1piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate 4- (4- (2-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Column chromatography; acetic ester / 5 methanol (5: 1)

Yield: 71%

Melting point: 219 ° C (decomposition) MS: (M + H) ⁺ = 450 (free base)

5. Example 4- (4- (3-Trifluoromethyl-carbonyl) -1-piperazinyl) -3-trifluoromethylbenzoylguanidine hydrochloride

X CH ₃ SO ₃ H

x 4- (4- (4- (2-Pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester)

Column chromatography: acetic ester / methanol (5: 1)

Yield: 66%

Melting point: 246 ° C

MS: (M + H) ⁺ = 409 (free base)

3. Example 4- (4- (4-fluorophenylcarbonyl) 1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate

4- (4- (3-Trifluoromethyl) -tiphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Column chromatography: acetic ester / methanol (5: 1)

Yield: 25%

Melting point: 140 ° C (decomposition)

MS: (M + H) ⁺ = 488 (free base)

6. Example 4- (4- (4-Phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-hydrochloride of 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Column chromatography: acetic ester / methanol (5: 1)

Yield: 40%

Melting point: 140 ° C

MS: (M + H) ⁺ = 438 (free base)

4. Example 4- (4- (2-Methoxyphenylcarbonyl) -1-piperazinyl) -trifluoromethyl-benzoylguanidine hydrochloride x CH ₃ SO ₃ H

4- (4-Phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

x HCI

Column chromatography: acetic ester / methanol (5: 1)

Yield: 64%

Melting point: 214 ° C

MS: (M + H) ⁺ = 420 (free base)

7. Example 4- (4- (2-furylcarbonyl) -1piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate

piperazinyl) -3-trifluoromethyl-benzoylguanidine-dimethanesulfonate 4- (4- (2-furylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Crystallization from ether

Yield: 19%

Melting point: 190 ° C (decomposition) MS: (M + H) ⁺ = 410 (free base)

8. Example 4- (4- (3-methylphenylcarbonyl) 1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate

4- (4- (3-Methylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethylbenzoic acid methyl ester

Crystallization from ether / acetic ester

Yield: 76%

Melting point: 199 ° C

MS: (M + H) + = 434 (free base)

9. Example 4- (4- (4- (1-pyrrolyl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-dimethanesulfonate

X 2 CH ₃ SO ₃ H

4- (4- (4- (1-Pyryl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Crystallization from methanol

Yield: 48%

Melting point: 150 ° C (decomposition)

MS: (M + H ⁺ = 485 (free base)

10. Example 4- (4- (2-Pyridylcarbonyl) -1-x 2 CH ₃ SO ₃ H from 4- (4- (2-pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoic acid methyl ester

Column chromatography: acetic ester: methanol (5: 1)

Yield: 34%

Melting point: 115 ° C (decomposition) MS: (M + H) ⁺ = 421 (free base) Pharmacological data

Suppression of Na ⁺ / H ⁺ / equilibrium in human gut cancer cells (HT-29):

HT-29 cells were incubated in plant medium at 37 ° C, 5% CO ₂ . After 3-5 days, the medium was removed, the cells were washed and loaded with 7.5 μΜ BCECF-AM (pH-sensitive fluorescent dye) at 37 ° C without CO ₂ . After 30 min, the cells were washed and acidified with the following medium: 70 mM colchloride, 20 mM NH ₄ Cl, 1 mM MgCl ₂ , 1.8 mM CaCl ₂ , 5 mM glucose and 15 mM HEPES, pH 7.5. After 6 min incubation at 37 ° C without CO ₂ , the cells were washed and incubated with plant medium: 120 mM chlorochloride, 5 mM KCL, 1 mM MgCl ₂ , 1.8 mM CaCl ₂ , 5 mM glucose and 15 mM MOPS, pH 7.0 .

The plant medium was removed and control medium was added with or without test compound: 120 mM NaCl, 5 mM KCL, 1 mM MgCl ₂ , 1.8 mM CaCl ₂ , 5 mM glucose and 15 mM MOPS, pH 7.0.

Cells were incubated for 4 min at 37 ° C and measured fluorimetrically (Cytofluor 2350). The fluorescence of the BCECF dye was measured at variable wavelengths of 485 nm (pH-sensitive) and 440 nm (insensitive-pH) and at an emission wavelength of 530 nm. The cytoplasmic pH is calculated from the fluorescence ratio at 485 and 440 nm. The fluorescence ratio was calibrated with nigericin by measuring the fluorescence signal after equalizing the external and internal pH.

Example IC50 / 10 ' ⁶ mol D ¹ 1 O.076 3 0.038 4 0.084 5 0.023 7 0.84 8 0.061 10 0.079

The compounds of the invention unexpectedly exhibit very high bioavailability and a long half-life after oral administration - qualities that make them extremely suitable for oral administration.

Pharmacokinetic data

Male rats weighing about 200 g (not fed) were used for studies. For intravenous and oral administration, the substances are dissolved in an acidified aqueous solution (pH 3). The individual single injections of 90.5 mg / kg intravenously, 2.5 mg / kg orally) were injected into the tail vein (0.2 ml / 200 g) or fed through the cannula into the stomach (1 ml / 200 g). The solutions given were analyzed to confirm the dose administered. 0.5 ml aliquots of blood are taken from the retro-orbital venous plexus in short halothosis anesthesia with heparized glass capillaries according to the following scheme:

- after intravenous administration: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h;

- after oral administration: 15 min, 1h, 2 h, 4 h, 6 h, 8 h, 24 h, 32 h.

Samples were centrifuged and the plasma was stored at -20 ° C until analysis. Sampling is performed by liquid-liquid extraction according to an internal standard. Plasma extracts were analyzed by reversed phase HPLC coupled to an electrospray tandem mass spectrometer. Pharmacokinetic data are determined by free comparisons with a topfit program. (Heincel, G., Woloszczak, R., Thonann, P. TopFit 2.0Pharmacokinetic and pharmacodynamic data analysis, PC system, Gustv Fischer Verlag, Stuttgart, Jena, New York, 1993).

Example F you / 2 (intravenously) ti / 2 (oral) 2 63 1.3 5.0 3 71 3.1 5.4 5 58 5.4 7.5

Claims (9)

Claims 1. Benzoylguanidine derivatives of general formula I, in which it may mean: »· Compounds of general formula I according to claim 1, characterized in that R 1 may mean an unsubstituted phenyl ring or phenyl ring which may be substituted by fluorine or methyl, trifluoromethyl, methoxy or pyrrole, or 59 3.4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate X CH3SO3H R1 is; C 1 -C 4 -alkyl, heteroaryl, unsubstituted or mono- or polysubstituted with a branched or unbranched C 1 -C ₄ -alkyl group, cycloalkyl group, with a branched or unbranched C 1 -C ₄ alkoxy group, NH 2 -pyrene or primary or - 20-membered amino group, trifluoromethyl group, cyano or nitro group or halogen, aryl, unsubstituted or mono- or polysubstituted with a branched or unbranched C 1 -C 6 alkyl group, branched or unbranched C 1 -C 6 -alkoxy group, NH ₂ - a group or a primary or secondary amino group, trifluoromethyl group, cyano-; or a nitro group or halogen or a 5 or 6 membered heteroalkyl group which may contain one, two, three or 39 five heteroatoms from the nitrogen, oxygen or sulfur group, identical or different, alkylaryl, unsubstituted or mono- or polysubstituted in an aryl and / or alkylpartial structure, branched or unbranched, 3-branched C 1 -C ₄ -alkyl group, branched or unbranched C ₁ -C ₄ -alkoxy group, NH ₂ group, or a primary or secondary amino group, with trifluoromethyl a group consisting of cyano or nitro group or halogen, optionally in the form of a moiety or 49, optionally enantiomers and mixtures thereof, as well as in the form of free bases or the corresponding acid addition salts with pharmacologically acceptable acids. 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-fluoro methyl-benzoylguanidine-methanesulfonate X CH3SO3H 5. A process for the preparation of compounds of general formula I NH№ < NH ₂ (|) characterized in that 4- (1-piperazinyl) -3-trifluoromethylbenzoic acid ester of general formula II -θ ₄ 'Alkyl (I) is reacted with a compound of general formula III R, C (O) Q (III) 649S5 in which Q represents a leaving group which may be substituted by piperizine nitrogen, optionally in the presence of auxiliaries, preferably carbonyl diimidazole, and the benzoic acid derivative of the general formula IV (IV) ^{15 obtained} is suspended in a suitable, preferably anhydrous solvent, preferably dimethylformamide and mixed with a mixture of solution or suspension on a base, preferably sodium hydride in a suitable anhydrous solvent, preferably dimethylformamide with guanides a new salt, preferably guanidine anhydride chloride and the reaction product is isolated, optionally forming the desired acid addition salt by reaction with a pharmaceutically acceptable acid. A pharmaceutical formulation for administration comprising a compound according to any one of claims 1 to 4 and their acid addition salts in combination with conventional excipients and carriers. Compounds according to any one of claims 1 to 4 for use as pharmaceutical compositions. Use of the compounds according to claims 1 to 4 for the preparation of a pharmaceutical composition having an inhibitory effect with respect to Na ⁺ / H ⁺ equilibrium. Use of the compounds of general formula I, their acid addition salts, for the preparation of a medicament for the therapeutic treatment of ischemia.