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    • 专利摘要:
    The present invention relates to novel benzoylguanidine derivatives of formula (I), their preparation and their use in the manufacture of a medicament. Formula I
    公开号:KR20010079884A
    申请号:KR1020017003627
    申请日:1999-09-16
    公开日:2001-08-22
    发明作者:블레히슈테판-마티아스；뷔르거에리히；아익마이어크리스티안；루스오토
    申请人:클래스 하인츠-게르트；베링거 잉겔하임 파르마 카게；
    IPC主号:
    专利说明:

    Benzoylguanidine derivatives with advantageous properties, method for producing them and their use in the production of medicaments}
    [1] The present invention provides novel benzoylguanidine derivatives of formula (I), optionally individual tautomers, enantiomers or mixtures thereof, and corresponding acid addition salts with organic bases or pharmaceutically acceptable acids, methods for their preparation and pharmaceutical compositions To its use in.
    [2]
    [3] In the above formula,
    [4] R 1 is C 1-8 -alkyl,
    [5] Unsubstituted, branched or straight chain C 1-4 -alkyl group, cycloalkyl group, branched or straight chain C 1-4 -alkoxy group, NH 2 group, primary or secondary amino group, trifluoromethyl group, cyano Or heteroaryl mono- or polysubstituted by a nitro group or halogen,
    [6] Unsubstituted, branched or straight chain C 1-4 -alkyl group, branched or straight chain C 1-4 -alkoxy group, NH 2 group, primary or secondary amino group, trifluoromethyl group, cyano or nitro group, Mono- or polysubstituted by halogen or by 5- or 6-membered heteroaryl groups which may contain the same or different 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen or sulfur Aryl,
    [7] Unsubstituted, branched or straight chain C 1-4 -alkyl group, branched or straight chain C 1-4 -alkoxy group, NH 2 group, primary or secondary amino group, trifluoromethyl group, cyano or nitro group, Or alkylaryl mono- or polysubstituted in the partial structure of aryl and / or alkyl by halogen.
    [8] Preferred compounds for the purposes of the present invention include a phenyl ring having R 1 unsubstituted or a fluorine, methyl, trofluoromethyl, methoxy group, pyrrolyl group, , or A compound of formula I which represents a phenyl ring substituted by.
    [9] Particular preference is given to the following compounds:
    [10] 4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine methanesulfonate
    [11]
    [12] And
    [13] 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine methanesulfonate.
    [14]
    [15] Generally C 1-4 -alkyl or C 1-8 -alkyl is a branched or straight chain hydrocarbon group of 1 to 4 or 1 to 8 carbon atoms which may be unsubstituted or substituted with one or more halogen atoms, preferably fluorine, the same or different. Indicates. The following hydrocarbon groups are examples of such:
    [16] Methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3- Methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 1,1-dimethylbutyl, 1,2-dimethybutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethybutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless stated otherwise, preferred hydrocarbon groups are lower alkyl groups of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl to be.
    [17] Generally, alkoxy is a straight or branched chain alkyl group bonded through oxygen. Preference is given to lower alkoxy groups having 1 to 4 carbon atoms. Methoxy groups are particularly preferred.
    [18] Generally, aryl is a composition of one or more lower alkyl groups, trifluoromethyl groups, cyano groups, alkoxy groups, nitro groups, amino groups and / or aromatic groups which may be substituted with one or more halogen atoms, which may be the same or different. An aromatic group having 6 to 10 carbon atoms including; Preferred aryl groups are substituted or unsubstituted with phenyl groups, while preferred substituents are halogen, such as fluorine, chlorine or bromine, cyano and hydroxyl; Fluorine is the preferred halogen for the purposes of the present invention. In addition, allyl substituents (preferably phenyl) are 5- or 6-months which may contain 1, 2, 3, 4 or 5 hetero atoms which may be the same or different from the group comprising nitrogen, oxygen and sulfur. Heteroaryl.
    [19] In general, aralkyl refers to an aryl group having 7 to 14 carbon atoms bonded through an alkylene chain, wherein the aromatic group is a lower alkyl group, an alkoxy group, a nitro group, an amino group and / or one or more halogen atoms, the same or different Substituted or unsubstituted. Preferred are aralkyl groups having 1 to 6 carbon atoms in the aliphatic moiety and aralkyl groups having 6 carbon atoms in the aromatic moiety.
    [20] Unless stated otherwise, preferred aralkyl groups are benzyl, phenethyl and phenylpropyl.
    [21] Unless stated otherwise, halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or iodine.
    [22] Unless stated otherwise, amino refers to an NH 2 functional group which may be unsubstituted or substituted with 1 or 2 C 1-8 -alkyl, aryl or aralkyl groups which may be the same or different.
    [23] Thus, alkylamino represents, for example, methylamino, ethylamino, propylamino, 1-methylene-ethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.
    [24] Correspondingly, dialkylamino is for example dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (1-methylethyl) amino, di- (1-methylpropyl) amino, di-2- Methylpropylamino, ethylmethylamino and methylpropylamino are shown.
    [25] Cycloalkyl generally refers to a saturated or unsaturated cyclic hydrocarbon group of 5 to 9 carbon atoms which may be unsubstituted or substituted with halogen atoms or halogen atom groups (preferably fluorine) which may be the same or different. Preference is given to cyclic hydrocarbon groups having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and cyclononinyl Include.
    [26] In general, heteroaryl for the purpose of the above definitions refers to 5- to 6-membered rings which may contain oxygen, sulfur and / or nitrogen as hetero atoms and another aromatic ring which may be fused. Preference is given to 5- and 6-membered aromatic rings which contain oxygen, sulfur and / or up to two nitrogens, optionally benzo-condensed.
    [27] Examples of specific heterocyclic systems include acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazenyl, azabenzanthracenyl, azabenzanthrenyl, azacrisenyl, azasai Clazinyl, azaindolyl, azanaphthacenyl, azanaphthalenyl, azaprenyl, azatriphenylenyl, azepineyl, azininoindolyl, azinopyrrolyl, benzacridinyl, benzazininyl, benzofuryl, benzo Naphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl, benzoquinolinyl, benzoquinolinyl, benzothiefinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl , Caprolactamyl, carbazolyl, carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl, coumarinyl, comaronyl, decahydroquinolinyl, decahydroquinoloyl, diazanthracenyl, dia Japhenanthrenyl, dibenazazinyl, dibenzofuranyl, diben Thiphenyl, Dichromillenyl, Dihydrofuranyl, Dihydroisocoumarinyl, Dihydroisoquinolinyl, Dihydropyranyl, Dihydropyridinyl, Dihydropyridonyl, Dihydropyronyl, Dihydrothio Pyranyl, diprilenyl, dioxanthenyl, oenantholactamyl, flavanyl, flavonyl, fluoranyl, fluoresceinyl, furandionyl, furanochromenyl, furanonyl, furanoquinolinyl, fura Neil, furopyranyl, furopyronyl, heteroazulenyl, hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydrofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl, hydroqui Nolinyl, hydrothiochromenyl, hydrothiophenyl, indolidininyl, indolinyl, indolonil, isatinyl, isatogenyl, isobenzofurandionyl, isobenzfuranyl, isochromenyl, isoflavonyl, this Indolinyl, isoindolebenzazazinyl, isoindolinyl, isoquinolinyl, isoquinuclidinyl, lactamil, lactonyl, maleimidyl, monoazabenzonaphthenyl, naphthalenyl, naphthymidazopyridinedionyl , Naphtholinoligindionyl, naphthodihydropyranyl, naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxoleyl, perhydroazolopyridinyl, perhydroindolyl, phenanthraquinonyl , Phthalideisoquinolinyl, phthalimidyl, phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl, pyranoazinyl, pyranoazolyl, pyranopyridinyl, pyranopyridinyl, Pyranoquinolinyl, pyranopyrazinyl, pyranyl, pyrazolopyridinyl, pyridinthionyl, pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl, pyridocolinyl, pyridoindolyl, pyridopyridinyl , Pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl, pyro , Pyrrocolinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolodioazinyl, pyrrolonyl, pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl, quinacridonyl, quinoli Neil, Quinolizinyl, Quinolizinyl, Quinolonyl, Quinuclindinyl, Rhodaminil, Spirocoumaranyl, Succinimidyl, Sulfonanyl, Sulfonenyl, Tetrahydrofuranyl, Tetrahydroisoquinolinyl, Tetra Hydrofuranyl, tetrahydropyridinyl, tetrahydrothiapyranyl, tetrahydrothiophenyl, tetrahydrotipyranylyl, tetrahydrotipyranyl, tetronyl, thiaphenyl, thiachromenyl, thiadecalinyl, thianaphthenyl , Thiapyranyl, thiapyronyl, thiazolopyridinyl, thienopyridinyl, thienopyrrolyl, thienothiophenyl, thiefinyl, thiochromenyl, thiocoumarinyl, thiopyranyl, triazaanthracenyl, tri Azinoindolyl, Triage Nolopyridinyl, trofanyl, xanthenyl, xanthoneyl, xanthrolyl, adeninyl, aloxanyl, aloxazinyl, anthranyl, azabenzanthrenyl, azabenzonaphthenyl, azanaphthacenyl, azafe Noxazinyl, azapurinyl, azinyl, azoazinyl, azolyl, barbituric acid, benzazinyl, benzimidazolionyl, benzimidazoloyl, benzisothiazolyl, benzisoxazolyl, benzosinolinyl , Benzodiazoxyl, benzodioxolanyl, benzodioxolyl, benzopyridazinyl, benzothiazepinyl, benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnaolinyl, Depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxazolyl, dihydropyridazinyl, dihydropyridin Midinyl, dihydrothiazinyl, dioxa , Dioxenyl, dioxepinyl, dioxynonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl, dithiolanyl, dithiolenyl, dithiolonyl, flavinyl, furypyrimididi Neyl, Glycosiamidinyl, Guanyl, Hexahydropyrazinoisoquinolinyl, Hexahydropyrazinyl, Hydantoinyl, Hydroimidazolyl, Hydroparazinyl, Hydropyrazolyl, Hydropyridazinyl, Hydropyri Midinyl, imidazolinyl, imidazolyl, imidazoquinazolinyl, imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoaloxazinyl, isothiazolyl, isoxazolidinyl , Isoxazolininyl, isoxazolinyl, isoxazolinyl, isoxazolyl, lumaginyl, methylthyminyl, methylurasilyl, morpholinyl, naphthymidazolyl, orotisyl, oxatinil, oxatiola Neil, Oxazinononyl, Oxazolidinonyl, Oxazoli Nil, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazoloyl, oxazolopyrimidinyl, oxazolyl, perhydrocinolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydro Thiazinonyl, perimidyl, phenazinyl, phenothiazinyl, phenoxatiinyl, phenoxazinyl, phenoxazoniyl, phthalazinyl, piperazindionyl, polyquinoxalinyl, pterridinyl, pterinyl, Furinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolononyl, pyrazolinyl, pyrazolobenzodiazepinyl, pyrazoloyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyrida Genyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinthionyl, pyrimidinyl, pyrimidionyl, pyrimidadozepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pi Rolodiazinyl, pyrrolopyrimidinyl, quinazolidinyl, quinazolininoyl, Nazolinyl, Quinoxalinyl, Sultamyl, Sultinyl, Sultonyl, Tetrahydrooxazolyl, Tetrahydropyrazinyl, Tetrahydropyridazinyl, Tetrahydroquinoxalinyl, Tetrahydrothiazolyl, Thiazinyl, Thiazinyl , Thiazolidinonyl, thiazolidinyl, thiazolininyl, thiazolinyl, thiazolobenzimidazolyl, thiazolyl, thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, urasilyl , Xanthinyl, xylitolyl, azabenzonaphthenyl, benzofuroxanyl, benzothiadiazinyl, benzotriazininoyl, benzotriazolyl, benzoxadiazinyl, dioxadiazinyl, dithiazozolyl, dithia Zolyl, furazanyl, furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxdiazolyl, oxthiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, pentazinyl, polyoxadiazolyl, cy Nilyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, thiadiazinyl, thiadiazolinyl, thiadiazolyl, thiadioxazinyl, thiariazinyl, thiadiazolyl, thiadiazolyl, triazinyl, Triazinoindolyl, triazinyl, triazolindionyl, triazolinyl, triazolyl, trioxanyl, trifenodioxazinyl, trifenodithiazinyl, trithiadiazepiniyl, tritianyl or trioxolanyl It includes.
    [28] Compounds of this type are already known from German patent 196 01 303.8.
    [29] Depending on their effect as inhibitors of intracellular Na + / H + exchange, the compounds can be used as active ingredients of pharmaceutical compositions or as intermediate products for the preparation of such active ingredients. The compounds according to the invention are effective against arrhythmias that arise, for example, from hypoxia. They can also be used for diseases associated with ischemia (e.g. heart, brain, gastrointestinal-mesenteric thrombosis / embolism, lungs, kidney ischemia, liver ischemia, skeletal muscle ischemia). Such diseases include, for example, coronary heart disease, myocardial infarction, angina pectoris, stable angina pectoris, ventricular arrhythmias, subventricular arrhythmias, cardiac insufficiency-also support for lateral manipulation, support for open heart surgery, support for blocking blood supply to the heart And in support for heart transplantation-reperfusion injury due to embolism in the pulmonary circulation, acute or chronic kidney disease, chronic renal failure, cerebral infarction, resumption of blood supply to the brain area after treatment of vascular occlusion and acute and chronic bleeding of the brain Includes disability. Herein, the above-mentioned compounds can be used in combination with thrombolytic agents such as t-PA, streptokinase and urokinase.
    [30] During the effects of the ischemic heart (after the invention of angina or myocardial infarction), irreversible damage can occur to cardiomyocytes at the affected site. The compounds according to the invention have cardiolytic activity, among others, in this case in particular.
    [31] In addition, the prevention of damage to the graft may include the storage of organs before, during and after transplantation, and for transplantation, in order to protect the early stages of ischemia that may occur in connection with the transplantation (e.g., liver, kidney, heart or lung). Should be included). The compound is also a compound that has a protective effect during angiogenesis surgery against heart and peripheral blood vessels.
    [32] In basic hypertension and diabetic nephropathy, sodium proton exchange of cells is increased. Thus, the compounds according to the invention are suitable for the inhibition of such exchanges to prevent such diseases.
    [33] In addition, the compounds according to the invention are characterized by a potent inhibitory effect on cell proliferation. As a result, the compounds are useful agents in the treatment of diseases in which cell proliferation acts as a first or second role, and are useful for cancer, benign tumors or, for example, prostatic hyperplasia, atherosclerosis, organ hypertrophy and hyperplasia, fibrotic It can be used as a medicament for diseases and late diabetic complications.
    [34] Compounds of this type are also known to have a beneficial effect on the blood levels of serum lipoproteins.
    [35] Surprisingly, the compounds of formula (I) presently are more unexpected and more effective than the benzoylguanidine derivatives already known in the prior art, and have the advantage of being suitable for oral administration.
    [36] The active substances of formula (I) can be used for aqueous solutions for injection (eg intravenous, intramuscular or subcutaneous administration), tablets, suppositories, ointments, transdermal plasters, inhalation aerosols or nasal sprays through the lungs. have.
    [37] The content of active substance in tablets or suppositories is 5 to 200 mg, preferably 10 to 50 mg. Each dosage for inhalation is from 0.05 to 20 mg, preferably from 0.2 to 5 mg. The single dose for parenteral injection is 0.1 to 50 mg, preferably 0.5 to 20 mg. The dosage may be administered several times a day if necessary.
    [38] The following are examples of pharmaceutical formulations containing the active substance:
    [39] refine
    [40] 20.0 mg of active substance of formula (I)
    [41] Magnesium Stearate 1.0mg
    [42] Corn Starch 62.0mg
    [43] Lactose 83.0mg
    [44] Polyvinylpyrrolidone 1.6mg
    [45] Injectable Solution
    [46] 0.3 g of active substance of formula (I)
    [47] 0.9 g of sodium chloride
    [48] The rest in 100 ml of water for injection
    [49] The solution can be sterilized by standard methods.
    [50] Aqueous solution for nasal administration and inhalation
    [51] 0.3 g of active substance of formula (I)
    [52] 0.9 g of sodium chloride
    [53] Benzalkonium chloride 0.01mg
    [54] Remainder in 100 ml of purified water
    [55] The solution is preferably suitable for nasal administration in nebulizers and for pulmonary administration, when used in combination with a device for producing an aerosol having a particle size of 2-6 μm.
    [56] Inhalation Capsule
    [57] Compounds of formula (I) are packed into hard gelatin capsules in micronized form (particle size: basically 2-6 μM) and optionally micronized carrier material such as lactose is added. These are inhaled using conventional powder inhalation devices. Each capsule is packed with, for example, 0.2 to 20 mg of the compound of formula (I) and 0 to 40 mg of lactose.
    [58] Inhalation Aerosols
    [59] 1 part active substance of formula (I)
    [60] Soya Lecithin Part 0.2
    [61] Remainder of 100 parts propellant gas mixture
    [62] Preferably, the formulation is transferred to an aerosol container using a metered valve, injecting a 0.5 mg dose of each spray. For other dosages in a particular range, preparations containing large or small amounts of the active substance are conventionally used.
    [63] Ointment (composition g / ointment 100 g)
    [64] 2 g of active substance of formula (I)
    [65] Hydrochloric acid gas 0.011 g
    [66] Sodium Pyrosulphite 0.05g
    [67] 20 g of a mixture of cetyl alcohol and stearyl alcohol
    [68] 5g white petrolatum
    [69] Artificial Bergamot Oil 0.075g
    [70] Rest of 100 distilled water
    [71] The components are processed in the usual way to form an ointment.
    [72] In general, methods for the preparation of compounds according to the invention are known in the prior art and therefore the compounds of the invention can be obtained by the following process:
    [73] The benzoic acid derivative of formula (IV) obtained by reacting the 4- (1-piperazinyl) -3-trifluoromethylbenzoic acid ester of formula (II) with the compound of formula (III), optionally in the presence of an adjuvant, preferably carbonyldiimidazole Is suspended in a suitable solvent, preferably anhydrous solvent, preferably dimethylformamide, and a solution or suspension of a base in a suitable anhydrous solvent, preferably dimethylformamide, preferably sodium hydride, and a guanidine salt, preferably Mix with a mixture of guanidine hydrochloride and separate the reaction product.
    [74]
    [75] R 1 C (O) Q
    [76]
    [77] In the above formula,
    [78] Q is a leaving group which may be substituted by piperazine nitrogen.
    [79] The invention is illustrated by the following examples.
    [80] Methyl 4-fluoro-3-trifluoromethyl-benzoate
    [81] 35.4 g (170 mmol) of 4-fluoro-3- (trifluoromethyl) -benzoic acid in 250 ml of methanol are mixed with 68 ml of SOCl 2 for 25 minutes at 5 ° C. while cooling on ice. After all additions, the reaction mixture is refluxed for an additional 3 hours. The reaction solution is cooled to ambient temperature and evaporated under vacuum. The oily residue is dissolved in 200 ml of diethyl ether and extracted with water, saturated NaHCO 3 solution and again water. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo.
    [82] Yield: 29.0 g (77%)
    [83] Methyl 4- (4-benzyl-1-piperazinyl) -3-trifluoromethyl-benzoate
    [84] Dissolve 7 g (31.5 mmol) of methyl 4-fluoro-3-trifluoromethyl-benzoate in 60 mL of anhydrous dimethylsulfoxide (DMSO), 5.55 g (31.5 mmol) of N-benzylpiperazine and 4.35 g of potassium carbonate. (31.5 mmol). The mixture is stirred at 90 ° C. for 12 h. 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 under vacuum. The residue is chromatographed on silica gel using a mixture of ethyl acetate and n-heptane.
    [85] Yield: 3.93 g (33%)
    [86] Methyl 4- (1-piperazinyl) -3-trifluoromethyl-benzoate
    [87] 20.2 g (53.3 mmol) of methyl 4- (4-benzyl-1-piperazinyl) -3-trifluoromethyl-benzoate are dissolved in 200 ml of methanol, mixed with 2 g of palladium on charcoal and 5 bar hydrogen. Hydrogenate at 70 ° C. for 1.4 h under pressure. The solution is suction filtered on celite and distilled under vacuum.
    [88] Yield: 14.85 g (97%)
    [89] General method for coupling methyl 4- (1-piperazinyl) -3-trifluoromethyl-benzoate with benzoic acid
    [90] The corresponding carboxylic acid 5 mmol is dissolved in 30 ml of anhydrous tetrahydrofuran (THF), combined with 810 mg (5 mmol) of carbonyldiimidazole under protective gas at 0 ° C. and stirred at ambient temperature (about 25 ° C.) for 2 hours. Then 1.44 g (5 mmol) of methyl 4- (1-piperazinyl) -3-trifluoromethyl-benzoate are added and the mixture is stirred for an additional 12 hours. The solution is evaporated to dryness in vacuo and dissolved in ethyl acetate. After washing with saturated NaHCO 3 solution, saturated NaCl solution and water, the organic phase is dried over MgSO 4 and evaporated in vacuo. After crystallization in a suitable solvent or chromatography on silica gel with a suitable eluent, the following compounds are obtained.
    [91] 1.Methyl 4- (4- (3-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [92] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [93] Yield: 81%
    [94] 2. Methyl 4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [95] Crystallization from methanol
    [96] Yield: 75%
    [97] Melting Point: 149 ℃
    [98] 3. Methyl 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [99] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [100] Yield: 77%
    [101] 4. Methyl 4- (4- (2-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [102] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [103] Yield: 79%
    [104] 5. Methyl 4- (4- (3-trifluoromethylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [105] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [106] Yield: 83%
    [107] 6. Methyl 4- (4- (phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl-benzoate
    [108] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [109] Yield: 87%
    [110] 7. Methyl 4- (4- (2-furylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [111] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [112] Yield: 75%
    [113] 8. Methyl 4- (4- (3-methylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [114] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [115] Yield: 79%
    [116] 9. Methyl 4- (4- (4- (1-pyryl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [117] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [118] Yield: 87%
    [119] 10.Methyl 4- (4- (2-pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate
    [120] Column Chromatography: Ethyl Acetate / n-heptane (2: 1)
    [121] Yield: 73%
    [122] General method for preparing acyl guanidine from the corresponding methyl carbonate
    [123] 5.09 g (127.2 mmol) of 60% NaH in white oil are washed twice with ether and removed by decant. 200 mL of anhydrous DMF is added and a small amount of 12.15 g (127.2 mmol) of guanidine hydrochloride is added while stirring under protective gas. After stirring for 1 hour, the corresponding methyl ester 21.2 mmol is added and the solution is stirred for an additional 2 hours at a temperature of about 120 ° C. The reaction mixture is then cooled to ambient temperature, filtered and the filtrate is evaporated in vacuo. Chromatography on silica gel with a suitable eluent and conversion to the corresponding salts with etheric hydrochloric acid or other pharmacologically acceptable acids yield the following compounds (in the following structural formulas, bound to carbon or nitrogen atoms) Hydrogen atoms not required for the understanding of the present invention have been omitted).
    [124] Example 1
    [125] 4- (4- (4-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-hydrochloride
    [126]
    [127] The title compound is prepared from methyl 4- (4- (3-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [128] Column Chromatography: Ethyl Acetate / Methanol (5: 1)
    [129] Yield: 71%
    [130] Melting Point:> 200 ℃
    [131] MS: (M + H) + = 450 (free base)
    [132] Example 2
    [133] 4- (4- (2-Pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate
    [134]
    [135] The title compound is prepared from methyl 4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [136] Column Chromatography: Ethyl Acetate / Methanol (5: 1)
    [137] Yield: 66%
    [138] Melting Point: 246 ℃
    [139] MS: (M + H) + = 409 (free base)
    [140] Example 3
    [141] 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate
    [142]
    [143] The title compound is prepared from methyl 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [144] Column Chromatography: Ethyl Acetate / Methanol (5: 1)
    [145] Yield: 40%
    [146] Melting point: 140 ℃
    [147] MS: (M + H) + = 438 (free base)
    [148] Example 4
    [149] 4- (4- (2-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-hydrochloride
    [150]
    [151] The title compound is prepared from methyl 4- (4- (2-methoxyphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [152] Column Chromatography: Ethyl Acetate / Methanol (5: 1)
    [153] Yield: 71%
    [154] Melting Point: 219 ℃ (Decomposition)
    [155] MS: (M + H) + = 450 (free base)
    [156] Example 5
    [157] 4- (4- (3-Trifluoromethylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-hydrochloride
    [158]
    [159] The title compound is prepared from methyl 4- (4- (3-trifluoromethylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [160] Column Chromatography: Ethyl Acetate / Methanol (5: 1)
    [161] Yield: 25%
    [162] Melting Point: 140 ℃ (Decomposition)
    [163] MS: (M + H) + = 488 (free base)
    [164] Example 6
    [165] 4- (4-phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-hydrochloride
    [166]
    [167] The title compound is prepared from methyl 4- (4-phenylcarbonyl-1-piperazinyl) -3-trifluoromethyl-benzoate.
    [168] Column Chromatography: Ethyl Acetate / Methanol (5: 1)
    [169] Yield: 64%
    [170] Melting Point: 214 ℃
    [171] MS: (M + H) + = 420 (free base)
    [172] Example 7
    [173] 4- (4- (2-furylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate
    [174]
    [175] The title compound is prepared from methyl 4- (4- (2-furylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [176] Crystallization from ether
    [177] Yield: 19%
    [178] Melting Point: 190 ℃ (Decomposition)
    [179] MS: (M + H) + = 410 (free base)
    [180] Example 8
    [181] 4- (4- (3-methylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulfonate
    [182]
    [183] The title compound is prepared from methyl 4- (4- (3-methylphenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [184] Crystallization from methanol / ethyl acetate
    [185] Yield: 76%
    [186] Melting point: 199 ℃
    [187] MS: (M + H) + = 434 (free base)
    [188] Example 9
    [189] 4- (4- (4- (1-pyrrolyl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-dimethylsulfonate
    [190]
    [191] The title compound is prepared from methyl 4- (4- (4- (1-pyryl) phenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [192] Crystallization from methanol
    [193] Yield: 48%
    [194] Melting Point: 150 ℃ (Decomposition)
    [195] MS: (M + H) + = 485 (free base)
    [196] Example 10
    [197] 4- (4- (2-Pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-dimethanesulfonate
    [198]
    [199] The title compound is prepared from methyl 4- (4- (2-pyridylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoate.
    [200] Column Chromatography: Ethyl Acetate / Methanol (5: 1)
    [201] Yield: 34%
    [202] Melting Point: 115 ℃ (Decomposition)
    [203] MS: (M + H) + = 421 (free base)
    [204] Pharmacological data
    [205] Inhibition of Na + / H + exchange in human intestinal cancer cells (HT-29)
    [206] HT-29 cells are incubated in growth medium at 37 ° C. with 5% CO 2 . After 3-5 days, growth medium is removed, cells are washed and filled at 37 ° C. without CO 2 using 7.5 μM BCECF-AM (pH-sensitive fluorescent dye). After 30 minutes, the cells are washed and acidified with the following medium: choline chloride 70 mM, NH 4 Cl 20 mM, MgCl 2 1 mM, CaCl 2 1.8 mM, glucose 5 mM and HEPES 15 mM, pH 7.5.
    [207] After 6 min incubation at 37 ° C. without CO 2 , cells were washed and 5 min using wash medium (120 mM choline chloride, 5 mM KCl, 1 mM MgCl 2 , CaCl 2 1.8 mM, glucose 5 mM and MOPS 15 mM, pH 7.0). Incubate for a while.
    [208] Wash medium is removed and control medium is added with or without test compound: NaCl 120 mM, KCl 5 mM, MgCl 2 1 mM, CaCl 1.8 mM, Glucose 5 mM and MOPS 15 mM, pH 7.0.
    [209] Cells are incubated for 4 minutes at 37 ° C. without CO 2 and measured by fluorometry (CytoFluor 2350). The fluorescence of the dye BCECF is measured at stimulation wavelengths of 485 nm (pH sensitivity) and 440 nm (non-pH sensitivity) and absorption wavelength of 530 nm. Cytoplasmic pH is calculated from the fluorescence ratio at 485 and 440 nm. Fluorescence ratio is measured by measuring the fluorescence signal after equilibration of external and internal pH using nigericin.
    [210] ExampleIC 50/10 -6 mol l -1One0.076 30.038 40.084 50.023 70.084 80.061 100.079
    [211] In addition, the compounds according to the invention surprisingly have very good bioavailability and properties which make them very suitable for oral use and a long half-life after oral administration.
    [212] Drug Bioreactive Data:
    [213] Male rats (not starving) weighing about 200 g are used for testing. For intravenous and oral administration, the material is dissolved in acidified aqueous solution (pH 3). Each pill infusion (0.5 mg / kg intravenous, 2.5 mg / kg p.o.) is injected into the tail vein (0.2 ml / 200 g) or administered via the cannula up (1 ml / 200 g). The administered solution is analyzed to identify the given dose. 0.5 ml of blood fractions are taken from retro-orbital vein reticular tissue under short halotan anesthesia, using heparinized glass capillaries according to the following scheme:
    [214] After intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours;
    [215] After oral administration: 15 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 32 hours.
    [216] Samples are centrifuged and plasma is stored at -20 ° C until ready for analysis. The preparation of the samples is carried out by liquid-liquid extraction using internal standards. Plasma extracts are analyzed by reversed phase HPLC coupled with an electrospray in-line mass spectrometer.
    [217] Drug bioreactive data can be obtained from the TopFit program [Heinzel, G., Woloszczak, R., Thomann, P. TopFit 2.0-Drug bioreactive and drug biomechanical data analysis, systems for PC, Gustav Fischer Verlag, Stuttgart, Jena, New York, 1993] is determined from the corresponding plasma concentrate by compartment-free analysis.
    [218] ExampleFt 1/2 (intravenous)t 1/2 (po) 2631.35.0 3713.15.4 5585.47.5
    [219] The entire contents of German Patent No. 198 43 489, which is a priority of the present application, are incorporated herein by reference.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] Benzoylguanidine derivatives of formula (I), optionally individual tautomers, enantiomers or mixtures thereof, and corresponding acid addition salts with organic bases or pharmaceutically acceptable acids.
    Formula I

    In the above formula,
    R 1 is C 1-8 -alkyl,
    Unsubstituted, branched or straight chain C 1-4 -alkyl group, cycloalkyl group, branched or straight chain C 1-4 -alkoxy group, NH 2 group, primary or secondary amino group, trifluoromethyl group, cyano Or heteroaryl mono- or polysubstituted by a nitro group or halogen,
    Unsubstituted, branched or straight chain C 1-4 -alkyl group, branched or straight chain C 1-4 -alkoxy group, NH 2 group, primary or secondary amino group, trifluoromethyl group, cyano or nitro group, Mono- or polysubstituted by halogen or by 5- or 6-membered heteroaryl groups which may contain the same or different 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen or sulfur Aryl,
    Unsubstituted, branched or straight chain C 1-4 -alkyl group, branched or straight chain C 1-4 -alkoxy group, NH 2 group, primary or secondary amino group, trifluoromethyl group, cyano or nitro group, Or alkylaryl mono- or polysubstituted in the partial structure of aryl and / or alkyl by halogen.
    [2" claim-type="Currently amended] The compound of claim 1, wherein R 1 is an unsubstituted phenyl ring or a fluorine, methyl, trifluoromethyl, methoxy group, pyrrolyl group, , or A compound of formula (I), characterized by a phenyl ring substituted by.
    [3" claim-type="Currently amended] 4- (4- (2-pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine methanesulfonate

    [4" claim-type="Currently amended] 4- (4- (4-fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine methanesulfonate.

    [5" claim-type="Currently amended] The benzoic acid derivative of formula (IV) obtained by reacting the 4- (1-piperazinyl) -3-trifluoromethylbenzoic acid ester of formula (II) with the compound of formula (III), optionally in the presence of an adjuvant, preferably carbonyldiimidazole Is suspended in a suitable solvent, preferably anhydrous solvent, preferably dimethylformamide, and a solution or suspension of a base in a suitable anhydrous solvent, preferably dimethylformamide, preferably sodium hydride, and a guanidine salt, preferably A process for preparing a compound of formula I, characterized in that it is mixed with a mixture of guanidine hydrochloride, the reaction product is separated, and optionally forms the desired acid addition salt with a pharmacologically acceptable acid.
    Formula I

    Formula II

    Formula III
    R 1 C (O) Q
    Formula IV

    In the above formula,
    Q is a leaving group which may be substituted by piperazine nitrogen.
    [6" claim-type="Currently amended] A pharmaceutical formulation, characterized in that it contains a compound according to any one of claims 1 to 4 and acid addition salts thereof with conventional excipients and carriers.
    [7" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 4 as a pharmaceutical composition.
    [8" claim-type="Currently amended] Use of a compound after use of the compound according to claim 7 as a pharmaceutical composition having an inhibitory effect on Na + / H + exchange.
    [9" claim-type="Currently amended] Use of a compound of formula (I) and acid addition salts thereof for the manufacture of a medicament for the treatment of ischemia.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-09-22|Priority to DE19843489A
    1998-09-22|Priority to DE19843489.8
    1999-09-16|Application filed by 클래스 하인츠-게르트, 베링거 잉겔하임 파르마 카게
    2001-08-22|Publication of KR20010079884A
    2006-09-13|Application granted
    2006-09-13|Publication of KR100621821B1
    优先权:
    申请号 | 申请日 | 专利标题
    DE19843489A|DE19843489B4|1998-09-22|1998-09-22|Benzoylguanidine derivatives having advantageous properties, processes for their preparation and their use in the preparation of medicaments, and pharmaceutical compositions containing them|
    DE19843489.8|1998-09-22|
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