Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—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
  • 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
  • C07D207/34—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• the present invention relates to novel benzoylguanidine derivatives, processes for their preparation and their use in the manufacture of medicaments.
• novel benzoylguanidine derivatives correspond to the general formula (I)
• R 1 R 3 - SO 2 - or R 3 - NH - SO 2 -, F, Cl or CF 3 ;
• n 1 + 2 + 3 + 4 + 6
• n is an integer 0 or 1
• p is an integer 0, 1, 2, 3 or 4;
• a is an integer from 0 to 8, preferably 1, 2, 3 or 4, b is 0, 1 or 2, preferably 1,
• d 0, 1 or 2, preferably 1;
• R 2 unsubstituted or substituted C 1 -C 8 alkyl, unsubstituted
• R 3 is C 1 -C 8 alkyl, halogen- or phenyl-substituted C 1 -C 8 alkyl, the
• Phenyl radical can have up to three substituents from the group halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy,
• R 4 and R 4 ' which may be the same or different, are hydrogen, C 1 -C 4 alkyl, R 4 and R 4 ' are also phenyl, benzyl and C 3 -C 7 cycloalkyl,
• R 5 is hydrogen or C 1 -C 8 alkyl, aryl, aralkyl,
• R 6 is hydrogen or C 1 -C 8 alkyl, aryl, aralkyl,
• R 7 can denote hydrogen, C 1 -C 4 alkyl, aryl or aralkyl
• Preferred compounds of the general formula I are those in which
• n is an integer 0 or 1
• p is an integer 0, 1, 2, 3 or 4;
• a is an integer from 0 to 4,
• R 2 unsubstituted or substituted C 1 -C 4 alkyl, unsubstituted
• R 7 may optionally be substituted by B;
• R 3 is C 1 -C 4 alkyl;
• R 4 and R 4 ' which may be the same or different, are hydrogen, C 1 -C 4 alkyl, R 4 and R 4 ' are also phenyl, benzyl and C 3 -C 7 cycloalkyl;
• R 5 is hydrogen or C 1 -C 4 alkyl, aryl, aralkyl
• R 6 is hydrogen or C 1 -C 4 alkyl, aryl, aralkyl
• R 7 can mean C 1 -C 4 alkyl, aryl or aralkyl.
• a is an integer from 0 to 4,
• R 2 is a 5-membered heterocycle which may optionally be fused by one or two phenyl systems and in which U, V, W, X, Y and optionally Z: CH 2 , CH, NR 7 , N, O or S, where in the hydrogen-bearing members a hydrogen or R 7 can optionally be substituted by B and only one hetero atom is present in the ring system;
• R 3 is C 1 -C 4 alkyl
• R 4 and R 4 ' which may be the same or different, are hydrogen, C 1 -C 4 alkyl;
• R 5 is hydrogen or C 1 -C 4 alkyl, aryl, aralkyl
• R 6 is hydrogen or C 1 -C 4 alkyl, aryl, aralkyl
• R 7 can denote hydrogen, C 1 -C 4 alkyl, aryl or aralkyl.
• C 1 -C 4 alkyl or C 1 -C 8 alkyl generally represents a branched or unbranched hydrocarbon radical with 1 to 4 or 8 Carbon atom (s), which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be the same or different from one another.
• halogen atoms preferably fluorine
• lower alkyl radicals having 1 to 4 carbon atoms such as methyl; Ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl.
• Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 8 bonded via an oxygen atom Carbon atom (s).
• a lower alkoxy radical having 1 to 4 carbon atoms is preferred.
• the methoxy group is particularly preferred.
• Aryl generally represents an aromatic radical having 6 to 10
• Alkoxy group (s), nitro group (s), amino group (s) and / or one or more halogen atom (s) - with one another the same or different - can be substituted;
• the preferred aryl radical is an optionally substituted phenyl radical, halogen - such as fluorine, chlorine or bromine - cyano and hydroxyl being preferred as substituents.
• Aralkyl generally represents an aryl radical having 7 to 14 carbon atoms bonded via an alkylene chain, the aromatic having one or more
• Lower alkyl group (s), alkoxy group (s), nitro group (s), amino group (s) and / or one or more halogen atom (s) - can be substituted for one another, identically or differently.
• Aralkyl radicals with 1 to 6 are preferred
• Carbon atom (s) in the aliphatic part and 6 carbon atoms in the aromatic part are carbon atoms in the aromatic part.
• aralkyl radicals are benzyl, phenethyl and phenylpropyl.
• Halogen represents fluorine, chlorine, bromine, iodine and preferably chlorine and bromine.
• amino represents an NH 2 function which, if appropriate, can be substituted by one or two C 1 -C 8 -alkyl, aryl or aralkyl radicals, the same or different.
• alkylamino represents methylamino, ethylamino, propylamino, 1-methylenethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1, 1-dimethylethylamino.
• Dialkylamino stands for example for dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (1-methylethyl) amino, di- (1-methylpropyl) amino, di-2-methylpropylamino, ethylmethylamino, methylpropylamino.
• Cycloalkyl generally represents a saturated or unsaturated cyclic hydrocarbon radical having 5 to 9 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be identical or different from one another. Cyclic hydrocarbons having 3 to 6 carbon atoms are preferred.
• Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl,
• Heteroaryl in the context of the definition given above generally represents a 5- to 6-membered ring which can contain oxygen, sulfur and / or nitrogen as heteroatoms and to which a further aromatic ring can be fused.
• 5- and 6-membered aromatic rings are preferred, the one
• heterocyclic systems examples include acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl,
• Diazaphenanthrenyl dibenzazapinyl, dibenzofuranyl, dibenzothiphenyl,
• Flavonyl Fluoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl, furopyranyl, furopyronyl, heteroazulenyl,
• Isobenzofurandionyl isobenzfuranyl, isochromanyl, isoflavonyl, isoindolinyl, isoindolobenzazapinyl, isoindolyl, isoquinolinyl, isoquinuclidinyl, lactamyl, lactonyl, maleimidyl, naphthimidylhythidylhythidylhyphid Oxepinyl, oxindolyl, Oxolenyl, Perhydroazolopyridinyl, perhydroindolyl, Phenanthrachinonyl, Phthalideisoquinolinyl, phthalimidyl, Phthalonyl, piperidinyl, piperidonyl, prolinyl, Parazinyl, Pyranoazinyl, Pyranoazolyl, Pyranopyrandionyl, Pyranopyridinyl, Pyranochinoliny
• Triazinoindolyl triazolopyridinyl, tropanyl, xanthenyl, xanthonyl, xanthydrolyl, adeninyl, alloxanyl, alloxazinyl, anthranilyl, azabenzanthrenyl,
• Benzothiazepinyl benzothiazinyl, benzothiazolyl, benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl, depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl, dibenzoxazepinyl, dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrooxyridiazyridyldiazidyl
• Benzotriazepinonyl benzotriazolyl, benzoxadiazinyl, dioxadiazinyl, dithiadazolyl, dithiazolyl, furazanyl, furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxadiazolyl, oxathiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, petra
• the compounds of the general formula I can be used as active ingredients in pharmaceuticals or can be used as intermediates for the preparation of such active ingredients.
• the compounds according to the invention act against arrhythmias which occur, for example, in hypoxia. They can also be used for diseases which are related to ischemia (examples: cardiac, cerbral, gastrointestinal, pulmonary, renal ischemia, ischemia of the liver, ischemia of the skeletal muscles).
• Corresponding diseases are, for example, coronary heart disease, angina pectoris, embolism in the pulmonary circulation, acute or chronic kidney failure, chronic renal failure, cerebral infarction, reperfusion damage in the re-perfusion of areas of the brain after dissolution of vascular occlusions and acute and chronic circulatory disorders in the brain.
• the compounds mentioned are also useful in combination with thrombolytic agents such as t-PA, streptokinase and urokinase.
• the compounds according to the invention have a cardioprotective effect in such a case.
• the ischemia field of application also includes the prevention of damage to grafts (e.g. as protection of the graft before, during and after the implantation and during the storage of the grafts), which can occur in connection with transplants.
• the compounds are also protective Medicines used to perform angioplasty surgery on the heart and peripheral vessels.
• the compounds according to the invention are furthermore distinguished by a strongly inhibiting effect on the proliferation of cells. That is why they are
• HT-29 cells were incubated at 37 ° C, 5% CO 2 in growth medium. After 3-5 days, the growth medium was removed, the cells were washed and loaded with 7 5 ⁇ M BCECF-AM (pH-sensitive fluorescent dye) at 37 ° C. without CO 2 . After 30 mm, the cells were washed and acidified with the following medium: 70 mM choline chloride, 20 mM NH 4 CI, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 5 mM glucose and 15 mM HEPES, pH 7.5.
• BCECF-AM pH-sensitive fluorescent dye
• the cells were washed and incubated for 5 mm with washing medium 120 mM choline chloride, 5 mM KCI, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 5 mM glucose and 15 mM MOPS, pH 7.0 .
• the washing medium was removed and control medium with or without test compound was added: 120 mM NaCl, 5 mM KCI, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 5 mM glucose, 15 mM MOPS, pH 7.0.
• the cells were incubated for 4 min at 37 ° C. without CO 2 and measured fluorimetrically (CytoFluor 2350).
• the fluorescence of the BCECF dye was measured at the excitation wavelengths 485 nm (pH sensitive) and 440 nm (not pH sensitive) and at the emission wavelength 530 nm.
• the cytoplasmic pH was calculated from the ratio of the fluorescence at 485 and 440 nm.
• the fluorescence ratio was calibrated by measuring the fluorescence signal after equilibration of external and internal pH with Nigericin.
• the active compounds according to general formula I can be aqueous
• Injection solution e.g. for intravenous, intramuscular or subcutaneous application
• a tablet e.g., as a suppository, as an ointment, as a plaster for transdermal application, as an aerosol for inhalation via the lungs or as a nasal spray.
• the active substance content of a tablet or a suppository is between 5 and 200 mg, preferably between 10 and 50 mg.
• the single dose is between 0.05 and 20 mg, preferably between 0.2 and 5 mg.
• the single dose is between 0.1 and 50 mg, preferably between 0.5 and 20 mg. If necessary, the doses mentioned can be given several times a day.
• the solution can be sterilized using standard procedures.
• the solution outlined above is suitable for nasal application in a spray, or in combination with a device that produces an aerosol with a particle size preferably between 2 and 6 ⁇ m, for use via the lungs.
• the compounds of general formula 1 are in micronized form
• micronized carrier substances such as lactose
• hard gelatin capsules Particle size essentially between 2 and 6 ⁇ M
• micronized carrier substances such as lactose
• the usual devices for powder inhalation are used for inhalation. In every capsule for example between 0.2 and 20 mg of the active ingredient of the general formula I and 0 to 40 mg of lactose.
• the preparation is preferably filled into an aerosol container with a metering valve, and the individual stroke is dimensioned such that a dose of 0.5 mg is dispensed. Preparations with a higher or lower active ingredient content are expediently used for the other dosages in the specified range.
• the corresponding benzoic acid derivatives consist in that a benzoic acid derivative of the general formula II in which P is a nucleofuge
• the activated acid derivatives can be obtained in a manner known per se directly from the underlying benzoic acid derivatives of the general formula IV
• Carboxylic acid derivatives based on the benzoic acid derivatives of the general formula IV are given, citing source literature, in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.
• An activated carboxylic acid derivative is reacted with a guanidine salt in a manner known per se in a protic or aprotic polar but inert organic solvent.
• the corresponding benzoic acids are obtained, for example, by reacting the correspondingly substituted piperazines with 4-chloro-3-methylsulfonylbenzoic acid, nucleophilic substitution in the 4-position.
• 10 mM 4-chloro-3-methylsulfonylbenzoic acid and 50 mM piperazine are heated at 120 ° C. for 4 hours under an inert gas. Crystallization from methanol gives the correspondingly substituted benzoic acids.
• 10 mM of the corresponding benzoic acid derivative are suspended in 40 ml of anhydrous DMF and mixed with 10 mM N-methylmorpholine.

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