Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
• • 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
  • A61P9/10—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
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

• the invention relates to heterocyclically substituted benzoylguanidines of the formula I
• R(1) is —(CF 2 ) c —CF 3 ;
• c is zero, 1, 2 or 3;
• R(2) is (C 1 -C 9 )-heteroaryl, linked via C or N, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxyl, amino, methylamino and dimethylamino;
• R(3) is H, F, Cl, Br, I, CN, NO 2 or (C 1 -C 8 )-alkyl;
• R(4) is H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, F, Cl, Br, I, CN or —(CF 2 ) o —CF 3 ;
• o is zero, 1 or 2;
• Preferred compounds of the formula I are those in which:
• R(1) is trifluoromethyl
• R(2) is imidazolyl or benzimidazolyl, linked via C or N, each of which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, hydroxyl, amino, methylamino and dimethylamino;
• R(3) is H, F, Cl or (C 1 -C 4 )-alkyl
• R(4) is H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, F, Cl or CF 3 ;
• R(1) is trifluoromethyl
• R(2) is imidazolyl or benzimidazolyl, linked via N, each of which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 and methoxy;
• R(3) is H
• R(4) is H, methyl, methoxy, Cl or CF 3 ;
• (C 1 -C 9 )-heteroaryl is understood as meaning radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups are replaced by S, NH or O (with formation of a five-membered aromatic ring).
• one or both atoms of the condensation site of bicyclic radicals can also be nitrogen atoms.
• (C 1 -C 9 )-heteroaryl is in particular furanyl, thienyl, pyrrolyl, imidazolyl, benzimidazole, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl; very particularly imidazolyl or benzimidazolyl.
• substituents R(1) to R(4) contains one or more asymmetric centers, these can be either of the S or R configuration.
• the compounds can be present as optical isomers, as diastereomers, as racemates or as mixtures thereof.
• the designated alkyl radicals can be either straight-chain or branched.
• the invention furthermore relates to a process for the preparation of the compound I, which comprises
• R(1) to R(4) have the meaning indicated and L is an easily nucleophilically substitutable leaving group, with guanidine.
• reaction is advantageously carried out with addition of an acid scavenger, e.g. in the form of excess guanidine for -removing the hydrohalic acid.
• an acid scavenger e.g. in the form of excess guanidine for -removing the hydrohalic acid.
• benzoylguanidines I are weak bases and can bind acid with formation of salts.
• Possible acid addition salts are salts of all pharmacologically tolerable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.
• EP 602 523 (HOE 92/F 405) and EP 640 588 (HOE 93/F 254) describe benzoylguanidines of similar constitution, which also carry fluorinated alkyl substituents in the 5 position in addition to a multiplicity of other substituents R(1), and can also carry (C 1 -C 9 ) heteroaryls in the 4 position in addition to a multiplicity of substituents.
• these compounds having fluoroalkyl and hetaryl substitution especially would display an outstanding action.
• the compounds according to the invention are NHE inhibitors which additionally inhibit the noninactivating sodium channel (veratridine-activatable sodium channel) induced during ischemia, to which the outstanding action can be attributed.
• the compounds are outstandingly suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment, and also for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias.
• the compounds of the formula I according to the invention can be used, as a result of inhibition of the cellular Na + /H + exchange mechanism, as pharmaceuticals for the treatment of all acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby.
• This relates to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantations, where the compounds can be used for the protection of organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bathing fluids, and also during transfer to the recipient's body.
• the compounds are also valuable pharmaceuticals having a protective action when carrying out angioplastic surgical interventions, for example on the heart and also on peripheral vessels.
• the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the CNS, where they are suitable, for example, for the treatment of stroke or of cerebral edema.
• the compounds of the formula I according to the invention are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and of bacterial shock.
• the compounds of the formula I according to the invention are distinguished by strong inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of smooth vascular muscle cells.
• the compounds of the formula I are therefore suitable as valuable therapeutics for illnesses in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophy and hyperplasia, in particular in prostate hyperplasia or prostate hypertrophy.
• the compounds according to the invention are efficacious inhibitors of the cellular sodium/proton antiporter (Na + /H + exchanger), which is raised in numerous diseases (essential hypertension, atherosclerosis, diabetes etc.) even in those cells which are easily accessible to measurements, such as, for example, in erythrocytes, platelets or leukocytes.
• the compounds according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostics for the determination and differentiation of certain forms of hypertension, but also of atherosclerosis, of diabetes, proliferative diseases etc.
• the compounds of the formula I are suitable for preventive therapy for the prevention of the genesis of high blood pressure, for example of essential hypertension.
• compositions which contain a compound I can in this case be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration being dependent on the particular course of the disease.
• the compounds I can be used here on their own or together with pharmaceutical excipients, namely both in veterinary and in human medicine.
• excipients which are suitable for the desired pharmaceutical formulation.
• solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants.
• the active compounds are mixed with the additives suitable for this, such as vehicles, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions.
• Inert carriers which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, preparation can be carried out both as dry and as moist granules.
• Possible oily vehicles or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.
• the active compounds for subcutaneous or intravenous administration, the active compounds, if desired with the substances customary for this such as solubilizers, emulsifiers or further excipients, are brought into solution, suspension or emulsion.
• Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or otherwise a mixture of the various solvents mentioned.
• Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents.
• a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents.
• the formulation can also contain still other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers and also a propellant.
• Such a preparation customarily contains the active compound in a concentration of approximately 0.1 to 10, in particular from approximately 0.3 to 3, % by weight.
• the dose of the active compound of the formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; additionally also on the type and severity of the illness to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
• the daily dose of a compound of the formula I in the case of a patient weighing approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, at most 10 mg/kg, preferably 1 mg/kg, of body weight.
• even higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day.
• up to 200 mg per day may be necessary.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Veterinary Medicine (AREA)
• Diabetes (AREA)
• Cardiology (AREA)
• Biomedical Technology (AREA)
• Urology & Nephrology (AREA)
• Neurosurgery (AREA)
• Heart & Thoracic Surgery (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Neurology (AREA)
• Immunology (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Vascular Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Applications Claiming Priority (4)

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• 1999
  • 1999-10-22 DE DE19950898A patent/DE19950898A1/de not_active Withdrawn
• 2000
  • 2000-10-07 EP EP00966135A patent/EP1226124A1/de not_active Withdrawn
  • 2000-10-07 CN CN00812869A patent/CN1373757A/zh active Pending
  • 2000-10-07 WO PCT/EP2000/009838 patent/WO2001030761A1/de not_active Application Discontinuation
  • 2000-10-07 CZ CZ20021218A patent/CZ20021218A3/cs unknown
  • 2000-10-07 EE EEP200200142A patent/EE200200142A/xx unknown
  • 2000-10-07 JP JP2001533115A patent/JP2003512457A/ja not_active Withdrawn
  • 2000-10-07 AU AU76630/00A patent/AU7663000A/en not_active Withdrawn
  • 2000-10-19 AR ARP000105513A patent/AR026179A1/es unknown
• 2001
  • 2001-07-11 US US09/901,624 patent/US20010049446A1/en not_active Abandoned
• 2002
  • 2002-02-15 US US10/075,394 patent/US20020099222A1/en not_active Abandoned
• 2003
  • 2003-01-28 US US10/352,216 patent/US6617344B2/en not_active Expired - Fee Related

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