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 (3) H, F, Cl, Br, I, CN, NO 2 or (C ⁇
• Preferred compounds of the formula I are those in which: R (1) trifluoromethyl;
• R (3) H, F, Cl or (C ⁇
• R (4) H, (C-1-C4) alkyl, (C-1-C4) alkoxy, F, Cl or CF 3; and their pharmaceutically acceptable salts.
• Derive naphthyl in which one or more CH groups are replaced by N and / or in which at least two adjacent CH groups (to form a five-membered aromatic ring) are replaced by S, NH or O. Furthermore, one or both atoms of the condensation site of bicyclic radicals (as in indolizinyl) can also be N atoms.
• Benzimidazole pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, c especially imidazolyl or benzimidazolyl.
• substituents R (1) to R (4) contains one or more centers of asymmetry, these can be configured both S and R.
• the compounds can exist as optical isomers, as diastereomers, as racemates or as mixtures thereof.
• the designated alkyl radicals can be either straight-chain or branched.
• the invention further relates to a process for the preparation of compound I, characterized in that
• R (1) to R (4) have the meaning given and L represents an easily nucleophilically substitutable leaving group, reacted with guanidine ,.
• An activated carboxylic acid derivative of the formula II is reacted with guanidine in a manner known per se in a protic or aprotic polar but inert organic solvent.
• Most of the reactions of compounds II with salt-free guanidine were advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane and dioxane.
• water can also be used as a solvent in the reaction of II with guanidine using a base such as NaOH.
• benzoic acid derivatives of the formula II are known and described in the literature.
• the unknown compounds of formula II can be prepared by methods known from the literature.
• the benzoic acids obtained are converted into compounds I according to the invention by one of the process variants described above.
• Benzoylguanidines I are generally weak bases and can bind acid with the formation of salts.
• Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates,
• Methyl sulfonates p-toluenesulfonates.
• EP 602 523 (HOE 92 / F 405) and EP 640 588 (HOE 93 / F 254) describe benzoylguanidines of a similar constitution which, in the 5-position, also carry fluorinated alkyl substituents in addition to a large number of other substituents R (1) , and in the 4-position can also carry (C 1 -C 9 ) heteroaryls in addition to a large number of substituents.
• C 1 -C 9 heteroaryls
• the compounds according to the invention are NHE inhibitors which additionally inhibit the non-inactivating sodium channel (veratridine-activatable sodium channel) induced during ischemia, whereupon the outstanding effect can be attributed.
• the compounds are outstandingly suitable as antiarrhythmic medicaments with cardioprotective components for the prevention of infarction and the treatment of infarction, and for the treatment of angina pectoris, and they also prevent or inhibit the pathophysiological processes in the occurrence of ischemically induced damage, particularly when triggering ischemically induced cardiac arrhythmias greatly decrease.
• the compounds of the formula I according to the invention can be used as a medicament for the treatment of all acute or chronic damage caused by ischemia or diseases which are primarily or secondarily induced thereby.
• This affects their use as medicines for surgery, e.g. B. in organ transplants the compounds can be used both for protecting the organs in the donor before and during removal, for protecting removed organs, for example during treatment with or their storage in physiological bath fluids, as well as for the transfer into the recipient organism ,
• the compounds are also valuable, protective drugs when performing angioplasty, such as heart surgery also on peripheral vessels.
• the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular the CNS, whereby they are suitable, for example, for the treatment of stroke or brain edema.
• the compounds of formula I according to the invention are also suitable for the treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.
• the compounds of the formula I according to the invention are notable for a 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 useful therapeutic agents for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotic agents, agents for late diabetic complications,
• fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophies and hyperplasias, in particular in prostate hyperplasia or prostate hypertrophy can be used.
• the compounds according to the invention are effective inhibitors of the cellular sodium proton antiporter (Na + / H + exchanger), which is increased in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) even in cells which are easily accessible, for example in erythrocytes, platelets or leukocytes.
• the compounds of the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostics for determining and differentiating certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc.
• the compounds of the formula I are for preventive therapy to prevent the genesis of high blood pressure, for example essential hypertension.
• Medicaments which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred one Application depends on the particular appearance of the disease.
• auxiliaries which are suitable for the desired pharmaceutical formulation on the basis of his specialist knowledge.
• solvents In addition to solvents,
• Active substance carriers can, for example, antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives,
• Solubilizers or dyes are used.
• the active compounds are mixed with the suitable additives, such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by the usual methods, such as tablets, dragées, push-fit capsules, aqueous, alcoholic or oily solutions.
• suitable additives such as carriers, stabilizers or inert diluents
• suitable dosage forms by the usual methods, such as tablets, dragées, push-fit capsules, aqueous, alcoholic or oily solutions.
• inert carriers such.
• the preparation can take place both as dry and as moist granules.
• Vegetable or animal oils such as sunflower oil or cod liver oil, are suitable as oily carriers or as solvents.
• the active compounds are brought into solution, suspension or emulsion, if desired with the usual substances such as solubilizers, emulsifiers or other auxiliaries.
• solvents such as water, physiological saline or alcohols, e.g. As ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.
• Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for. B. solutions, suspensions or emulsions of Active ingredient of 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 other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and a propellant.
• Such a preparation usually contains the active ingredient in a concentration of approximately 0.1 to 10, in particular approximately 0.3 to 3% by weight.
• the dosage of the active ingredient of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; also on the type and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
• the average daily dose of a compound of the formula I in a patient weighing approximately 75 kg is at least 0.001 mg / kg, preferably 0.01 mg / kg, to at most 10 mg / kg, preferably 1 mg / kg body weight.
• more frequent doses may be necessary, e.g. B. up to 4 single doses per day.
• up to 200 mg per day may be necessary.
• the benzoic acid derivative of the formula II is dissolved or suspended in anhydrous THF (5 ml / mmol) and then mixed with 1.1 eq. Carbonyldiimidazole. After stirring for 2 hours at RT, 5.0 eq. Guanidine introduced into the reaction solution. After stirring overnight, the THF is distilled off under reduced pressure (Rotavapor), water is added and the mixture is made up with 2N HCl pH 6 to 7 and the corresponding benzoylguanidine (formula I) is filtered off.
• the benzoylguanidines thus obtained can be converted into the corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically acceptable acids.
• Example 1 4-N-Imidazolyl-3-trifluoromethyl-benzoylguanidine dihydrochloride: Colorless crystals, mp. 244-248 ° C.
• Example 2 4-N- (4'-methyl-imidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride Colorless crystals, mp. 236 ° C.
• Example 6 4-N- (5 ', 6'-dimethyl-benzimidazolyl) -3-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 255 ° C.
• Example 7 4-N- (4 ', 5'-dimethyl-imidazolyl) -2-methyl-5-trifluoromethyl-benzoylguanidine dihydrochloride: colorless crystals, mp. 235 ° C.
• Example 8 4-N-Benzimidazolyl-2-methyl-5-trifluoromethyl-benzoylguanidine dihychloride: Colorless crystals, mp. 199-202X
• Example 10 2-chloro-4-N- (5 ', 6'-dichlorobenzimidazolyl) -5-trifluoromethylbenzoylguanidine dihydrochloride: colorless crystals, mp. 199-200 ° C.

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• 1999
  • 1999-10-22 DE DE19950898A patent/DE19950898A1/de not_active Withdrawn
• 2000
  • 2000-10-07 WO PCT/EP2000/009838 patent/WO2001030761A1/de not_active Application Discontinuation
  • 2000-10-07 JP JP2001533115A patent/JP2003512457A/ja not_active Withdrawn
  • 2000-10-07 EP EP00966135A patent/EP1226124A1/de not_active Withdrawn
  • 2000-10-07 CN CN00812869A patent/CN1373757A/zh active Pending
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• 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
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