WO2001087829A1 - Bisacylguanidine - Google Patents

Bisacylguanidine Download PDF

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Publication number
WO2001087829A1
WO2001087829A1 PCT/EP2001/004425 EP0104425W WO0187829A1 WO 2001087829 A1 WO2001087829 A1 WO 2001087829A1 EP 0104425 W EP0104425 W EP 0104425W WO 0187829 A1 WO0187829 A1 WO 0187829A1
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WO
WIPO (PCT)
Prior art keywords
methyl
guanidine
phenyl
benzoyl
oxo
Prior art date
Application number
PCT/EP2001/004425
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German (de)
English (en)
Inventor
Rolf Gericke
Norbert Beier
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to AU2001258349A priority Critical patent/AU2001258349A1/en
Publication of WO2001087829A1 publication Critical patent/WO2001087829A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton

Definitions

  • the invention relates to bisacylguanidines of the formula I.
  • X is missing or S, S0 2 , (CH 2 ) n , CO, O or OCH 2 ,
  • Ph unsubstituted or mono-, di- or trisubstituted by A, OA, NH 2 , NHA, NA 2 , F, CI, Br and / or CF 3 ,
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the new compounds are inhibitors of the cellular Na + / H + antiporter of subtype 1, ie active substances which inhibit the Na + / H + exchange mechanism of the cells (Düsing et al., Med. Klin. 87, 378-384 (1992)) and thus represent good antiarrhythmics which are particularly suitable for the treatment of arrhythmias which occur as a result of lack of oxygen.
  • the new compounds can also be used to treat insulin-independent diabetes meilitus (NIDDM).
  • NIDDM insulin-independent diabetes meilitus
  • amiloride The best-known active ingredient in the group of acylguanidines is amiloride. However, this substance primarily shows an antihypertensive and saluretic effect, which is particularly undesirable in the treatment of cardiac arrhythmia, while the antiarrhythmic properties are only very weak.
  • Benzoylguanidines are described, for example, in DE 44 04 183. However, the compounds described in the prior art are structurally distinctly different from those claimed here.
  • the invention relates to compounds of the formula I and their physiologically acceptable salts.
  • Infarct treatment infarct prophylaxis and for the treatment of angina pectoris. Furthermore, the substances counteract all pathological hypoxic and ischemic damage, so that the diseases caused primarily or secondarily can be treated.
  • the active ingredients are also well suited for preventive applications.
  • the compounds can also be used as therapeutic agents in diseases caused by cell proliferation, such as arteriosclerosis, late diabetic complications, tumor diseases, fibrotic diseases, in particular of the lungs, liver and kidneys, and organ hypertrophies and hyperplasias.
  • diseases caused by cell proliferation such as arteriosclerosis, late diabetic complications, tumor diseases, fibrotic diseases, in particular of the lungs, liver and kidneys, and organ hypertrophies and hyperplasias.
  • Diagnostic substances for the detection of diseases which are accompanied by increased activity of the Na + / H + antiporter for example in erythrocytes, thrombocytes or leukocytes.
  • Suitable experimental animals are, for example, mice, rats, guinea pigs, dogs, cats, monkeys or pigs.
  • the invention relates to the compounds of the formula I according to claims 1 to 2 and to their physiologically acceptable salts and solvates as medicaments.
  • the compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
  • the invention therefore also relates to the drugs mentioned as inhibitors of the cellular Na + / H + antiporter of subtype 1 and to these drugs for the treatment of arrhythmias, angina pectoris, infarcts and insulin-independent diabetes mellitus (NIDDM).
  • NIDDM insulin-independent diabetes mellitus
  • A denotes a branched or unbranched alkyl group having 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, in particular 1, 2 or 3, carbon atoms, in particular preferably methyl, furthermore preferably Ethyl, propyl, isopropyl, butyl, isobutyl, further preferably sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).
  • a 1-7 H atoms can also be replaced by fluorine or chlorine. A therefore means e.g. also trifluoromethyl or pentafluoroethyl.
  • radicals R 1 , R 2 , R 3 , R 4 or R 5 Preferably one of the radicals R 6 , R 7 , R 8 , R 9 or R 10
  • radicals H one and / or two other radicals H, alkyl having 1, 2, 3 or 4 carbon atoms or alkylsulfonyl having 1, 2, 3 or 4 carbon atoms, and the remaining radicals H.
  • X is preferably S, S0 2 , CH 2 , CH 2 CH 2 , CO or X is absent.
  • Ph preferably means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) - phenyl, o-, m- or p- (N-methylaminocarbonyl) phenyl, o-, m- or p- acetamidophenyl, o-, m- or p-methoxyphenyl, o-,
  • Het means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5- Pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4- Pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-l-, -4- or -5-yl, 1, 2,4-triazol-1-, -3 - or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yl, 1, 3,4-thiadiazol-2- or -5 -yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4-
  • 5-, 6- or 7- benzisoxazolyl 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- Quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1, 4] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl , 2,1, 3-benzothiaediazol-4- or -5-yl or 2,1, 3-benzoxadiazol-5-yl.
  • heterocyclic radicals can also be partially or completely hydrogenated.
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,
  • Solvates are understood to mean, for example, hydrates, such as the hemi, mono- or dihydrates, or, for example, alcohol addition compounds, such as, for example, with methanol or ethanol.
  • the invention relates in particular to the compounds of the formula Ia below
  • X is missing or S, S0 2 , (CH 2 ) n , CO,
  • A is alkyl with 1-8 C atoms, n is 1 or 2,
  • the invention further relates to a process for the preparation of the compounds of the formula I according to claim 1, and of their salts and / or solvates, characterized in that
  • the compounds of the formula I are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons , Inc., New York; and in the above-mentioned patent application), under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • the starting materials can also be formed in situ in such a way that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.
  • Compounds of the formula I are preferably prepared by using an activated carboxylic acid derivative of the formula II, Q being particularly preferably CI, Br, I or a reactively modified OH group such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C-
  • Atoms preferably methylsulfonyloxy
  • arylsulfonyloxy having 6-10 C atoms preferably phenyl- or p-tolylsulfonyloxy
  • carboxylic acids of the formula II used as intermediates in which two of the radicals R 1 -R 10 are COOH, are known or can be prepared by customary methods.
  • the compounds with the 2-methyl-propenoic acid guanidide structure are generally also produced from the dicarboxylic acid: a) by reduction to the dialcohols (for example with LiAIH), b) subsequent oxidation to the dialdehydes (for example with DMSO / oxalyl chloride) Swern), c) olefination with 2-phosphonopropionic acid triethyl ester according to Horner-Emmons (as described in Eur. J. Physiol.
  • reaction of a reactive carboxylic acid derivative of the formula II with guanidine is preferably carried out in a manner known per se in one protic or aprotic polar or non-polar inert organic solvents.
  • a preferred variant also consists in reacting the reactants directly with one another without the addition of a solvent.
  • Suitable bases are preferably e.g. Alkali metal or alkaline earth metal hydroxides, carbonates, alcoholates or organic bases such as triethylamine, pyridine or N-ethyldiisopropylamine, which can also be used in excess and can then simultaneously serve as solvents.
  • Alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol are particularly suitable as inert solvents; Ethers such as diethyl ether, diisopropyl ether, THF or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Nitriles such as acetonitrile; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate; Amides such as phosphoric acid hexamethyl triamide; Sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1, 2-dichloroethane or carbon tetrachloride; Hydrocarbon
  • Particularly suitable solvents are methanol, THF, dimethoxyethane,
  • reaction temperature is, for example, temperatures between 20 ° and
  • Boiling point of the solvent suitable The response times are between 5 minutes and 12 hours.
  • guanidine in a protected form, e.g. as
  • the compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino groups contain corresponding protected amino groups (prodrugs), preferably those which instead of an H atom which is connected to an N atom is an amino protective group, especially those which carry an R'-N group instead of an HN group, in which R 'is an amino protective group.
  • protected amino groups prodrugs
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction at another point in the
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluoyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC).
  • Preferred amino protecting groups are BOC, DNP and BOM, furthermore CBZ, benzyl and acetyl.
  • the liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - e.g. with strong acids, suitably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid.
  • strong acids suitably with trifluoroacetic acid or perchloric acid
  • other strong inorganic acids such as hydrochloric acid or sulfuric acid
  • strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids
  • benzene or p-toluenesulfonic acid strong organic carboxylic acids
  • the presence of an additional inert solvent is possible, but not always necessary.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol and water. Mixtures of the abovementioned solvents are also suitable. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 °; preferably one works between 15 and 30 ° (room temperature).
  • the BOC group can e.g. preferably with 40% trifluoroacetic acid in dichloromethane or with about 3 to 5N HCl in dioxane at 15-60 °, the FMOC group with an about 5-20% solution of dimethylamine, diethylamine or piperidine in DMF at 15- 50 °.
  • the DNP group can be split off e.g. also with an approximately 3-10% solution of 2-mercaptoethanol in DMF / water at 15-30 °.
  • Protective groups which can be removed hydrogenolytically can be expediently, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium. be split off moderately on a support such as coal).
  • a catalyst for example a noble metal catalyst such as palladium. be split off moderately on a support such as coal.
  • Suitable solvents are those mentioned above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF.
  • Hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 °
  • a base of the formula I can also be converted into the associated acid addition salt using an acid. Come for this implementation
  • inorganic acids can be used, e.g. Sulfuric acid.
  • Nitric acid hydrohalic acids such as hydrochloric acid or hydrobromic acid
  • phosphoric acids such as orthophosphoric acid
  • sulfamic acid furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • Formic acid acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, asotonic acid, ascorbic acid - Tic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid.
  • Salts and / or solvates can be used for the production of pharmaceutical preparations, especially in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredient (s).
  • the invention thus also relates to pharmaceutical preparations containing at least one medicament according to one of the claims 5 to 6 and optionally carriers and / or auxiliaries and optionally other active ingredients.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly.
  • tablets, dragees, capsules, syrups, juices or drops are used, for rectal use suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use, ointments, creams, pastes, Lotions, gels, sprays, foams, aerosols, solutions (e.g. solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1, 2-propanediol or their mixtures with one another and / or with water) or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables.
  • Liposomal preparations are also particularly suitable for topical use.
  • the specified preparations can be sterilized and / or contain auxiliaries such as conductors, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or flavoring substances. If desired, they can also contain one or more other active ingredients, e.g. one or more vitamins.
  • the compounds of the formula I and their physiologically acceptable salts can be administered to humans or animals, in particular mammals such as monkeys, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in combating diseases, in particular in the case of the therapy and / or prophylaxis of disorders of the cardiovascular system. They are therefore suitable for the treatment of arrhythmias, in particular especially if these are caused by lack of oxygen, from angina pectoris, infarcts, ischemia of the nervous system such as stroke or cerebral edema, from shock conditions and for preventive treatment.
  • the invention also relates to the use of compounds according to claims 1 and 2 and / or their physiologically acceptable salts for the manufacture of a medicament for combating diseases, preferably arrhythmias, angina pectoris, infarcts and insulin-independent diabetes mellitus (NIDDM).
  • diseases preferably arrhythmias, angina pectoris, infarcts and insulin-independent diabetes mellitus (NIDDM).
  • NIDDM insulin-independent diabetes mellitus
  • the substances can also be used as therapeutic agents for diseases in which cell proliferation plays a role, such as arteriosclerosis, late diabetic complications, tumor diseases, fibroses, and organ hypertrophies and hyperplasias, especially in diseases of the prostate.
  • the substances according to the invention are generally used in analogy to known antiarrhythmics, e.g. Aprindine administered, preferably in dosages between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg per dosage unit.
  • the daily dosage is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg / kg body weight.
  • the specific dose for each particular patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and on the combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • customary workup means:
  • a suspension of 1.0 g of 4- [2- (3-carboxyphenyl) ethyl] benzoic acid in 35 ml of THF is mixed with 1.2 g of 1,1'-carbonyldiimidazole and stirred and stirred for 2 hours.
  • a mixture of 2.12 g of guanidinium chloride in 4.1 ml of sodium methylate (30% solution in methanol) is concentrated and the benzoic acid solution is added and the mixture is stirred for 2 hours.
  • the mixture is worked up in the customary manner and 0.84 g of A / - ⁇ 4- [2- (3-guanidinocarbonylphenyl) ethyl] benzoyl ⁇ guanidine, dihydrochloride, mp. 262-266 ° (decomposition).
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 ⁇ 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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Abstract

L'invention concerne des bisacylguanidines de formule (I), dans laquelle les restes R?1, R2, R3, R4, ou R5¿ et un des restes R?6, R7, R8, R9 ou R10¿ désignent (Ia). L'invention concerne également leurs sels et/ou solvates physiologiquement tolérables. Ces composés présentent des propriétés cardioprotectrices et servent d'inhibiteurs de l'antiporteur cellulaire Na+/H+ du sous-type 1.
PCT/EP2001/004425 2000-05-17 2001-04-19 Bisacylguanidine WO2001087829A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001258349A AU2001258349A1 (en) 2000-05-17 2001-04-19 Bisacylguanidine

Applications Claiming Priority (2)

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DE10024319.3 2000-05-17
DE10024319A DE10024319A1 (de) 2000-05-17 2000-05-17 Bisacylguanidine

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WO2001087829A1 true WO2001087829A1 (fr) 2001-11-22

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US7285682B2 (en) 2005-02-14 2007-10-23 Wyeth Terphenyl guanidines as β-secretase inhibitors
US7417047B2 (en) 2005-06-30 2008-08-26 Wyeth Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7423158B2 (en) 2005-09-26 2008-09-09 Wyeth Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase
WO2008115999A1 (fr) * 2007-03-19 2008-09-25 Xenon Pharmaceuticals Inc. Composés biaryle et bihétéroaryle utiles pour le traitement des troubles du fer
US7452885B2 (en) 2005-06-30 2008-11-18 Wyeth Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation
US7456186B2 (en) 2004-06-16 2008-11-25 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7482349B2 (en) 2004-06-16 2009-01-27 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7488832B2 (en) 2005-02-14 2009-02-10 Wyeth Azolylacylguanidines as β-secretase inhibitors
US7563796B2 (en) 2005-01-14 2009-07-21 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7582667B2 (en) 2006-02-24 2009-09-01 Wyeth Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
US7723368B2 (en) 2007-03-23 2010-05-25 Wyeth Llc Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase
US7732457B2 (en) 2005-02-01 2010-06-08 Wyeth Llc Amino-pyridines as inhibitors of β-secretase
SG165988A1 (en) * 2001-11-29 2010-11-29 Theracos Inc Compounds for treatment of inflammation, diabetes and related disorders
US8410119B2 (en) 2003-07-14 2013-04-02 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

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US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US8410119B2 (en) 2003-07-14 2013-04-02 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
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US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis

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