WO1998055475A1 - Derives de guanidine utilises comme inhibiteurs de l'echange na+/h+ dans les cellules - Google Patents

Derives de guanidine utilises comme inhibiteurs de l'echange na+/h+ dans les cellules Download PDF

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Publication number
WO1998055475A1
WO1998055475A1 PCT/JP1998/002288 JP9802288W WO9855475A1 WO 1998055475 A1 WO1998055475 A1 WO 1998055475A1 JP 9802288 W JP9802288 W JP 9802288W WO 9855475 A1 WO9855475 A1 WO 9855475A1
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Prior art keywords
compound
nmr
benzoxepin
ethyl
salt
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PCT/JP1998/002288
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English (en)
Inventor
Kohei Takenaka
Yoshikazu Inoue
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Fujisawa Pharmaceutical Co., Ltd.
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Priority claimed from AUPO7133A external-priority patent/AUPO713397A0/en
Priority claimed from AUPO9368A external-priority patent/AUPO936897A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP50203199A priority Critical patent/JP2002502414A/ja
Publication of WO1998055475A1 publication Critical patent/WO1998055475A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • This invention relates to new guanidine derivatives.
  • One object of this invention is to provide the new and useful guanidine derivatives and salts thereof which possess a strong inhibitory activity on Na + /H + exchange in cells.
  • Another object of this invention is to provide processes for preparation of the guanidine derivatives and salts thereof.
  • guanid e derivatives having pharmaceutical activities such as inhibitory activity on Na + /K + exchange in cells have been known as described m WO 94/26709.
  • guanidine derivatives of the present invention are novel and can be represented by the following general formula (I) :
  • R is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, protected amino, aryl or a heterocyclic group
  • R ⁇ is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, protected amino, aryl or a heterocyclic group
  • X is -CH 2 -/ -S-, -S0 2 ⁇ , -0- or -NH-;
  • V is bond or XCH 2 ) n -. in which n is 1, 2 or 3 ; Z Z is bond or XCH2. m -/ in which m is 1 or 2; and
  • the object compound (I) of the present invention can be prepared by the following process.
  • R , RX X, Y, Z and ⁇ X( are each as defined above .
  • the starting compound (II) can be prepared by the following processes or Preparations mentioned below, or similar manners thereto.
  • R ⁇ , R r> , X, Y and Z are each as defined above,
  • R J is lower alkyl
  • R- is lower alkyl
  • L is a leaving group
  • Salts of the object guanidine derivatives (I) are pharmaceutically acceptable, conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, triflu
  • lower is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
  • Suitable “lower alkyl” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyi, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atom(s) .
  • Suitable "lower alkylene” is straight or branched one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methylmethylene, dimethylmethylene, ethylmethylene, diethylmethylene, ethylethylene, dimethylethyiene, ethylethylene, diethylethylene, methyltrimethylene, hexamethylene, and the like, in which the preferred one is methylene, ethylene, trimethylene or dimethylmethylene.
  • Suitable "lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which the preferred one may be ⁇ -C ⁇ alkoxy.
  • Suitable "halogen” may include fluorine, bromine, chlorine and iodine.
  • Suitable "aryl” may include phenyl, naphthyl and the like.
  • Suitable “protected amino” may include an acylamino or an amino group substituted by a conventional protecting group such as ar (lower) alkyl (e.g., benzyl, trityl, etc.) or the like .
  • acyl moiety in the term “acylammo” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • acyl may be illustrated as follows : Carboxy; Carbamoyl; Thiocarbamoyl; Suifamoyl;
  • Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.
  • alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl
  • lower or higher alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
  • lower or higher alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
  • lower or higher alkylsulfinyl e.g., methylsulfinyl, ethylsulfinyl, etc.
  • lower or higher alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
  • lower or higher alkoxysulfinyl e.g., methoxysulfinyl, ethoxysulfinyl, etc.
  • fluoromethylsulfonyl difluoromethylsulfonyl, trifluoromethylsulfonyl, chloromethylsulfonyl, dichloromethylsulfonyl, trichloromethylsuifonyl,
  • Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenyli ⁇ obutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar (lower) alkenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl,
  • arylglyoxyloyl e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.
  • Heterocyclic acyl such as heterocycliccarbonyl ; heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like .
  • heterocyclic (lower) alkanoyl e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.
  • heterocyclic (lower) alkenoyl e.g., heterocyclicpropenoyl, heterocyclic
  • Suitable “heterocyclic” and “heterocyclic” moiety in the terms “heterocycliccarbonyl”, “heterocyclic (lower) - alkanoyl”, heterocyclic (lower) alkenoyl", “heterocyclicglyoxyloyl”, etc. may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2, 4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1,2,3- triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl
  • the acyl moiety as stated above may have one to ten, same or different, suitable substituent (s) such as lower alkyl as exemplified above; lower alkoxy as exemplified above; lower alkylthio wherein lower alkyl moiety is as exemplified above; lower alkylamino wherein lower alkyl moiety is as exemplified above; halogen; amino; protected amino as exemplified above; hydroxy; cyano; nitro; carboxy; sulfo; sulfamoyl; imino; oxo; amino (lower) alkyl wherein lower alkyl moiety is as exemplified above; carbamoyioxy; hydroxy (lower) alkyl wherein lower alkyl moiety is as exemplified above; diamino (lower) alkylidene (e.g., diaminomethylene, etc.); di (lower) alkylamino wherein lower alkyl moiety
  • Suitable “leaving group” may include acid residue and the like, and suitable examples of “acid residue” may be halogen (e.g., fluorine, chlorine, bromine, iodine), acyloxy [e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] or the like.
  • halogen e.g., fluorine, chlorine, bromine, iodine
  • acyloxy e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] or the like.
  • the compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the carboxy group, or a salt thereof with the compound (III) or its reactive derivative at the imino group, or a salt thereof.
  • Suitable reactive derivative at the imino group of the compound (III) may include a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide [e.g. N- (trimethylsilyl) - acetamide], bis (trimethylsilyl) urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.
  • Suitable reactive derivative at the carboxy group of the compound (II) may include a conventional one such as an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g.
  • substituted phosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid halogenated phosphoric acid, etc.
  • dialkylphosphorous acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid halogenated phosphoric acid, etc.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile,
  • the reaction when the compound (II) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N' -dicyclohexylcarbodiimide; N-cyclohexyl-N' -morpholinoethylcarbodiimide; N-cyclohexyl-N' - ( 4-diethylaminocyclohexyl ) carboxiimide ; N,N' -diethylcarbodiimide, N,N' -diisopropylcarbodiimide; N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide; N,N' -carbonyl-bis (2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri (lower) alkylamme (e.g. triethylamine, etc.), pyrid e, N- (lower ) alkylmorpholine,
  • an inorganic or organic base such as an alkali metal bicarbonate, tri (lower) alkylamme (e.g. triethylamine, etc.), pyrid e, N- (lower ) alkylmorpholine,
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the compound (VI) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) .
  • This reaction can be carried out in the manner disclosed in Preparation 13 or 15 or similar manners thereto .
  • the compound (VII) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to cyclization reaction. This reaction can be carried out n the manner disclosed in Preparation 1 or similar manners thereto.
  • Process (A)-(D) The compound (VIII) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to reduction reaction.
  • the compound (Ila) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to dehydration reaction. This reaction can be carried out in the manner disclosed in Preparation 5 or similar manner thereto.
  • Process (A) - (j) The compound (lib) or a salt thereof can be prepared by subjecting the compound (Ila) or a salt thereof to hydrogenation reaction.
  • This reaction can be carried out in the manner disclosed in Preparation 7 or similar manners thereto.
  • the object compound (I) may include one or more stereoisomer (s ) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
  • the object compound including the group of such tautomeric isomers is represented by using one of the expressions therefor, that is the formula :
  • isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included witn the scope of the present invention.
  • solvatmg form of the compound (I) e.g. hydrate, etc.
  • any form of the crystal of the compound ( I ) are included within the scope of the present invention.
  • Suitable salts of the object and starting compounds and their reactive derivatives m Process (1) can be referred to the ones as exemplified for the compound (I) .
  • the new guanidme derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention possess a strong inhibitory activity on Na + /H + exchange cells and therefore are useful as an inhibitor on Na + /H + exchange m cells.
  • the new guanidme derivatives (I) and a pnarmaceutically acceptable salt thereof can be used for tne expectorant and for the treatment and/or prevention of cardiovascular diseases [e.g. hypertension, angina pectoris, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), arrhythmia (e.g.
  • cardiovascular diseases e.g. hypertension, angina pectoris, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), arrhythmia (e.g.
  • arrhythmia due to myocardial infarction, arrhythmia after PTCA (percutaneous translummal coronary angioplasty) , thrombolysis or CABG (coronary artery bypass graft) , etc.), restenosis after PTCA or PTA (percutaneous translummal angioplasty), etc.], cerebrovascular diseases [e.g. iscnemic stroke, hemorrhagic stroke, edema, etc.], renal diseases [e.g. diabetic nepnropathy, lschemic acute renal failure, etc.], arteriosclerosis, shock [e.g.
  • hemorrnagic shocK hemorrnagic shocK, endotoxin shock, etc.] hyperlipidemia and the like, and can also be used as an agent for ischemic reperfusion injury, myocardial protection, organ protection organ transplantation, in non-cardiac and cardiac surgery, and the like.
  • guanid e derivatives (I) In order to show the utilities of the guanid e derivatives (I) and a pharmaceutically acceptable salt thereof of the present mvention, pharmacological test data of tne representative compound of the guanid e derivatives (I) are illustrated in the following.
  • Assay This method detects the swelling that accompanies activation of NaXH " * " exchanger in cells incubated with sodium propionate. Propionic acid rapidly penetrates through the membrane. Intracellular dissociation brings about cyt ⁇ plasmic acidification and consequently activation of Na ⁇ /H + exchanger, which exchange extracellular Na + for cytoplasmic H + . The uptake of osmotically obliged water was manifested as cell swelling. Cell sizing and counting were performed electrically with the Coulter Counter-Channelyzer (AT-II) .
  • AT-II Coulter Counter-Channelyzer
  • Thymocytes solution were suspended in 20 ml sodiu - propionate medium (140 mM sodium propionate, 1 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose, 20 mM N-2-hydroxyethyloiperazine- N'-2-ethanesulfonic acid (HEPES) pH 6.8) including test compound solved in dimethyl sulfoxide (final concentration of dimethyl sulfoxide was 0.1%) .
  • sodiu - propionate medium 140 mM sodium propionate, 1 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose, 20 mM N-2-hydroxyethyloiperazine- N'-2-ethanesulfonic acid (HEPES) pH 6.8
  • test compound solved in dimethyl sulfoxide final concentration of dimethyl sulfoxide was 0.1%) .
  • the object compound (I) or its pharmaceutically acceptable salts can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as oral dosage form (e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.), injection dosage form, suppository, ointment, or the like.
  • oral dosage form e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.
  • injection dosage form e.g., suppository, ointment, or the like.
  • the pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose such as excipient (e.g., sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g., cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g., starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycolestarch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g., citric acid, menthol, glycine, orange powders, etc.), preservative (
  • the effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 500 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
  • Preferred embodiments of the object compound (I) are as follows.
  • R 1 is hydrogen, halogen (more preferably fluorine, chlorine or iodine) , lower alkyl (more preferably Cy-C ⁇ alkyl, most preferably methyl or isopropyl), lower alkoxy (more preferably C-i-C 4 alkoxy, most preferably methoxy) , nitro, amino, protected amino (more preferably lower alkoxycarbonylamino, lower alkanoylamino, lower alkylsulfonylamino, ureido, N'- (lower) - alkylureido, thioureido or N'- (lower) - alkylthioureido, most preferably methoxycarbonylamino, acetylamino, methanesuifonylamino, N 1 -ethylureido or N' -ethylthioureido) , aryl (more preferably c 6 -c 10 ar y
  • N' - (lower) alkylthioureido most preferably methoxycarbonylamino, acetylamino, methanesuifonylamino, N' -ethylureido or N' -ethylthioureido
  • aryl more preferably c 6 ⁇ c 10 ar YX m °st preferably phenyl
  • a heterocyclic group more preferably unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), saturated 3 to 8- membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s) or saturated 3 to 8-membered (more preferably 5 or 6-membered) heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), most preferably pyrrolyl, pyrrolidin
  • X is -CH ? -, -S- -S0 2 - or -0-
  • Y is bond or -CH - z is bond or -Cn 2 -
  • nitric acid (15 ml, d 1.42) was added in small portions ethyl 2, 3-dihydro-9-iodo-l-benzoxepin-4- carboxylate (5.16 g) below 10°C under ice-sodium chloride cooling.
  • the reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and water.
  • the organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated m vacuo.
  • R 1 , R 2 , Y, Z and are each as defined above,
  • X- j _ is -S-, and X 2 is -S0 -.
  • the compound (lb) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to oxidation reaction.
  • This reaction can be carried out in the manner disclosed in Example 7 or similar manners thereto.

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Abstract

L'invention concerne des dérivés de guanidine de la formule (I), dans laquelle chaque symbole correspond à la définition donnée dans la description, et leurs sels pharmaceutiquement acceptables. L'invention concerne également: des procédés de préparation de ces dérivés ou de leurs sels, une composition pharmaceutique comprenant ceux-ci, et l'utilisation desdits dérivés ou de leurs sels pharmaceutiquement acceptables pour traiter des maladies cardiovasculaires, des maladies cérébrovasculaires, des maladies rénales, l'artériosclérose, un état de choc et d'autres troubles analogues chez l'homme et chez l'animal.
PCT/JP1998/002288 1997-06-02 1998-05-25 Derives de guanidine utilises comme inhibiteurs de l'echange na+/h+ dans les cellules WO1998055475A1 (fr)

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Application Number Priority Date Filing Date Title
JP50203199A JP2002502414A (ja) 1997-06-02 1998-05-25 細胞中のＮａ▲上＋▼／Ｈ▲上＋▼交換の阻害剤としてのグアニジン誘導体

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AUPO7133 1997-06-02
AUPO7133A AUPO713397A0 (en) 1997-06-02 1997-06-02 Guanidine derivatives
AUPO9368A AUPO936897A0 (en) 1997-09-23 1997-09-23 Guanidine derivatives
AUPO9368 1997-09-23

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Cited By (7)

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WO1999055690A1 (fr) * 1998-04-24 1999-11-04 Fujisawa Pharmaceutical Co., Ltd. Derives de guanidine
WO1999061414A1 (fr) * 1998-05-26 1999-12-02 Sumitomo Pharmaceuticals Company, Limited Nouveaux derives de guanidine substitues et procede de production de ces derniers
WO2000038661A2 (fr) * 1998-12-23 2000-07-06 Aventis Pharma Deutschland Gmbh Utilisation d'inhibiteurs de l'echangeur sodium-hydrogene pour preparer un medicament destine a prevenir les dysfonctionnements organiques dus au vieillissement, les affections dues au vieillissement et a augmenter l'esperance de vie
WO2000064445A1 (fr) * 1999-04-23 2000-11-02 Bristol-Myers Squibb Company Inhibiteurs d'echange sodium-protons a base de guandines d'acyle bicyclique et procede correspondant
EP1266881A1 (fr) * 2000-02-21 2002-12-18 Takeda Chemical Industries, Ltd. Procede de production de composes cycliques
US6566535B1 (en) 1999-05-18 2003-05-20 Takeda Chemical Industries, Ltd. Processes for the preparation of 2,3-dihydrothiepine derivatives
US6627651B1 (en) 1999-05-07 2003-09-30 Takeda Chemical Industries, Ltd. Cyclic compounds and uses thereof

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JPH08225513A (ja) * 1994-12-21 1996-09-03 Kanebo Ltd ナフトイルグアニジン誘導体
EP0738712A1 (fr) * 1995-04-18 1996-10-23 Hoechst Aktiengesellschaft Indénoylguanidines substituées à activité antiarrythmique et cardioprotective
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6346527B1 (en) 1998-04-24 2002-02-12 Fujisawa Pharmaceutical Co., Ltd. Guanidine derivatives
WO1999055690A1 (fr) * 1998-04-24 1999-11-04 Fujisawa Pharmaceutical Co., Ltd. Derives de guanidine
WO1999061414A1 (fr) * 1998-05-26 1999-12-02 Sumitomo Pharmaceuticals Company, Limited Nouveaux derives de guanidine substitues et procede de production de ces derniers
US6369110B1 (en) 1998-05-26 2002-04-09 Sumitomo Pharmaceuticals Company Substituted guanidine derivatives and process for producing the same
US6420430B1 (en) 1998-12-23 2002-07-16 Aventis Pharma Deutschland Gmbh Use of inhibitors of the sodium-hydrogen exchanger for preparing a medicament for preventing age-related disorders, and for prolonging life
WO2000038661A2 (fr) * 1998-12-23 2000-07-06 Aventis Pharma Deutschland Gmbh Utilisation d'inhibiteurs de l'echangeur sodium-hydrogene pour preparer un medicament destine a prevenir les dysfonctionnements organiques dus au vieillissement, les affections dues au vieillissement et a augmenter l'esperance de vie
WO2000038661A3 (fr) * 1998-12-23 2000-11-09 Aventis Pharma Gmbh Utilisation d'inhibiteurs de l'echangeur sodium-hydrogene pour preparer un medicament destine a prevenir les dysfonctionnements organiques dus au vieillissement, les affections dues au vieillissement et a augmenter l'esperance de vie
US6630506B1 (en) 1999-04-23 2003-10-07 Bristol-Myers Squibb Co. Bicyclic acyl guanidine sodium/proton exchange inhibitors and method
WO2000064445A1 (fr) * 1999-04-23 2000-11-02 Bristol-Myers Squibb Company Inhibiteurs d'echange sodium-protons a base de guandines d'acyle bicyclique et procede correspondant
EP1180029A4 (fr) * 1999-04-23 2002-10-02 Bristol Myers Squibb Co Inhibiteurs d'echange sodium-protons a base de guandines d'acyle bicyclique et procede correspondant
EP1180029A1 (fr) * 1999-04-23 2002-02-20 Bristol-Myers Squibb Company Inhibiteurs d'echange sodium-protons a base de guandines d'acyle bicyclique et procede correspondant
US6627651B1 (en) 1999-05-07 2003-09-30 Takeda Chemical Industries, Ltd. Cyclic compounds and uses thereof
US6566535B1 (en) 1999-05-18 2003-05-20 Takeda Chemical Industries, Ltd. Processes for the preparation of 2,3-dihydrothiepine derivatives
EP1266881A1 (fr) * 2000-02-21 2002-12-18 Takeda Chemical Industries, Ltd. Procede de production de composes cycliques
EP1266881A4 (fr) * 2000-02-21 2003-05-07 Takeda Chemical Industries Ltd Procede de production de composes cycliques
US6864367B2 (en) 2000-02-21 2005-03-08 Takeda Chemical Industries, Ltd. Process for producing cyclic compound
US7038042B2 (en) 2000-02-21 2006-05-02 Takeda Pharmaceutical Company Limited Process for producing cyclic compound
EP1760054A2 (fr) * 2000-02-21 2007-03-07 Takeda Pharmaceutical Company Limited Procédé de production de composés cycliques
EP1760054A3 (fr) * 2000-02-21 2009-12-30 Takeda Pharmaceutical Company Limited Procédé de production de composés cycliques

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