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WO1998046573A1 - Derives d'acide 2-substitue carbamoylimidazolecarboxylique et inhibiteur de l'epaississement de la paroi vasculaire - Google Patents

Derives d'acide 2-substitue carbamoylimidazolecarboxylique et inhibiteur de l'epaississement de la paroi vasculaire Download PDF

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Publication number
WO1998046573A1
WO1998046573A1 PCT/JP1998/001655 JP9801655W WO9846573A1 WO 1998046573 A1 WO1998046573 A1 WO 1998046573A1 JP 9801655 W JP9801655 W JP 9801655W WO 9846573 A1 WO9846573 A1 WO 9846573A1
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Prior art keywords
group
lower alkyl
alkyl group
imidazole
lower alkoxy
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PCT/JP1998/001655
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English (en)
Japanese (ja)
Inventor
Hiromu Harada
Hiroshi Kusama
Yoshinori Nonaka
Toshikazu Yazaki
Nobuhiko Fushimi
Koji Kamata
Original Assignee
Kissei Pharmaceutical Co., Ltd.
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.)
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Priority to AU67484/98A priority Critical patent/AU6748498A/en
Publication of WO1998046573A1 publication Critical patent/WO1998046573A1/fr

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    • 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
    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to 2-substituted rubamoyl imidazole carboxylic acid derivatives useful as pharmaceuticals and pharmacologically acceptable salts thereof.
  • Atherosclerosis progresses due to the accumulation of lipids in the blood vessel wall, cell proliferation in the intima of the blood vessel, and the accumulation of collagen, leading to thickening or occlusion of the blood vessel wall. If such a state is left unchecked, there is a danger of causing a serious situation such as angina pectoris, myocardial infarction or cerebral infarction. At present, no drug has been developed to suppress the thickening or occlusion of the blood vessel wall caused by such arteriosclerosis.
  • PTCA percutaneous transluminal coronary angioplasty
  • DCA directional coronary atherectomy
  • the present inventors have conducted intensive studies to find a compound having an inhibitory effect on abnormal proliferation of intimal cells, and as a result, it has been found that certain 2-substituted rubamoyl imidazole carboxylate derivatives have excellent vascular properties.
  • the present inventors have found that they have a smooth muscle cell proliferation inhibitory activity and the like and are useful as an agent for suppressing vascular wall thickening, and have accomplished the present invention.
  • the present invention has the general formula
  • R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl lower alkoxy group, an aryl lower alkoxy group, a lower acyl group, a mono or Di-lower alkyl-substituted amino group or lower alkoxycarbonyl group;
  • R 2 and R 3 may be the same or different; hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, cycloalkyl lower alkoxy group Or an aryl lower alkoxy group
  • the other is a lower alkoxycarbonyl group, a mono- or di-hydroxy lower alkoxycarbonyl group, a mono- or di-lower alkoxy lower alkoxycarbonyl group, a hydroxyaryl lower alkoxycarbonyl group, a lower alkoxyaryl group.
  • a lower alkoxycarbonyl group or a cycloalkyloxycarbonyl group optionally having one or more oxygen atoms in the ring wherein R 4 is a lower alkyl group, an amino lower alkyl group, a mono- or di-lower alkyl group; Substituted amino lower alkyl group, hydroxy lower alkyl group, mono- or di-lower alkoxy lower alkyl group, lower alkyl group having an alicyclic amino group which may have an oxygen atom in the ring, aryl lower alkyl group, Hydroxyl lower alkyl group, lower alkoxy A arylalkyl group or a cycloalkyl group optionally having one or more oxygen atoms in a ring, R 5 is a hydrogen atom or a lower alkyl group, R 4 and R 5 are An alicyclic amino group which may have an oxygen atom in the ring due to both force bonding and which may have a hydroxyl group, a lower alkoxy group
  • the present invention relates to a vascular wall thickening inhibitor comprising a 2-substituted rubamoyl imidazole carboxylic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. .
  • the present invention relates to the use of a 2-substituted rubamoyl imidazole rubonic acid derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as a vascular wall thickening inhibitor.
  • the present invention provides a 2-substituted rubamoyl imidazole carboxylic acid derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for the manufacture of a medicament for preventing or treating vascular wall thickening.
  • the present invention provides a method for preventing or treating vascular wall thickening by administering a 2-substituted rubamoyl imidazole carboxylic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof. It is about.
  • the present invention is characterized in that a 2-substituted rubamoylimidazole carboxylic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof is used as an active ingredient of a drug.
  • the present invention relates to a method for producing a drug for preventing or treating vascular wall thickening.
  • a lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a terbutyl group, a pentyl group, an isopentyl group, a neopentyl group, tert-A straight-chain or branched alkynol having 1 to 6 carbon atoms such as a pentyl group, a hexyl group, etc.
  • the hydroxy lower alkyl group refers to the lower alkyl group substituted with a hydroxyl group such as a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxypropyl group, and a 4-hydroxybutyl group.
  • amino lower alkyl group means the above lower alkyl group substituted by an amino group such as a 2-aminoethyl group, a 3-aminopropyl group, a 2-aminopropyl group or a 4-aminobutyl group.
  • the aryl lower alkyl group refers to the lower alkyl group substituted with an aromatic hydrocarbon group such as a phenyl group or a naphthyl group. Examples thereof include a benzyl group, a phenyl group, a 3-phenylpropyl group, and a 2-phenylpropyl group. Groups and the like.
  • Hydroxyaryl lower alkyl groups include 2-hydroxybenzyl group, 3-hydroxybenzyl group, 4-hydroxybenzyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, and 4-hydroxyphenyl group. Butyl, 3- (2-hydroxyphenyl) propyl, 3- (3-hydroxyphenyl) propyl, 3- (4-hydroxyphenyl) propyl, 2- (2-hydroxyphenyl) propyl , 2— (3-hydroxyphenyl) propyl group, 2— (4 —Hydroxyphenyl)
  • the aryl lower alkyl group in which an aryl moiety such as a propyl group is substituted with a hydroxyl group.
  • the cycloalkyl group optionally having one or more oxygen atoms in the ring is a 3- to 7-membered cyclic alkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloalkyl group.
  • 4 to 7 having one or more oxygen atoms in a ring such as —tetrahydroviranyl group, 3-tetrahydroviranyl group, 4—tetrahydropyranyl group, 2-tetrahydrofuranyl group, 3—tetrahydrofuranyl group
  • Member ring ⁇ ! Dog refers to an alkyl group.
  • Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t ⁇ rt-butoxy, pentyloxy, isopentyloxy, neopentyl A straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as a oxy group, a ter-pentyloxy group, a hexyloxy group and the like.
  • Lower alkoxyaryl lower alkyl group means 2-methoxybenzyl group, 2-ethoxybenzyl group, 3-methoxybenzyl group, 3-ethoxybenzyl group, 4-methoxybenzyl group, 4-ethoxybenzyl group, 2 —Methoxyphenethyl group, 2 —Ethoxyphenethyl group, 3 —Methoxyphenethyl group, 3 _Ethoxyphenethyl group, 4-Methoxyphenethyl group, 4-Ethoxyphenethyl group, 3- (2-Methoxyphenyl) propyl group, 3 _ (2-ethoxyphenyl) propyl group, 3- (3-methoxyphenyl) propyl group, 3- (3-ethoxyphenyl) propyl group, 3- (4-methoxyphenyl) propyl Group, 3- (4-ethoxyphenyl) propyl group, 2- (2-methoxyphenyl) propyl group, 2- (2-ethoxyphen
  • the hydroxy lower alkoxy group refers to the above-mentioned substituted with a hydroxyl group such as 2-hydroxyethoxy group, 3-hydroxypropoxy group, and 2-hydroxypropoxy group. Refers to a lower alkoxy group.
  • the aryl lower alkoxy group refers to the lower alkoxy group substituted with the aromatic hydrocarbon group such as a benzyloxy group, a phenethyloxy group, a 3-phenylpropoxy group, and a 2-phenylpropoxy group.
  • the cycloalkyl lower alkoxy group means the lower alkoxy group substituted with the cycloalkyl group such as cyclopentyl methoxy group, 2-cyclopentyl ethoxy group, cyclohexyl methoxy group, 2-cyclohexyl ethoxy group.
  • a mono- or di-lower alkoxy lower alkyl group is a methoxymethyl group, an ethoxymethyl group, a 2-methoxyl group, a 2-ethoxyl group, a 3-methoxypropyl group, a 3-ethoxypropyl group, or a 1-methoxyl 2 —
  • the lower being mono- or di-substituted by the lower alkoxy group such as propyl group, 1,3-dimethoxy-12-propyl group, 1-ethoxy-12-propyl group, 1,3-ethoxy-2-propyl group Refers to an alkyl group.
  • Lower alkoxycarbonyl group includes methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec_butoxycarbonyl group, tert-butoxycarbonyl group.
  • Mono or dihydroxy lower alkoxycarbonyl group means the lower alkoxycarbonyl group substituted by one or two hydroxyl groups (provided that two or more oxygen atoms are bonded to the same carbon atom) ), For example, 2-hydroxyethoxycarbonyl group, 3-hydroxypropoxycarbonyl group, 1-hydroxy-12-propoxycarbonyl group, 1,3-dihydroxy-12-propoxycarbonyl group and the like. it can.
  • the mono- or di-lower alkoxy lower alkoxy carbonyl group means the lower alkoxy group substituted by one or two lower alkoxy groups.
  • the hydroxyaryl lower alkoxycarbonyl group refers to the above-mentioned lower alkoxycarbonyl group substituted by a hydroxyaryl group such as a 2-hydroxyphenyl group, a 3-hydroxyphenyl group, or a 4-hydroxyphenyl group.
  • Lower alkoxyaryl lower alkoxycarbonyl group means 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group.
  • the lower alkoxycarbonyl group substituted with the aromatic hydrocarbon group substituted with the lower alkoxy group such as a group, for example, a 2-methoxybenzyloxycarboxy group, a 2-ethoxybenzyl group; Oxycarbonyl group, 3-methoxybenzyloxycarbonyl group, 3-ethoxybenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 4-ethoxybenzyloxycarbonyl group, 2-methoxycarbonyl group Enethyloxycarbonyl group, 2-ethoxyphenethyloxycarbonyl group, 3-methoxyphenethyloxy group Cicarbonyl group, 3-ethoxyphenethyloxycarbonyl group, 4-methoxyphenethyloxycarbonyl group, 4-ethoxyphenethyloxycarbonyl group, 3- (2-methoxyphenyl) pro Poxycarbonyl group, 3- (2-ethoxyphenyl) propoxycarbonyl group, 3- (3-
  • the cycloalkyloxycarbonyl group optionally having one or more oxygen atoms in the ring means a cycloalkyloxycarbonyl group in which the cycloalkyl moiety is as defined above, for example, cyclopropyl Oxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, 2-tetrahydroviranyloxycarbonyl group, 3-tetrahydroviranyloxycarbonyl group, 4 -Tetrahydrovinyloxycarbonyl group, 2-tetrahydrofuranyloxycarbonyl group, 3-tetrahydrofuranyloxycarbonyl group and the like.
  • Halogen atom means fluorine atom, chlorine atom, bromine atom and iodine atom.
  • the lower acetyl group refers to an alkylcarboxy group having 2 to 7 carbon atoms having a linear or branched alkyl group such as an acetyl group, a propionyl group, and a ptyryl group.
  • the mono- or di-lower alkyl-substituted amino group means an amino group or a dimethylamino group mono-substituted with the above lower alkyl group such as a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a acetylamino group, a dipropylamino group, an ethyl group. It refers to an amino group di-substituted with the same or different lower alkyl groups such as a methylamino group, a methylpropylamino group and an ethylpropylamino group.
  • Mono- or di-lower alkyl-substituted amino-lower alkyl group means 2-methylaminoethyl group, 2-ethylaminoethyl group, 2-propylaminoethyl group, 2-butylaminoethyl group, 2-dimethylaminoethyl group, Getylaminoethyl, 2-dipropylaminoethyl, 2-ethylmethylaminoethyl, 3-methylaminopropyl, 3-ethylaminopropyl, 3-propylaminopropyl, 3-butylamino Propyl group, 3-dimethylaminopropyl
  • a lower alkyl group substituted with the above-mentioned mono- or di-lower alkyl-substituted amino group such as a group, 3-ethylaminopropyl group, 3-dipropylaminopropyl group or 3-ethylmethylaminopropyl group
  • the alicyclic amino group which may have an oxygen atom in the ring means a 5- to 7-membered alicyclic amino group (however, when a hydroxyl group is used as a substituent, the substitution position except for the 2-position) ), For example, a 1-pyrrolidinyl group, a piperidino group, a morpholino group and the like.
  • the compound represented by the general formula (I) of the present invention can be produced, for example, as follows. That is, the general formula (I) of the present invention
  • R 1 is a hydrogen atom, a halogen atom, a hydroxyl group having a protecting group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group having a protecting group, a cycloalkyl lower alkoxy group, an aryl lower alkoxy group
  • R 2 and R 3 have the same meanings as above, and are a lower acyl group, a mono-lower alkyl-substituted amino group having a protective group, a di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group.
  • Carboxylic acid derivatives or reactive functional derivatives such as acid halides and active esters thereof, and the general formula (HI)
  • one of P and Q is an amino group
  • the other is a lower alkoxycarbonyl group, a mono- or dihydroxy-lower-alkoxycarbonyl group having a protecting group, a mono- or di-lower alkoxy-lower alkoxycarbonyl group
  • a hydroxyaryl lower alkoxycarbonyl group having a group, a lower alkoxyaryl lower alkoxycarbonyl group or an oxygen atom in the ring R 11 is a lower alkyl group, an amino lower alkyl group having a protecting group, a mono lower alkyl substituted amino lower alkyl group having a protecting group, a di lower alkyl substituted amino lower alkyl group, a protecting group.
  • R 11 and R 12 may be bonded to each other to have an oxygen atom in the ring, and a hydroxyl group having a protecting group as a substituent, a lower alkoxy group, a hydroxy group having a protecting group, a lower alkyl group or a lower alkoxy group.
  • [A 0 and B 0 in the formula are either general formulas.
  • R 2 , R 3 and R 1 G have the same meanings as described above), and the other is a lower alkoxycarbonyl group, a mono- or dihydroxy group having a protective group, a lower alkoxycarbonyl group, a mono- or Di-lower-alkoxy lower-alkoxy force carbonyl group, hydroxyaryl-lower-alkoxycarbonyl group having a protecting group, lower-alkoxyaryl-lower-alkoxycarbonyl group or oxygen atom in the ring
  • R 6 is a lower alkyl group such as a methyl group or an ethyl group.
  • an imidazole dicarboxylic acid derivative represented by the general formula:
  • the compounds represented by the general formulas (II) and (V) used as raw materials in the production method may be purchased as a commercial product, or may be produced by a known method described in a literature or a method similar thereto. it can.
  • the compound represented by the general formula (III) used as a raw material in the above-mentioned production method can be produced, for example, by a known method described in a literature or a method similar thereto (for example, Tetrahedron, 42). Vol. 10, No.
  • the compound represented by the general formula (IV) used as a raw material in the production method is, for example, a reactive functional group such as a caesmic acid derivative represented by the general formula (II) or an acid halide or an active ester thereof.
  • the rubonic acid derivative can be converted into a pharmacologically acceptable salt thereof by a conventional method.
  • salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene Acids with organic acids such as sulfonic acid, propionic acid, citric acid, conodic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid Salts with inorganic bases such as addition salts, sodium salts and potassium salts can be mentioned.
  • the compound represented by the general formula (I) of the present invention also includes a solvate with a pharmaceutically acceptable solvent such as hydrated ethanol.
  • the compound of the present invention represented by the general formula (I) has an unsaturated bond and thus has two geometric isomers.
  • the present invention relates to a cis-form (Z-form) compound and a trans-form (E-form) )).
  • trans-form (E-form) compounds are preferred.
  • a compound having an asymmetric carbon atom has two optical isomers of an R configuration and an S configuration. And mixtures of their optical isomers.
  • the compound of the present invention represented by the above general formula (I) is a very potent vascular smooth muscle in a cell growth inhibition test of nV itro using thoracic aortic vascular smooth muscle cells of spontaneously hypertensive rats. It has a cell growth inhibitory action.
  • the compounds of the present invention represented by the general formula (I) and their drugs Physiologically acceptable salts have excellent inhibitory activity on intimal cell hyperproliferation and are very useful compounds as vascular wall thickening inhibitors.
  • the compounds represented by the general formula (I) of the present invention include, for example, restenosis of the coronary artery after PTCA, restenosis after DCA, restenosis after placement of a stent in a blood vessel, autologous blood vessel and artificial blood vessel transplantation. It is effective in preventing or treating diseases caused by intimal cell hyperproliferation such as vascular wall thickening after organ transplantation, vascular wall thickening after organ transplantation, and arteriosclerosis.
  • the compound of the present invention represented by the above general formula (I) showed a high drug concentration in plasma in an oral administration test to mice.
  • the compound represented by the above general formula (I) and the pharmacologically acceptable salt thereof of the present invention are excellent compounds having good drug use efficiency.
  • the compound represented by the general formula (I) of the present invention is a highly safe compound, and is an excellent compound having high utility S as a vascular wall thickening inhibitor.
  • an appropriate pharmaceutical composition for example, It is administered orally or parenterally as tablets, powders, granules, capsules, injections and the like.
  • These pharmaceutical compositions can be prepared by pharmaceutical methods used in general preparations, by using carriers, excipients and other additives commonly used for pharmaceuticals.
  • the dose should be appropriately determined according to the gender, age, weight, and degree of symptoms of the target patient, and in the case of oral administration, it should be approximately 0.1 to 100 mg per adult per day. In the case of oral administration, the dose is generally in the range of 0.01 to 10 mg / day for adults, in single or divided doses. [Best Mode for Carrying Out the Invention]
  • N, N-dimethylformamide (0.1 ml) was added to a solution of 3,4,5-trimethoxycinnamic acid (10.0 g) and thionyl chloride (6.1 ml) in toluene (100 ml), and the mixture was stirred at 80 ° C for 3 hours. did. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane.
  • a 1 cm square aluminum foil (2.07 g) was added to a solution of mercuric chloride (829 mg) in water (83 ml), and the mixture was stirred at room temperature for 1 minute. The water was removed by decantation, and the aluminum amalgam was washed with water, methanol and getyl ether in the same manner. Under an argon atmosphere, a solution of dimethyl ether (59 ml) and isopropyl hydroxyiminocyanoacetate (10 g) in dimethyl ether (42 ml) was added to the obtained aluminum amalgam, and water (4.2 ml) was added dropwise under ice cooling. And heated to reflux for 30 minutes.
  • 3-Methoxypropyl hydroxyiminocyanoacetate (2.85 g) was added to water (20 ml), and saturated aqueous sodium hydrogen carbonate (16 ml) and sodium hydrosulfite (6.73 g) were added. Stirred for hours. An excessive amount of sodium chloride was added to the reaction mixture, and the mixture was sequentially extracted with methylene chloride and ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Ethanol (20 ml) and ethoxyiminoacetate (1.91 g) were added to the obtained residue, and the mixture was heated under reflux for 1 day and then stirred at room temperature for 19 hours.
  • the pyridinium chromate chromate (21.80 g) was suspended in methylene chloride (150 ml), sodium acetate (2.49 g) was added thereto, and the mixture was stirred at room temperature for 5 minutes.
  • a solution of 1,3-diethoxy-1-propanol (3.00 g) in methylene chloride (50 ml) was added dropwise, and the mixture was stirred at room temperature for 2 days. After the solvent was distilled off under reduced pressure, Celite (registered trademark) (5 g) and getyl ether (100 ml) were added to the obtained residue.
  • This mixture was purified by silica gel column chromatography (elution solvent: ethyl ether) to obtain 1,3-diethoxy-12-propanone (2.90 g).
  • 1,3-Jetoxy 2-propanone-oxime (3.09 g) was dissolved in ethanol (40 ml), and 10% palladium on carbon (570 mg) was added thereto. After stirring at 90 ° C. and 5 atm under a hydrogen stream for 2 days, the reaction mixture was filtered through Celite (registered trademark), and the insolubles were washed with gethyruether. The filtrate is concentrated under reduced pressure to give 2-amino-1,
  • S HR Spontaneously hypertensive rats
  • the radioactivity incorporated into the DNA fraction was measured and used as an index of the cell growth activity of the test compound.
  • the growth inhibitory activity of the test compound was represented by a concentration (IC 50 ) showing 50 % inhibition with respect to the untreated group (the DMEM culture solution added group containing no test compound). The results are shown in the table below.
  • mice Male ICR mice were fasted for 4 hours, and test compounds suspended in 0.5% sodium carboxymethylcellulose were orally administered at a dose of 30 mgZkg. Blood was collected from the vein 30 minutes, 1, 2 and 4 hours after administration. After centrifuging the blood and separating the plasma, the plasma concentration of the test compound was measured using high performance liquid chromatography. The results are shown in the table below. The plasma concentration of the compound was represented by the maximum plasma concentration (gZml).
  • mice Male 7-week-old ICR mice were fasted for 4 hours in groups of 5 mice, and suspended in 0.5% sodium carboxymethylcellulose (E) -12-ethylcarbamoyl -5 (4) I (3,4,5-trimethoxycinnamoylamino) imidazole 1 4 (5) Oral administration of monoethyl rubonate at a dose of 100, 300 or 100 Omg / kg . As a result, no deaths were observed in any of the administration groups, and no abnormalities occurred.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivés d'acide 2-substitué carbamoylimidazolecarboxylique représenté par la formule (I) et leurs sels acceptables sur le plan pharmacologique, dans laquelle un de A et de B représente un groupe représenté par la formule (a), dans laquelle R1 à R3 représentent chacun n'importe lequel de différents substituants contenant hydrogène, et l'autre représente un groupe ester carboxylique; R4 représente un alkyle inférieur substitué par hydroxy, amino etc.; R5 représente hydrogène ou un alkyle inférieur; à condition que R4 et R5 puissent être reliés l'un à l'autre afin de constituer un amino alicyclique éventuellement substitué. Ces composés ont pour effet d'inhiber la prolifération exagérée des cellules de l'intima et sont utiles en tant qu'inhibiteur de l'épaississement de la paroi vasculaire.
PCT/JP1998/001655 1997-04-15 1998-04-10 Derives d'acide 2-substitue carbamoylimidazolecarboxylique et inhibiteur de l'epaississement de la paroi vasculaire WO1998046573A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67484/98A AU6748498A (en) 1997-04-15 1998-04-10 2-substituted carbamoylimidazolecarboxylic acid derivatives and vascular-wall thickening inhibitor

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JP13274297 1997-04-15
JP9/132742 1997-04-15
JP9/273227 1997-08-28
JP27322797 1997-08-28
JP27322697 1997-08-28
JP9/273226 1997-08-28

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WO1998046573A1 true WO1998046573A1 (fr) 1998-10-22

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031900A1 (fr) * 1996-02-29 1997-09-04 Kissei Pharmaceutical Co., Ltd. Derives d'imidazole et inhibiteur d'epaississement de la paroi vasculaire

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031900A1 (fr) * 1996-02-29 1997-09-04 Kissei Pharmaceutical Co., Ltd. Derives d'imidazole et inhibiteur d'epaississement de la paroi vasculaire

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