WO1998034922A1 - Agent destine a la prophylaxie ou la therapie des complications diabetiques - Google Patents

Agent destine a la prophylaxie ou la therapie des complications diabetiques Download PDF

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Publication number
WO1998034922A1
WO1998034922A1 PCT/JP1998/000256 JP9800256W WO9834922A1 WO 1998034922 A1 WO1998034922 A1 WO 1998034922A1 JP 9800256 W JP9800256 W JP 9800256W WO 9834922 A1 WO9834922 A1 WO 9834922A1
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WO
WIPO (PCT)
Prior art keywords
group
phenyl
methyl
pharmacologically acceptable
tetrazol
Prior art date
Application number
PCT/JP1998/000256
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English (en)
Japanese (ja)
Inventor
Toshio Sada
Hiroyuki Koike
Hiroaki Yanagisawa
Original Assignee
Sankyo Company, Limited
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 Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU55764/98A priority Critical patent/AU5576498A/en
Publication of WO1998034922A1 publication Critical patent/WO1998034922A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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 a composition for preventing or treating diabetic complications, comprising an imidazole carboxylic acid, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof as an active ingredient; Use of imidazole carboxylic acids, pharmacologically acceptable salts or pharmaceutically acceptable esters thereof, or imidazole carboxylic acids, pharmacologically acceptable salts thereof, for producing a composition for therapy
  • a method for preventing or treating diabetic complications by administering an effective amount of a pharmacologically acceptable ester to a warm-blooded animal, or an imidazole carboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient
  • a composition for the prevention or treatment of renal disease comprising Use of imidazole carboxylic acids, pharmacologically acceptable salts or pharmacologically acceptable esters thereof, or imidazole carboxylic acids, pharmacologically acceptable salts thereof, or
  • Diabetes particularly, non-insulin-dependent diabetes mellitus (NIDDM)], Syndrome X (Syndrome X), which simultaneously complicates hypertension and hyperlipidemia [Diaby Taste, Vol. 37, pp. 1595 to 1607] (1988): Diabetes, 37, 1595-1607 (1988)] is an increasing number of patients. In such patients, they develop coronary artery disease The risk of infection is very high and useful preventive or therapeutic measures have been sought.
  • Syndrome X insulin dysfunction, that is, insulin resistance [Diabetologia, Vol. 21, pp. 165 to 171 (1981): Diabetologia, 21, 165-171 (1981)] is included in the disease state.
  • angiotensin-converting enzyme (ACE) inhibitors which have recently been used as antihypertensive agents, for diabetic nephropathy [New England Journal ⁇ Saibu Medicine, Vol. 313, pp. 1617 to 1617 1620 (1985): New. Eng. J. Med., 313, 1617-1620 (1985)], but it is said that this drug also improves insulin resistance.
  • the mechanism is considered to be a kinin-type potentiator [Hypertension, Vol. 23, pp. 450-455 (1992): Hypertension, 23-450-455 (1992)].
  • Angiotensin II receptor antagonist which is the same renin 'angiotensin system inhibitor, can also be expected to have a renal protective effect.
  • renal diseases for example, eye disease (IgA) nephropathy [Berber disease], membranous nephropathy, proliferative glomerulonephritis, sclerosing glomerulonephritis, focal glomerulosclerosis
  • IgA nephropathy eye disease
  • membranous nephropathy membranous nephropathy
  • proliferative glomerulonephritis glomerulonephritis
  • sclerosing glomerulonephritis focal glomerulosclerosis
  • the pathogenesis and progression mechanism of glomerulonephritis classified as a type such as minimal change nephrotic syndrome has not been elucidated to date.
  • IgA nephropathy which is considered to be the most common type of glomerulonephritis as an example
  • IgA-based immune complexes develop in the glomeruli of the kidney and develop through various processes, eventually becoming glomerular.
  • immunosuppressants mainly for adrenocortical steroids
  • corticosteroids and immunosuppressants have problems with long-term administration because of side effects.
  • the effect is divided, and the effective rate is not high.
  • the number of kidney disease patients undergoing dialysis is on the rise, but about 40% of the causes are glomerulonephritis.
  • the renal protection mechanisms of ACE inhibitors include lowering glomerular pressure [hyperfiltration
  • the present inventors have conducted various studies in view of the importance of prevention and treatment of diabetic complications, especially nephropathy, hyperlipidemia and hypertension associated with NIDDM, and as a result, have found that a specific angiotensin II Receptor antagonists have an excellent inhibitory effect on nephropathy, hyperlipidemia and hypertension in NIDDM model rats, have few side effects, and have diabetic complications, especially nephropathy, It has been found to be a prophylactic or therapeutic agent for hyperlipidemia and / or hypertension.
  • the present inventors have conducted various studies in view of the importance of prevention and treatment of renal diseases, particularly glomerulonephritis, and as a result, a specific angiotensin II receptor antagonist has been It has an excellent inhibitory effect on glomerulonephritis, which has been specifically produced, and has few side effects, and has been found to be a prophylactic or therapeutic agent for renal diseases, particularly glomerulonephritis.
  • the present invention relates to a composition for preventing or treating diabetic complications comprising an imidazole carboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient, and a composition for preventing diabetic complications.
  • imidazole carboxylic acids, pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof, or imidazole carboxylic acids, pharmaceutically acceptable salts thereof, or a pharmaceutically acceptable salt thereof for producing a therapeutic composition A method for preventing or treating diabetic complications by administering an effective amount of a pharmacologically acceptable ester to a warm-blooded animal, or an imidazole carboxylic acid, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient
  • a composition for the prevention or treatment of renal disease comprising Imidazole carboxylic acids for the production of goods, the use of a pharmacologically acceptable Ru salt or its pharmacologically acceptable esters, or imidazole carboxylic Or a pharmacologically acceptable salt thereof or a pharmacologically effective salt thereof is administered to a warm-blooded animal.
  • imidazole carboxylic acids which are the active ingredients of the present invention include:
  • R 1 represents a d-C 4 alkyl group
  • R 2 and R 3 are the same or different and each represent a hydrogen atom or a -C 4 alkyl group
  • R 4 represents a hydrogen atom or a C, -C 4 alkyl group
  • R 5 represents a hydrogen atom
  • R 6 represents a carboxy group or a tetrazol-5-yl group.
  • the C, 1 C 4 alkyl group of FT, R 2 , R 3 and R 4 can be, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, and the d-C 4 alkyl group of FT is It is preferably an ethyl, propyl or butyl group, more preferably a propyl or butyl group, particularly preferably a propyl group, and the d-alkyl group of R 2 , R 3 and R 4 is Preferably, it is a methyl or ethyl group, and particularly preferably, a methyl group.
  • the ester residue (R 5 a) of the pharmacologically acceptable ester of compound (I) is, for example, The above d—C 4 alkyl group, C 2 —C 5 alkanoyloxymethyl or 1— (C 2 -C 3 alkanoyloxy) ethyl group (the C 2 —C 5 alkanoyl moiety is, for example, It may be acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, vivaloyl, preferably acetyl or vivaloyl.
  • Vivaloyl D -c 4 alkoxycarbonyl Nirusaiki Shimechiru or 1 one (d - c 4 alkoxycarbonyl old alkoxy) Echiru group (wherein d - c 4 alkoxy moiety, for example, methoxy, ethoxy, Purobokishi, iso Purobokishi, butoxy , Isobutoxy, preferably methoxy, ethoxy, propoxy or isopropoxy, particularly preferably ethoxy or isopropoxy.), (5-methyl-2-oxo-1, 3-dioxolen-14 Methyl), a methyl group, (5-phenyl-2-oxo-1,3-dioxolen-4-yl), a methyl group or a phthalidyl group, preferably a methyl group, an ethyl group, an acetyloxymethyl group, 1- (Acetoxy) ethyl group, Bivaloyl
  • esters of the carboxy group at the 5-position of the imidazole ring are preferred.
  • the compound (I) of the present invention can be converted into the corresponding pharmacologically acceptable salt by treating with an acid or a base according to a conventional method, if desired.
  • acid addition salts include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as maleic acid, fumaric acid, tartaric acid, and citric acid.
  • Examples of the salt with a base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and organic bases such as guanidine, triethylamine and dicyclohexylamine. Salt.
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide
  • alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide
  • organic bases such as guanidine, triethylamine and dicyclohexylamine. Salt.
  • the compound when an asymmetric carbon is present in the molecule of the compound (I), the compound includes racemates and optically active compounds, and also includes hydrates of the compound (I) or a salt thereof.
  • Compound (I) is preferably
  • R 1 is an ethyl group, a propyl group or a butyl group
  • R 2 and R 3 are the same or different and are a hydrogen atom or a methyl group
  • R 5 is a hydrogen atom or the formula R s a, R 5 a is a methyl group, E Ji group, ⁇ Se Bok Kishimechiru group, 1 i ( ⁇ Se Bok carboxymethyl) Echiru group, Bivaloyl xymethyl group, 1— (Bivaloyl xy) ethyl group, methoxycarbonyloxymethyl group, 11- (methoxycarbonyl oxy) ethyl group, ethoxycarbonyl xymethyl group, 1— (ethoxycarbonyl) Ethoxy group, propoxycarbonyloxymethyl group, 11- (propoxycarbonyloxymethyl) ethyl group, isopropoxycarbonyloxymethyl group, 11- (isopropoxycarbonyloxy) ethyl group , (5-methyl-2-yl-1,3-dioxolen-1-yl) A methyl group or a phthalidyl group.
  • R 5 is a hydrogen atom or the formula R 5 a
  • R 5 a is pivaloyl ingenuity Shimechiru group, an ethoxycarbonyl old Kishimechiru group, 1- (ethoxycarbonyl old carboxymethyl) Echiru group, isopropoxy It is a carbonyl group, a dimethyl group, a (isopropoxycarbonyl) ethyl group, a (5-methyl-2-chloro-1,3-dioxolen-4-yl) methyl group or a phthalidyl group.
  • R 5 has the formula R s a, R 5 a is Viva Roy Ruo carboxymethyl group or a (5-methyl-one 2-year old Kiso one 1, 3-di old Kisoren one 4- A) a compound which is a methyl group.
  • R 1 is selected from the group consisting of (3)
  • R 2 and R 3 are selected from the group consisting of (4)-(5)
  • (6)-(7) force> Choose R 4 from the group
  • R 1 is an ethyl group, a propyl group or a butyl group
  • R 2 and R 3 are the same or different and are a hydrogen atom or a methyl group
  • R 4 is a hydrogen atom or a methyl group
  • R 5 is a hydrogen atom or the formula R 5 a
  • R 5 a is a methyl group, Echiru group, Asetokishimechiru group, 1 i ( ⁇ Se Bok carboxymethyl) Echiru group, pivaloyl old Kishimechiru group, 1 i ( Bivaloyl) ethyl group, methoxycarbonyloxymethyl group, 1- (Methoxycarbonyl) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyl) ethyl, propoxycarbonyl-methyl, 1- (propoxycarbonyl) ethyl, iso- Propoxycarbonyl, a methyl group, 11- (isopropoxycarbonyl) ethyl group, (5-methyl-2-cyclo-1,3-dioxolen-4-yl) methyl group or phthalidyl group.
  • R 1 is a propyl group or a butyl group
  • R 2 and R 3 are the same and are methyl groups
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom or the formula R 5 a
  • R 5 a is pivaloyl old Kishime butyl group, an ethoxycarbonyl old Kishimechiru group, 1 i (ethoxycarbonyl O carboxymethyl) Echiru group, isopropoxycarbonyl old Kishimechiru
  • R 1 is a propyl group
  • R 2 and R 3 are the same, a methyl group
  • R 4 is a hydrogen atom
  • R 5 has the formula R 5 a, R 5 a is a pivaloyl old Kishimechiru group or (5-methyl-one 2-year old Kiso one 1, 3-di old Kisoren one 4-I) methyl group )
  • the exemplified compound number No. 7,8,9,10,11,12,13,14,15,16,17,18,19,22,23,24,25,26,27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 , 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 79 and 80,
  • Illustrative Compound No. 11 1 Bivaloyl oxymethyl 4-hydroxymethyl — 2-propyl-1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazoyl 5-carboxyle Uru,
  • Illustrative compound number No. 12 (5-Methyl-2-oxo-1,3-dihexolen-4-yl) methyl 4-hydroxymethyl-1-propyl-1- 1- [4-[2-1] (Tetrazole-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
  • Illustrative compound number No. 17 Bivaloyl dimethyl 4- (1-hydroxyethyl) 1-2-propyl-1- 1- "4-" 2- (tetrazol-5-yl) [Phenyl] methylimidazole-5-carboxylate
  • Exemplified Compound No. 18 (5-Methyl_2-year-old 1,3-di-year-old solen-41-yl) methyl 41- (1- (Hydroxityl) —2-propyl—1-1 [4- [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazolone 5-5-carboxylate,
  • Illustrative Compound No. 32 Bivaloyl xymethyl 4- (1-hydroxy-1-methylethyl) -12-propyl-11- [4- [2- (Tetrazol-5-yl) phenyl] phenyl] methylimidazole 5-Carboxylate
  • Exemplified Compound No. 33 Ethoxycarbonyl 4-methyl (4-hydroxy-1-methylethyl) 4- (1-hydroxy-1-methylethyl) 4- [1- [2- (tetrazolyl 5-) Phenyl) phenyl] methylimidazole-5-carboxylate,
  • Illustrative Compound No. 35 Isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methylethyl) -1-2-propyl-1- [4-1- [2- (tetrazol-5-yl) phenyl] phenyl] Methylimidazole-5-carboxylate,
  • Illustrative Compound No. 37 (5-Methyl-2-oxo-1,3, -dioxylene-41-yl) methyl 4- (1-hydroxy-11-methylethyl) -12-pro Pill-1-1 [4-1-1 [2- (tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate,
  • Illustrative Compound No. 71 Isopropoxycarbonyl 2-methyl 4-butyl (1-hydroxy-1-methylethyl) — 1- [4- [2- (tetrazol-5-yl) phenyl] phenyl] Methyl imidazole-5-carboxylate,
  • Illustrative Compound No. 72 1- (Isopropoxycarbonyl) ethyl 2-butyl-4- (1-hydroxy-1-methylethyl) —1-1 [4-1] [2- (tetrazol-5-yl) [Phenyl] phenyl] methylimidazole-5-force lipoxylate and
  • the compound (I), a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, which is the active ingredient of the present invention is known (for example, JP-A-5-78328) or a known method. (For example, JP-A-5-78328).
  • the compound (I), a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, which is an active ingredient of the present invention has an excellent inhibitory action on NIDDM complications and low toxicity, so that diabetic complications, especially It is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for nephropathy, hyperlipidemia, and hypertension or hypertension associated with NIDDM.
  • the compound (I), a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof, which is an active ingredient of the present invention, has an excellent nephritis inhibitory action and the like, and has a low toxicity.
  • a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof is used as a therapeutic or prophylactic agent for the above-mentioned diseases, As such or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., orally with tablets, capsules, granules, powders or syrups, or parenterally with injections, etc. In particular, it can be administered orally.
  • excipients eg, lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch.
  • Starch derivatives crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; Silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; calcium sulfate Sulphate derivatives such as Pum), binders (for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; magrogol and the like); disintegrants (for example, the above-mentioned excipients; croscarmellose sodium); Chemically modified starch such as sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc; stea
  • silicic acids such as silicic anhydride and silicic acid hydrate
  • the dosage varies depending on symptoms, age, etc.
  • the lower limit is lrng (preferably 10 mg) and the upper limit is 10 O Omg (preferably 500 mg) intravenously.
  • the lower limit of 0.5 mg (preferably 5 mg) and the upper limit of 500 mg (preferably 250 mg) can be administered to an adult 1 to 6 times per day depending on the symptoms. desirable.
  • ZDF Zucker Diabetic Fatty
  • the control group received a diet containing no drug.
  • Lean rats of the same age were used, and the rats were also fed a drug-free diet.
  • the compound which is the active ingredient of the present invention does not affect the body weight and blood glucose level, but has high blood pressure, increased excretion of urinary protein and increased plasma Significantly suppress the increase in lipids.
  • test compound was suspended in a 0.5% carboxymethylcellulose aqueous solution (CMC solution) and administered orally at 10 mg / kg / day after the nephritis was induced until the end of the experiment.
  • CMC solution carboxymethylcellulose aqueous solution
  • urinary protein and ⁇ -reactive protein were analyzed using the pyrogallol red 'molybdenum complex method and the ELISA (Enzyme-Linked Immunosorbent Assay). Bumin was measured and the degree of glomerular sclerosis was measured.
  • the compound that is the active ingredient of the present invention significantly suppresses the increase in urinary protein excretion and urinary albumin excretion, and significantly improves ovule hardening.
  • the powder After mixing the powder of the above formulation and passing through a 60 mesh sieve, the powder is placed in a 25 Omg No. 3 gelatin capsule to form a capsule.
  • the powder of the above formulation is mixed and tableted with a tableting machine to make a tablet of 200 mg per tablet.
  • the tablets can be sugar-coated as needed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette composition comprend en tant que principe actif un composé de l'acide imidazolecarboxylique, représenté par la formule générale (1), dans laquelle R1 représente un groupe alkyle, R2 et R3 représentent chacun un atome d'hydrogène ou un groupe alkyle, R4 représente un atome d'hydrogène ou un groupe alkyle, R5 représente un atome d'hydrogène et R6 représente un groupe carboxyle ou tétrazol-5-yle. Cette composition possède une excellente activité inhibitrice à l'égard des néphropathies du rat du type présentant un diabète non insulino-dépendant, et elle est utile en tant qu'agent destiné à la prophylaxie ou à la thérapie des complications diabétiques.
PCT/JP1998/000256 1997-02-05 1998-01-23 Agent destine a la prophylaxie ou la therapie des complications diabetiques WO1998034922A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55764/98A AU5576498A (en) 1997-02-05 1998-01-23 Prophylactic or therapeutic agent for diabetic complication

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP9/22576 1997-02-05
JP2257697 1997-02-05
JP9/57244 1997-03-12
JP5724497 1997-03-12

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WO1998034922A1 true WO1998034922A1 (fr) 1998-08-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000031071A1 (fr) * 1998-11-24 2000-06-02 Ferrer Internacional, S.A. Derives d'acetal 2-alkyl-5-halo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazole-4-carboxaldehyde, preparation et utilisation de ceux-ci
CN106458998A (zh) * 2014-05-13 2017-02-22 帝人制药株式会社 吡嗪衍生物

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JPH0578328A (ja) * 1991-02-21 1993-03-30 Sankyo Co Ltd ビフエニルメチルイミダゾール誘導体
JPH06503343A (ja) * 1990-12-14 1994-04-14 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 糖尿病性腎症の治療におけるアンジオテンシン２受容体拮抗剤の使用
JPH072667A (ja) * 1993-04-22 1995-01-06 Takeda Chem Ind Ltd 腎疾患の予防または治療剤
JPH09323991A (ja) * 1996-06-04 1997-12-16 Kotobuki Seiyaku Kk 新規カルボキシメチリデンシクロヘプトイミダゾール誘導体及びその製造方法並びにこれを含有する薬剤

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JPH06503343A (ja) * 1990-12-14 1994-04-14 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 糖尿病性腎症の治療におけるアンジオテンシン２受容体拮抗剤の使用
JPH0578328A (ja) * 1991-02-21 1993-03-30 Sankyo Co Ltd ビフエニルメチルイミダゾール誘導体
JPH072667A (ja) * 1993-04-22 1995-01-06 Takeda Chem Ind Ltd 腎疾患の予防または治療剤
JPH09323991A (ja) * 1996-06-04 1997-12-16 Kotobuki Seiyaku Kk 新規カルボキシメチリデンシクロヘプトイミダゾール誘導体及びその製造方法並びにこれを含有する薬剤

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Title
ATHEROSCLEROSIS, Vol. 108, No. 1, (1994), M.C. KOWALA et al., "Inhibitors of Angiotensin Converting Enzyme Decrease Early Atherosclerosis in Hyperlipidemic Hamsters. Fosinopril Reduces Plasma Cholesterol and Captopril Inhibits Macrophage-Foam Cell Accumulation Independently of Blood Pressure and Plasma *
CAN. J. CARDIOL., Vol. 11, Suppl. (1995), D. ZEEUW et al., "Losartan in Patients with Renal Insufficiency", pages 41F-44F. *
CLIN. EXP. PHARMACOL. PHYSIOL., Vol. 22, Suppl. 1, (1995), T. ROSENTHAL et al., "Enalapril Improves Glucose Tolerance in Two Rat Models: A New Hypertensive Diabetic Strain and a Fructose-Induced Hyperinsulinamic Rat", pages S353-S354. *
HYPERTENSION, Vol. 17, No. 4, (1991), B. FABRIS et al., "Salt Blocks the Renal Benefits of Ramipril in Diabetic Hypertensive Rats", pages 497-503. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000031071A1 (fr) * 1998-11-24 2000-06-02 Ferrer Internacional, S.A. Derives d'acetal 2-alkyl-5-halo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazole-4-carboxaldehyde, preparation et utilisation de ceux-ci
CN106458998A (zh) * 2014-05-13 2017-02-22 帝人制药株式会社 吡嗪衍生物

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