WO1994004510A1 - Derive de pyridazine - Google Patents

Derive de pyridazine Download PDF

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Publication number
WO1994004510A1
WO1994004510A1 PCT/JP1993/000730 JP9300730W WO9404510A1 WO 1994004510 A1 WO1994004510 A1 WO 1994004510A1 JP 9300730 W JP9300730 W JP 9300730W WO 9404510 A1 WO9404510 A1 WO 9404510A1
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Prior art keywords
group
halogen atom
optionally substituted
alkyl
branched
Prior art date
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PCT/JP1993/000730
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English (en)
Japanese (ja)
Inventor
Kiyotomo Seto
Hiroo Matsumoto
Yoshimasa Kamikawaji
Kazuhiko Ohrai
Keisuke Ohdoi
Tsutomu Higashiyama
Yukinori Masuda
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Nissan Chemical Corp
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Nissan Chemical Corp
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Priority claimed from JP22400392A external-priority patent/JPH05201994A/ja
Application filed by Nissan Chemical Corp filed Critical Nissan Chemical Corp
Priority to AU40907/93A priority Critical patent/AU4090793A/en
Publication of WO1994004510A1 publication Critical patent/WO1994004510A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14—Oxygen atoms
    • C07D237/16—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
    • C07D237/22—Nitrogen and oxygen atoms

Definitions

  • the present invention relates to novel substituted pyridazine compounds useful as angiotensin II antagonists in the treatment of hypertension, congestive heart failure and chronic kidney disease.
  • the renin-angiotensin system plays a central role in normal blood pressure regulation and plays a major role in the development of hypertension and congestive heart failure.
  • Angiotensin II is an octapeptide hormone, and is mainly produced in blood by cleaving angiotensin I, which is a depeptide, by an angiotensin converting enzyme (ACE).
  • ACE angiotensin converting enzyme
  • This ACE is located on the vascular endothelium of the lung, kidney and many other organs.
  • a powerful arterial contractile, the end product of the renin-angiotensin system acts on specific receptors on the cell membrane surface.
  • One way to control the renin-angiotensin system is to antagonize the angiotensin II receptor.
  • the compound of the present invention is represented by the following general formula.
  • the present inventors surprisingly found that the pyridazine compound of the present invention, which is different from any of the compounds disclosed in the above documents, and derivatives thereof are useful as an angiotensin II antagonist.
  • they have found that they are more excellent compounds as antihypertensive agents, and can be active ingredients for the prevention or treatment of the above-mentioned depressive heart failure, chronic kidney disease and the like, and completed the present invention.
  • I 1 , R 2 and R 3 are each independently a hydrogen atom, a straight-chain or branched alkyl group of Ci to C 6 (the alkyl group is a halogen atom or a halogen atom) , a nitro group, a carboxyl group, an alkyl group of - also is properly.
  • Fuweniru group may also be optionally substituted with ⁇ ⁇ of ⁇ alkoxy group I Fuweniru group may be substituted.
  • C 2 -C 6 straight or branched alkenyl group (the alkenyl group may be optionally substituted with halogen atom.)
  • an alkynyl group (the alkynyl group linear is also rather was branched C 2 -C 6 may be optionally substituted with halogen atom.)
  • a cycloalkyl group said cycloalkyl group C 3 -C may be optionally substituted with a halogen atom or Fuweniru group.
  • Fuweniru group (The phenyl group is a halogen atom , Nitro group, carboxyl group, Ci -.
  • ⁇ C ⁇ alkoxy group of the alkyl group or to c 4 may be substituted at any)
  • the Is (CH 2) m X (wherein, m represents 0, 1 or 2, X is a halogen atom, Shiano group, nitro group, CH (CN) 2, CH (C0 2 Me) 2, CH (C0 2 Et) 2, ⁇ ⁇ linear Ashiru group properly is that branched, Ci ⁇ Ri by the alkyl group of C 4 esterified which may be force carboxyl group, a sulfonic acid group, or - YR 6 [Y Is 0, S (0) n (n represents 0, 1 or 2) or NR (R represents a hydrogen atom or a linear or branched alkyl group of), and R 6 is A hydrogen atom, a linear or branched alkyl group having a halogen atom, a halogen atom, a nitro group, a carboxyl group, a C i -C 4 alkyl group or
  • C (0) a (a is a hydrogen atom, and linear-Ji 6 properly is branched alkyl group (the alkyl group, halogen atom optionally or halogen atom, a nitro group, a carboxyl group, an alkyl group or an optionally substituted which may be phenyl group by an alkoxy group Ci ⁇ C 4 of Ci ⁇ C 4, Even if A C 2 -C 6 straight-chain or branched alkenyl group (the alkenyl group may be optionally substituted with a halogen atom), a C 2 -C 6 straight-chain or alkynyl group branched (the alkynyl group may be optionally substituted with halogen atom.), a cycloalkyl group ( ⁇ Shi click port alkyl C 3 -C 6 are optionally a halogen atom or Fuweniru group May be substituted.
  • a phenyl group (the phenyl group may be arbitrarily substituted with a halogen atom, a nitro group, a carboxy group, a C ⁇ alkyl group or a ⁇ 4 alkoxy group), or NR 7 R 8 (R 7 and R 8 are each independently a hydrogen atom, a linear or branched alkyl group of (the alkyl group is a halogen atom, Or a halogen atom, a nitro group, a carboxyl group, may be substituted in arbitrary with C 1 -C 4 alkyl group properly is or Cj C optionally substituted which may be phenyl group by an alkoxy group.
  • Arukeniru group (said Arukeniru groups linear or branched C 2 -C 6 may be optionally substituted with halogen atom.), A straight-chain or branched alkynyl group of C 2 -C 6 (The alkynyl group may be optionally substituted with a halogen atom.), A C 3 -C 6 cycloalkyl group (the cycloalkyl group is optionally substituted with a halogen atom or a phenyl group.
  • a phenyl group (the phenyl group may be optionally substituted with a halogen atom, a nitro group, a carboxy group, a C alkyl group or a ⁇ alkoxy group). ) Means ). ].
  • R 5 is a carboxyl group (the carboxyl group may be esterified by an alkyl group of ⁇ to ⁇ ⁇ ), a sulfonic acid group (the sulfonic acid group is esterified by an alkyl group of ⁇ C, may also be), sulfonic acid amino de group, it may be esterified with an alkyl group of P0 2 H (Cj ⁇ C 4) , P0 3 H 2 ( Ji! ⁇ in. of ⁇ alkyl group optionally esterified Or a tetrazolyl group (the tetrazolyl group may be arbitrarily substituted with a benzyl group, a methoxymethyl group, or a triphenylmethyl group).
  • the present invention relates to a body and salts and a pharmaceutical composition containing these as an active ingredient.
  • I 1 , R 2 , R 3 and R 5 in the compound of the present invention represented by the above general formula [I] will be described.
  • RR 2 and R 3 include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, and a t-group.
  • Xylthio group amino group, methylamino group, ethylamino group, n-propylamino group, i-propylamino group, n-butylamino group, i-butylamino group, sec-butylamino group, t-butylamino group Group, benzylamino group, 3-ethoxy-4-methoxybenzylamino group, 2-pyridylmethylamino group,
  • R 5 include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, n -propoxycarbonyl, n-butoxycarbonyl, SO, Me, SO ⁇ Et ⁇ SO n Pr, and SO 3 n Bu, S0 3 H, SO NH 2 , P0 2 Me 2 , P0 2 Et 2 , P0 2 n Pr 2 , P0 2 n Bu 2 , P0 2 H 2 , P0 3 Me 2 , P0 3 Et 2 , P0 3 n Pr 2, PO two n Bu 2, P0 3 H 2 , 1- trimethyl-5-te Torazori group, 2-preparative Rimechiru 5 Te preparative Razori group, 1-main Tokishime chill 5- Te Torazoriru Group, 2-methoxymethyl-5-tetrazolyl group, 1-benzyl-5-tetrazolyl group, 2-benzyl-5-tetrazolyl group, 5-tetrazolyl group, etc
  • Examples of the compound of the present invention include the compounds described in Table 1 and pharmacologically acceptable salts thereof in addition to the compounds described in the examples relating to the production method described later.
  • n normal, i is iso, c is cyclo, Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl, Pent is pentyl, and Hex is hexyl.
  • the group Hep represents a heptyl group.
  • Q1 to Q6 are as follows. Means a substitution group
  • O n Pr is ⁇ 1 in 1 ⁇ vi
  • the pyridazine compound of the general formula [I] of the present invention and, if possible, a pharmaceutically acceptable salt thereof can be produced by the following method.
  • V represents a halogen such as a chlorine atom, a bromine atom and an iodine atom
  • reaction formula (1) a compound represented by the general formula (II) in which the 1-position of pyridazine is a hydrogen atom is reacted with a compound represented by the general formula (Ib), and represented by the general formula (I)
  • This is a method for producing the compound of the present invention.
  • deprotection reaction is performed if necessary.
  • This reaction can be carried out usually in the presence of an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, and lithium hydroxide.
  • metal hydrides such as sodium hydride and n-butyllithium can also be used.
  • ketone-based solvents acetone, methylethylketone, getylketone, etc.
  • amide-based solvents formamide
  • N, N-dimethylformamide, N, N-dimethylacetamide, etc.), alcoholic solvents (methanol, ethanol, etc.), water, etc., and mixed solvents thereof are preferred.
  • ether solvents are usually preferred.
  • the reaction temperature can be usually from 0 to the boiling point of the solvent when using an inorganic base, and usually from -78: to 60 when using a metal hydride. Ranges can be employed.
  • the molar ratio of the raw materials can be set arbitrarily, it is sufficient to use the compound represented by the general formula [Ib] in a molar amount of 1 to 5 times the compound of the general formula [II].
  • Deprotection can be performed by a known method. For example, methyl ester and ethyl ester can be eliminated by reacting with sodium hydroxide, potassium hydroxide or the like in a water-alcohol solvent under ice cooling to room temperature.
  • the triphenylmethyl group can be eliminated under aqueous acetic acid, ethanol-hydrochloride-ethanol or ethanol reflux conditions.
  • the benzyl group can be eliminated by hydrogenolysis with hydrogen gas using a Pd-carbon catalyst, and methoxymethyl ether can be eliminated with hydrochloric acid-ethanol.
  • M is an alkali metal such as lithium, sodium, and potassium, MgCl, MgBr, ZnCl, ZnBr, Znl, and the like. Means alkaline earth metal etc.
  • Scheme (2) is reacted with the general formula [II Ia] in represented Ru compounds general formula H- R 2 or M- R 2 in the compound represented with 4-position into a leaving group pyridazine, necessary Then, it is a method for producing the compound of the present invention by performing deprotection.
  • HR 2 is used in this reaction, the addition of a hydrogen halide removing agent generally improves the yield.
  • Preferred hydrogen halide removers do not participate in the reaction and may be any that can trap hydrogen halide, such as carbon dioxide lime, sodium carbonate, hydrogen carbonate lime, and hydrogen carbonate.
  • Examples thereof include inorganic bases such as sodium, and organic bases such as N, N-dimethylylamine, N, N-ethylylaniline, trimethylamine, triethylamine, and pyridine.
  • the reaction solvent include ether solvents such as benzene, toluene, hexane, tetrahydrofuran, getyl ether, 1,4-dioxane, formamide, N, N-dimethylformamide, N, N -Amide solvents such as dimethylacetamide and N-methylpyrrolidone; alcohol solvents such as acetonitril, dimethylsulfoxide, methanol, ethanol and propanol; pyridine and triethylamine
  • organic amine solvents, halogen solvents such as chloroform, methylene chloride, and ethylene dichloride, water, and the like, or a mixed solvent thereof.
  • the reaction temperature can range from -78 to the boiling point of the solvent used
  • Preferred HR 2 include mercaptanic acid, alcohols, and amines
  • preferred MR 2 include sodium hydroxide, potassium hydroxide, sodium amide, a Grignard reagent, and a metal salt of an active methylene compound. Is mentioned. Generally 1 to 10 mol per mol of pyridazine compounds molar ratio can be arbitrarily set force general formula HR 2 or the general formula represented by reduction compounds with MR 2 of the raw material [IIIa], rather preferably is 1.2-5 It is sufficient to use twice the molar amount.
  • M is an alkali metal such as lithium, sodium, and calcium, MgCl, MgBr, ZnCl, ZnB Means alkaline earth metals such as r and Znl.
  • Reaction formula (3) is to react a compound represented by the general formula [IIIb] having a leaving group at the 5-position of pyridazine with a compound represented by a single-arm HR 3 or M-R 3 if necessary. This is a method for producing the compound of the present invention by performing protection.
  • a hydrogen halide removing agent When HR 3 is used in this reaction, the addition of a hydrogen halide removing agent generally improves the yield.
  • a hydrogen halide removing agent any agent which does not participate in the reaction and can trap hydrogen halide may be used.
  • carbon dioxide lime, sodium carbonate, hydrogen carbonate lime, hydrogen carbonate examples thereof include inorganic bases such as stream, and organic bases such as N, N-dimethylylaniline, N, N-getylaniline, trimethylamine, triethylamine, and pyridine.
  • reaction solvent examples include benzene, toluene, hexane, tetrahydrofuran, dimethyl ether, ether solvents such as 1,4-dioxane, formamide, N, N-dimethylformamide, N, Amide solvents such as N-dimethylacetamide and N-methylpyrrolidone; alcohol solvents such as acetonitril, dimethylsulfoxide, methanol, ethanol and propanol; pyridine and triethylamine And organic solvents such as organic solvents, halogen solvents such as chloroform, methylene chloride and ethylene dichloride, water and the like, or a mixed solvent thereof.
  • the reaction temperature can range from -78: to the boiling point of the solvent used in the reaction.
  • Preferred HR 3 include mercaptanic acid, alcohols, and amines
  • preferred MR 3 include sodium hydroxide, potassium hydroxide, sodium amide, a Grignard reagent, and a metal salt of an active methylene compound.
  • the molar ratio of the raw material can be arbitrarily set, but usually 1 to 10 mols per mol of the pyridazine compounds of the general formula HR 2 or represented by reduction compounds with MR 2 Formula [IIIb], rather preferably is 1.2 It is enough to use 5 times mol.
  • the solvents preferably used for efficiently producing [IVa] include ether solvents (tetrahydrofuran, 1,4-dioxane) and amide solvents (formamid). , N, N-dimethylacetamide, N-methylpyrrolidone, etc.), acetonitrile, dimethylsulfoxide, alcoholic solvents (methanol, ethanol, propanol, etc.), organic amine solvents (pyridine , Triethylamine, N, N-dimethylaminoethanol, triethanolamine, etc.), water and the like, or a mixed solvent thereof.
  • Solvents that are preferably used to efficiently produce [IVb] include benzene solvents (benzene, toluene, xylene, chlorobenzene, and dichloromethane), and saturated hydrocarbon solvents (pentane, hexane, and hexane). Heptane) or a mixed solvent thereof.
  • any agent that does not participate in the reaction and can trap hydrogen hydride is used.
  • carbon dioxide lime, sodium carbonate, hydrogen carbonate lime, and carbonate examples thereof include inorganic bases such as hydrogen sodium, and organic bases such as N, N-dimethylylaniline, ⁇ , ⁇ -ethylylaniline, trimethylamine, triethylamine, and pyridine.
  • Reaction solvents include ether solvents such as benzene, toluene, hexane, tetrahydrofuran, getyl ether, 1,4-dioxane, formamide, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ - Amide solvents such as dimethyl acetate and ⁇ -methylpyrrolidone, alcohol solvents such as acetonitril, dimethyl sulfoxide, methanol, ethanol and propanol, pyridine and triethylamine Examples thereof include organic amine solvents, halogen solvents such as chloroform, methylene chloride, and ethylene dichloride, water, and the like, or a mixed solvent thereof. As the reaction temperature, a range from ⁇ 78 C to the boiling point of the solvent used in the reaction can be adopted.
  • Preferred HR 13 include mercapbutanoic acid, alcohols, and amines
  • preferred MR 13 include sodium hydroxide, potassium hydroxide, sodium amide, and Grignard reagent. Metal salts of active methylene compounds, etc.
  • the molar ratio of the raw material can be arbitrarily set, but in general formula H- generally 1 to 10 moles of the compound represented by R 13 or M- R 13 relative to pyridazine compounds of the general formula [IV], is favored properly 1.2 It is enough to use up to 5 times mol.
  • the reaction formula (5) converts the compound represented by the general formula (VI) in which the 6-position of the pyridazine is a hydrogen atom into nitrogen, converts it into the compound represented by the general formula (VIa), - represented by R 1 or M- R 1 is reacted with a compound, a process for producing by Ri invention compound and this performing deprotection if necessary.
  • Nitrogenation can be carried out by the methods described in Japanese Patent Publication No. 42-1299, Japanese Patent Publication No. 44-20096, and US Pat. No. 3,661,904.
  • a hydrogen halide removing agent generally improves the yield.
  • any agent which does not participate in the reaction and can trap hydrogen halide may be used.
  • carbon dioxide lime, sodium carbonate, hydrogen carbonate lime, sodium hydrogen carbonate And inorganic bases such as N, N-dimethylaniline, N, N-ethylylaniline, trimethylamine, triethylamine, pyridine and the like.
  • reaction solvent examples include benzene, toluene, hexane, tetrahydrofuran, ether solvents such as dimethyl ether, 1,4-dioxane, formamide, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide.
  • Solvents such as amide, ⁇ -methylpyrrolidone, etc., alcohol solvents such as acetonitrile, dimethyl sulfoxide, methanol, ethanol, propanol, etc., organic amine solvents such as pyridine, triethylamine, etc.
  • halogen-based solvents such as formaldehyde, methylene chloride and ethylene dichloride, water and the like, and a mixed solvent thereof.
  • the reaction temperature may range from -78 to the boiling point of the solvent used in the reaction.
  • Preferred HR 1 include mercaptanic acid, alcohols, and amines.
  • Preferred MR 1 is sodium hydroxide, potassium hydroxide, sodium amide, a Grignard reagent, a metal of an active methylene compound. And the like.
  • the molar ratio of the raw material can be arbitrarily set, but usually 1 to 10 mols per mol of the pyridazine compounds of the general formula HR 1 or represented by reduction compounds with MR 1 Formula [VIa], the rather to preferred 1.2 to It is enough to use 5 times mol.
  • Pyridazine serving as the core is described in Dot Patent Publication No. 1670169, Japanese Patent Publication Nos. 58-183675, 63-301870, U.S. Pat.No. 4978665, European Patent Publication 275997, etc.
  • the pyridazine compound represented by the general formula [I] of the present invention and, if possible, a pharmaceutically acceptable salt thereof may be administered by injection.
  • Parenteral administration tablette, subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc.
  • Oral administration can be mentioned, for example, as a pessel, granule, pill, syrup, solution, emulsion, suspension or the like.
  • the above pharmaceutical composition containing the compound of the present invention contains about 0.1 to 99.5%, preferably about 0.5 to 95%, of the compound of the present invention based on the weight of the whole composition.
  • compositions may contain more than one of the compounds of the present invention.
  • the clinical dose of the compound of the present invention varies depending on the age, body weight, patient sensitivity, degree of symptoms, etc., but the effective dose is usually 0.003 to 1.5 g per day for an adult. It is about 0.01-0.6g. However, amounts outside the above range can be used if necessary.
  • the compounds of the present invention are formulated for administration by conventional pharmaceutical means.
  • Tablets, capsules, granules and pills for oral administration are excipients such as sucrose, lactose, glucose, starch, mannite; binders such as syrup, gum arabic, gelatin, sorbitol, tragan , Methylcellulose, polyvinylpyrrolidone; disintegrants, such as starch, carboxymethylcellulose or its calcium salts, microcrystalline cellulose, polyethylene glycol; lubricants, such as talc, magnesium or calcium stearate, silica; lubrication It is prepared using an agent such as sodium laurate, glycerol and the like.
  • excipients such as sucrose, lactose, glucose, starch, mannite
  • binders such as syrup, gum arabic, gelatin, sorbitol, tragan , Methylcellulose, polyvinylpyrrolidone
  • disintegrants such as starch, carboxymethylcellulose or its calcium salts, microcrystalline cellulose, polyethylene glycol
  • Injectables, solutions, emulsions, suspensions, syrups and aerosols are active ingredient solvents such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; Activators, such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents, such as carboxymethyl cellulose It is prepared by using sodium salts, cellulose derivatives such as methylcellulose, natural rubbers such as tragacanth and arabia gum; preservatives, for example, esters of paraoxybenzoic acid, benzalkonium chloride, sorbate and the like. Suppositories are examples For example, it is prepared using polyethylene glycol, lanolin, coconut oil and the like. BEST MODE FOR CARRYING OUT THE INVENTION
  • Synthesis Example 84
  • the heron was exsanguinated and killed under pentobarbital anesthesia, and the thoracic aorta was immediately removed.
  • the aorta was a helix strip, kept at 37, suspended in a nutrient solution (Krebs-Henseleit solution) aerated with 95% oxygen, 5% carbon dioxide gas, and its isometric contraction was measured. After the sample while exchanging the nutrient solution was 1 hour stability every 20 minutes, Angi O tensin I (AngI:.
  • the heron was exsanguinated and killed under pentobarbital anesthesia, and the thoracic aorta was immediately removed.
  • the aorta was a helix strip, kept at 37, suspended in a nutrient solution (Krebs-Henseleit solution) aerated with a mixture of 95% oxygen and 5% carbon dioxide, and its isometric contraction was measured. After the sample while exchanging the nutrient solution was 1 hour stability every 20 minutes, Angi O tensin II: elicited contraction by (AngII 10- 8 M).
  • the evaluation of the compound of the present invention was carried out by pre-treating the compound of the present invention (10 6 ⁇ or 10 7 ⁇ ) 20 minutes before the fourth administration of Angll, and calculating the inhibition rate with the third Angll contraction as 100%.
  • the compound of the present invention was dissolved in dimethyl sulfoxide (DMSO), and corrected by a control (DMSO).
  • the above ingredients are mixed in a conventional manner and then filled into gelatin capsules to produce 10,000 capsules containing 1 mg of active ingredient per capsule.
  • the above ingredients are melt-mixed in a conventional manner, poured into a suppository container, and cooled and solidified to produce 1,000 lg suppositories containing 1 mg of the active ingredient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé répondant à la formule générale [I], utile comme remède contre l'hypertension, l'insuffisance congestive et les maladies rénales chroniques. Dans ladite formule [I], R?1, R2 et R3¿ représentent chacun, indépendamment l'un de l'autre, hydrogène, alkyle C¿1?-C6, cycloalkyle C3-C6, phényle, alcoxy C1-C7, cycloalcoxy C3-C6, amino, alkylureido C1-C6, pyridylméthylamino, benzoylamino, halogène, cyano, nitro, alcoxycarbonyle C2-C7, carboxyle, etc., et R?5¿ représente 5-tétrazolyle, carboxyle, etc.
PCT/JP1993/000730 1992-08-24 1993-05-31 Derive de pyridazine Ceased WO1994004510A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40907/93A AU4090793A (en) 1992-08-24 1993-05-31 Pyridazine derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP22400392A JPH05201994A (ja) 1991-10-08 1992-08-24 ピリダジン誘導体
JP4/224003 1992-08-24

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WO1994004510A1 true WO1994004510A1 (fr) 1994-03-03

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0445811A2 (fr) * 1990-03-07 1991-09-11 Takeda Chemical Industries, Ltd. Composés hétérocycliques contenant de l'azote, leur production et leur utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0445811A2 (fr) * 1990-03-07 1991-09-11 Takeda Chemical Industries, Ltd. Composés hétérocycliques contenant de l'azote, leur production et leur utilisation

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