WO1991018903A1 - Composes de pyrrolopyridazine - Google Patents

Composes de pyrrolopyridazine Download PDF

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Publication number
WO1991018903A1
WO1991018903A1 PCT/JP1991/000678 JP9100678W WO9118903A1 WO 1991018903 A1 WO1991018903 A1 WO 1991018903A1 JP 9100678 W JP9100678 W JP 9100678W WO 9118903 A1 WO9118903 A1 WO 9118903A1
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WIPO (PCT)
Prior art keywords
compound
alkyl
fluorophenyl
salts
nmr
Prior art date
Application number
PCT/JP1991/000678
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English (en)
Inventor
Masaaki Matsuo
Takashi Manabe
Hiroyuki Okumura
Hiroshi Matsuda
Naoaki Fujii
Original Assignee
Fujisawa 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.)
Filing date
Publication date
Priority claimed from GB909011837A external-priority patent/GB9011837D0/en
Priority claimed from GB909019173A external-priority patent/GB9019173D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1991018903A1 publication Critical patent/WO1991018903A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • PYRROLOPYRIDAZINE COMPOUNDS This invention relates to novel pyrrolopyridazine compounds and pharmaceutically acceptable salts thereof.
  • pyrrolopyridazine compounds and pharmaceutically acceptable salts thereof which have inhibitory activity against the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), to a process for preparation thereof, to a pharmaceutical composition containing the same, to a use of the same as a medicament, and to a method for
  • one object of the present invention is to provide pyrrolopyridazine compounds and pharmaceutically acceptable salts thereof, which inhibit the activity of HMG-CoA reductase and therefore are capable of lowering blood serum cholesterol levels and blood lipid levels.
  • Another object of the present invention is to provide a process for preparation of pyrrolopyridazine compounds and pharmaceutically acceptable salts thereof.
  • Another object of the present invention is to provide a pharmaceutical composition comprising, as an active
  • Still further object of the present invention is to provide a use of said pyrrolopyridazine compounds and pharmaceutically acceptable salts thereof as a medicament and a method for treating hypercholesterolaemic states, hyperlipoproteinaemic states and associated conditions in human being or animal.
  • HMG-CoA reductase are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C). It has now been established that lowering LDL-C levels affords protection from coronary heart disease.
  • LDL-C low density lipoprotein cholesterol
  • the pyrrolopyridazine compounds of this invention inhibit HMG-CoA reductase and so inhibit cholesterol
  • hypercholesterolaemic and hyperlipoproteinaemic states e.g. atherosclerosis
  • associated conditions e.g. angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism, peripheral vascular disease, recurrent
  • pancreatitis and xanthomas pancreatitis and xanthomas
  • R 1 and R 2 are each lower alkyl, cyclo(lower) alkyl, cyclo(lower) alkyl (lower) alkyl, aryl or substituted aryl,
  • R 3 and R 4 are each hydrogen, lower alkyl, lower
  • Y is vinylene or ethylene
  • Z is a group of the formula:
  • R 5 is carboxy or protected carboxy
  • R 8 is hydrogen or hydroxy-protective group
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt,
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • an ammonium salt e.g. sodium salt, magnesium salt, etc.
  • an organic base salt for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt,
  • 1-phenylethylamine salt etc.
  • a salt with a basic amino acid e.g. arginine, etc.
  • a salt with an acid such as an inorganic acid addition salt (e.g. hydrochloride,
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.
  • a salt with an acidic amino acid e.g. aspartic acid, glutamic acid, etc.
  • the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
  • R 1 , R 2 , R 3 , R 4 , Y and Z are each as defined above, at least one of and is hydrogen, and the other is
  • the compound (II) used in the Process 1 is new and can be prepared, for example, by the following methods or a conventional manner.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each as defined above,
  • R 6 is protected carboxy
  • R 7 is lower alkyl
  • R 8 is hydroxy-protective group
  • R 9 is protected carboxy
  • R 10 is lower alkyl.
  • Suitable “lower alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl,
  • preferable example may be C 1 -C 4 alkyl and the most
  • preferable one may be methyl, ethyl and isopropyl for R 1 and/or R 2 , methyl, ethyl, isopropyl and t-butyl for R 3 and/or R 4 , t-butyl for R 7 , and methyl for R 10 .
  • Suitable "lower alkenyl” may include vinyl, allyl, and the like, in which more preferable example may be C 2 -C 4 alkenyl, and the most preferable one may be allyl.
  • Suitable "aryl” may include phenyl, tolyl, xylyl, cumenyl, mesithyl, naphthyl and the like, in which more preferable example may be phenyl,
  • aryl is optionally substituted by one or more, preferably one to three suitable substituent(s) such as:
  • halogen e.g. chlorine, fluorine, etc.
  • substituted aryl thus defined may be phenyl, which is substituted by one to three suitabl substituent(s) selected from a group consisting of halogen, hydroxy, C 1 -C 4 alkyl, phenoxy, trihalo(C 1 -C 4 )alkyl and C 1 -C 4 alkoxy, and the more preferable may be :
  • halophenyl e.g. 4-fluorophenyl, 2,4(or 3,4)-di- fluorophenyl, 2 (or 3)-chloro-4-fluorophenyl, etc.
  • R 1 and/or R 2 e.g. 4-fluorophenyl, 2,4(or 3,4)-di- fluorophenyl, 2 (or 3)-chloro-4-fluorophenyl, etc.
  • Suitable “protected carboxy” may include esterified carboxy and amidated carboxy, wherein “esterified carboxy” and “amidated carboxy” can be referred to the ones as mentioned below.
  • ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g.
  • methyl ester ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.
  • suitable substituent(s) for example, lower alkanoyloxy( lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,
  • 2-mesylethyl ester, etc. mono(or di or tri)halo(lower)- alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester
  • alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester e.g.
  • lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc.
  • ar( lower)alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl)methyl ester,
  • aryl ester which may have at least one
  • suitable substituent( s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • phthalidyl ester e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • esterified carboxy thus defined may be C 1 -C 4 alkoxycarbonyl, and (triphenyl) (hydroxy) (C 1 -C 4 )alkoxycarbonyl and the most preferable one may be methoxycarbonyl for R 3 and/or R 4 .
  • amidated carboxy may include
  • Suitable "halogen” may include chlorine, bromine, iodine and fluorine, in which more preferable example may be chlorine and fluoride.
  • Suitable "trihalo(lower) alkyl” may include straight or branched one such as trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, and the like, in which more preferable example may be trihalo(C 1 -C 4 )alkyl.
  • Suitable "lower alkoxy" may include straight or
  • branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy and the like, in which more preferable example may be C 1 -C 4 alkoxy.
  • Suitable "cyclo( lower) alkyl” may include
  • cyclic(C 3 -C 8 ) alkyl such as cyclopropyl, cyclobutyl,
  • cyclopentyl cyclohexyl, cycloheptyl, cyclooctyl, and the like, in which more preferable example may be
  • cyclo(C 3 -C 7 ) alkyl and the most preferable example may be cyclopropyl.
  • Suitable "cyclo(lower)alkyl(lower)alkyl” means lower alkyl as mentioned above, which is substituted by
  • cyclo(lower) alkyl in which more preferable example may be cyclo(C 3 -C 7 ) alkyl(C 1 -C 4 ) alkyl.
  • Suitable "ar(lower)alkyl” means afore-mentioned lower alkyl, which is substituted by aryl as mentioned above, wherein more preferable example may be phenyl(C 1 -C 4 ) alkyl.
  • N-[ar(lower)alkyl]carboxamido" and "ar(lower)alkylamine” may be afore-mentioned ar (lower)alkyl such as phenylmethyl, phenylethyl, phenylpropyl, 1-methyl-2-phenylethyl,
  • phenylbutyl phenylpentyl, phenylhexyl, and the like, in which more preferable example may be phenyl(C 1 -C 4 ) alkyl and the most preferable one may be 1-phenylethyl.
  • Suitable "lower alkylthio” may include straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, pentylthio,
  • hexylthio and the like, in which more preferable example may be C 1 -C 4 alkylthio and the most preferable one may be methylthio for R 3 and/or R 4 .
  • Suitable "arylthio” may include phenylthio, tolylthio, xylylthio, cumenylthio, mesithylthio, naphthylthio and the like, in which more preferable example may be phenylthio, wherein said arylthio is optionally substituted by one or more, preferably one to three suitable substituent(s) such as:
  • halogen e.g. chlorine, fluorine, etc.
  • - lower alkyl as mentioned above (e.g. methyl, t-butyl, etc.);
  • substituted arylthio thus defined may be phenylthio, which is substituted by one to three suitable substituent(s) selected from a group
  • preferable may be : - di(lower) alkyl-hydroxy-phenyl (e.g.
  • acyl may include carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl
  • the aliphatic acyl may include saturated or
  • alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl
  • alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl,
  • N-alkylcarbamoyl e.g. methylcarbamoyl, ethylcarbamoyl, etc.
  • alkoxycarbonyl such as lower alkoxycarbonyl
  • alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.),
  • cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl,
  • acyl may be lower alkanoyl and the most preferable one may be formyl.
  • N-containing heterocyclic group in the term of "N-containing heterocyclic group which may have suitable substituent(s)" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom and optionally other hetero-atom(s) such as an oxygen, sulfur, nitrogen atom and the like.
  • N-containing heterocyclic group such as :
  • indolyl isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.;
  • heterocyclic group is optionally
  • N-containing heterocyclic group which has suitable substituent( s) thus defined may be 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) such as dihydropyridyl substituted by one to four suitable substituent( s) selected from the group consisting of C 1 -C 4 alkoxycarbonyl and C 1 -C 4 alkyl, and the most
  • one may be 3,5-dimethyl-2,6-bis (methoxycarbonyl)- 1,4-dihydropyridin-4-yl.
  • Suitable "hydroxy-protective group” means a conventional hydroxy-protective group such as acyl as mentioned above; ar (lower) alkyl such as mono- or di- or triphenyK lower) alkyl (e.g. benzyl, benzhydryl, trityl, etc.), etc.;
  • trisubstituted silyl such as tri(lower)alkylsilyl (e.g., tri(lower)alkylsilyl (e.g., tri(lower)alkylsilyl (e.g., tri(lower)alkylsilyl (e.g., tri(lower)alkylsilyl (e.g., tri(lower)alkylsilyl (e.g.
  • triarylsilyl e.g. triphenylsilyl, etc.
  • triar (lower)alkylsilyl e.g. tribenzylsilyl, etc.
  • R 1 is lower alkyl (e.g. methyl, ethyl, isopropyl,
  • phenyl e.g. 4-fluoprophenyl, etc.
  • C 3 -C 7 cycloalkyl e.g. cyclopropyl, etc.
  • R 2 is lower alkyl (e.g. isopropyl, etc.), phenyl or
  • halophenyl e.g. 4-fluorophenyl, 2,4 (or
  • R 3 is hydrogen, halogen (e.g. chlorine, etc.),
  • R 4 is hydrogen, halogen (e.g. chlorine, bromine, etc.) , lower alkyl (e.g. methyl, ethyl, isopropyl, t-butyl, etc.), C 2 -C 6 alkenyl (e.g. allyl, etc.), lower alkylthio (e.g. methylthio, etc.), phenyl, lower alkoxycarbonyl, lower alkanoyl, phenylthio substituted by the group consisting of hydroxy and lower alkyl (e.g.
  • N-containing unsaturated 5 or 6-membered heteromonocyclic group which is unsubstituted or substituted by the group consisting of lower alkyl and lower alkoxycarbonyl (e.g. 3 , 5-bismethoxy- carbonyl-2,6-dimethyll,4-dihydropyridinyl, etc.); Y is as defined above;
  • R 5 is carboxy or lower alkoxycarbonyl (e.g. methoxycarbonyl, etc.), and
  • R 8 is hydrogen.
  • the compound (I-a) or salts thereof can be prepared by reducing the compound (II) or salts thereof.
  • Suitable salts of the compounds (I-a) and (II) may be the same as those for the compound (I).
  • the reduction method applicable for this removal reaction is a conventional one which is capable of reducing a ketone group to a hydroxy group and may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a chrome compound (e.g.
  • a metal e.g. zinc, zinc amalgam, etc.
  • a chrome compound e.g.
  • chromous chloride chromous acetate, etc.
  • organic or inorganic acid e.g. acetic acid, propionic acid,
  • a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g.
  • platinum plate spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • sodium borohydride a combination of tri (lower) alkylborane and sodium borohydride, diisobutylaluminum hydride, and the like, in which more preferable method is a combination of tri( lower)alkylborane and sodium borohydride.
  • This reaction is preferably carried out in the presence of a suitable cheating agent, which is capable of
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), benzene, toluene, xylene, and the like, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction
  • water e.g. methanol, ethanol, propanol, etc.
  • dioxane etrahydrofuran
  • acetic acid e.g. phosphate buffer, acetate buffer, etc.
  • buffer solution e.g. phosphate buffer, acetate buffer, etc.
  • benzene toluene
  • xylene xylene, and the like, or a mixture thereof.
  • the compound (I-c) or salts thereof can be prepared by subjecting the compound (I-b) or salts thereof to removal reaction of the caboxy-protective group on
  • Suitable salts of the compound (I-c) may be the same as those for the compound (I).
  • Suitable salts of the compound (I-b) may be salts with acids such as those given for the compound (I).
  • the present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
  • Suitable base may include an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g.
  • an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • an alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
  • alkaline earth metal hydride e.g. calcium hydride,
  • sodium carbonate, potassium carbonate, etc. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
  • an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.).
  • organic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g. phenol, anisole, etc.).
  • cation trapping agent e.g. phenol, anisole, etc.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof.
  • a liquid base or acid can be also used as the solvent.
  • reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
  • the reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g.
  • catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction
  • alcohol e.g. methanol, ethanol, propanol, etc.
  • dioxane etrahydrofuran
  • acetic acid e.g. phosphate buffer, acetate buffer, etc.
  • buffer solution e.g phosphate buffer, acetate buffer, etc.
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the carboxy-protective group is allyl group, it can be deprotected by hydrogenolysis using a palladium compound.
  • Suitable palladium compound used in this reaction may be palladium on carbon, palladium hydroxide on carbon, palladium chloride, a palladium-ligand complex such as tetrakis (triphenylphosphine)palladium(0),
  • reaction can preferably be carried out in the presence of a scavenger of allyl group generated in situ, such as amine (e.g. morpholine,
  • N-methylaniline, etc. an activated methylene compound (e.g. dimedone, benzoylacetate, 2-methyl-3-oxovaleric acid, etc.), a cyanohydrin compound (e.g.
  • lower alkanoic acid or a salt thereof e.g. formic acid, acetic acid, ammonium formate, sodium acetate, etc.
  • alkylamine e.g. butylamine, triethyamine, etc.
  • pyridine e.g. pyridine
  • the reaction can preferably be carried out in the presence of the corresponding ligand (e.g. triphenylphosphine, triphenyl phosphite, triethyl phosphite, etc.).
  • the corresponding ligand e.g. triphenylphosphine, triphenyl phosphite, triethyl phosphite, etc.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane,
  • the removal reaction can be selected according to a kind of the carboxy-protective group to be eliminated.
  • the compound (I-d) or salts thereof can be prepared by cyclizing the compound (I-c) or salts thereof.
  • Suitable salts of the compound (I-d) may be the same as those for the compound (I-b).
  • This reaction is usually carried out by a conventional method such as heating, or by a reaction in the presence of a condensing agent, and the like.
  • Preferable condensing agent may be a conventional one such as carbodiimide compound or a salt thereof [e.g.
  • oxalyl chloride a combination of triphenylphosphine with carbon tetrachloride or diazenedicarboxylate;
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, methanol, ethanol, propanol,
  • reaction temperature of this reaction is not
  • reaction is usually carried out under from cooling to heating.
  • the compound (I-f) or salts thereof can be prepared by reacting the compound (I-e) or salt thereof with
  • Suitable salts of the compounds (I-e) and (I-f) may be the same as those for the compound (I-b).
  • Suitable salts of ar (lower)alkylamine may be the same as those for the compound (I-b).
  • This reaction is usually carried out by heating the compound (I-e) and ar ( lower) alkylamine in or without a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, benzene, toluene, xylene, and the like, or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
  • diastereomer of the object compound (I-f) can be separated by a conventional method such as extraction, precipitation, fractional crystallization, recrystallization,
  • the compound (I-c) or salts thereof can be prepared by subjecting the compound (I-f) or salts thereof to hydrolysis of N-[ar(lower) alkyl]carboxamido of
  • the compound (I-h) or salts thereof can be prepared by reducing the compound (I-g) or salts thereof.
  • Suitable salts of the compounds (I-g) and (I-h) may be the same as those for the compound (I).
  • the method of reduction and the reaction conditions are substantially the same as those illustrated for the removal reaction of the carboxy-protective group of the compound (I-b) in
  • the compound (I-i) or salts thereof can be prepared by introducing a hydroxy-protective group into the compound (I-d) or salts thereof.
  • Suitable salts of the compound (I-i) may be the same as those for the compound (I).
  • Suitable introducing agent of the hydroxy-protective group used in this reaction may be a conventional agent which is capable of introducing aforementioned
  • hydroxy-protective group such as a trisubstituted silyl group as mentioned in the above explanation of
  • hydroxy-protective group for example, trisubstituted silyl halide (e.g. trisubstituted silyl chloride, etc.), and the like.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium,
  • potassium, etc. an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]- non-5-ene, 1,4-diazabicyclo[2.2.2]octane,
  • alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1,5-diazabicyclo[4.3.0]- non-5-ene
  • 1,4-diazabicyclo[2.2.2]octane 1,4-diazabicyclo[2.2.2]octane
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.],
  • reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction temperature is not critical and the
  • reaction is usually carried out under from cooling to
  • the compound (I-k) or salts thereof can be prepared by reacting the compound (I-j) or salts thereof with Vilsmeier reagent.
  • Suitable salts of the compounds (I-j) and (I-k) may be the same as those for the compound (I).
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as acetone, dioxane, dimethylformamide, dichloromethane, pyridine, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as acetone, dioxane, dimethylformamide, dichloromethane, pyridine, etc., or a mixture thereof.
  • the reaction temperature is not critical and the
  • reaction is usually carried out under from cooling to warming.
  • the compound (I-c) or salts thereof can be prepared by hydrolyzing the compound (I-d) or salts thereof.
  • the method of hydrolysis and the reaction conditions are substantially the same as those illustrated for removal reaction of the carboxy-protective group of the compound (I-b) in Process 2, and therefore are to be referred to said explanation.
  • the compound (I-d) or salts thereof can be prepared by subjecting the compound (I-i) or salts thereof to a removal reaction of the hydroxy-protective group.
  • This reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like.
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • tetra( lower)alkylammonium fluoride e.g. tetrabutylaramonium fluoride, etc.
  • the object compound (I) obtained according to these Processes can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like, and also they can be converted into its suitable salt by a conventional manner.
  • the compound (IV) or salts thereof can be prepared by reducing the compound (III) or salts thereof.
  • Suitable salts of the compounds (III) and (IV) may be the same as those for the compound (I-b).
  • reaction temperature e.g. reaction temperature, solvent, etc.
  • solvent e.g. solvent, etc.
  • the compound (V) or salts thereof can be prepared by oxidizing the compound (IV) or salts thereof. Suitable salts of the compound (V) may be the same as those for the compound (I-b).
  • Suitable oxidizing agent used in this reaction may be a conventional one which is capable of converting a
  • chromic compound e.g. chromium trioxide, chromic acid, sodium chromate, dichromic acid, sodium dichromate, pyridinium dichromate (optionally in the
  • haloperbenzoic acid e.g. m-chloroperbenzoic acid, etc.
  • reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dioxane, dimethylformamide,
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (VII) or salts thereof can be prepared by reacting the compound (V) with the compound (VI) (First Step), and then subjecting the resulting compound to a hydrolysis (Second Step).
  • Suitable salts of the compound (VII) may be the same as those for the compound (I-b).
  • This reaction can be carried out in the presence of phosphorus oxyhalide.
  • Preferable phosphorus oxyhalide used in this Step may be phosphorus oxychloride, etc.
  • This reaction can be carried out in the presence of a base such as an alkali metal hydroxide (e.g. sodium bicarbonate), sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sulfonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bi
  • hydroxide potassium hydroxide, etc.
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium
  • alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
  • alkaline earth metal hydride e.g. calcium hydride, etc.
  • alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g.
  • magnesium carbonate, calcium carbonate, etc. an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate etc.), lower alkyllithium (e.g. n-butyllithium, etc.), alkali metal di( lower) alkylamide (e.g. lithium
  • diisopropylamide, etc. prepared from a reaction of alkali metal (e.g. lithium, etc.) with lower alkyllithium as mentioned above, etc.
  • alkali metal e.g. lithium, etc.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, acetonitrile, pyridine,
  • the reaction temperature is not critical and the
  • reaction is usually carried out under from cooling to
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the compound (II) or salts thereof can be prepared by reacting the compound (VII) or salts thereof with the compound (VIII) or salts thereof.
  • This reaction can be carried out in the presence of a base such as an alkali metal hydroxide (e.g. sodium bicarbonate), sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sulfonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bi
  • hydroxide potassium hydroxide, etc.
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium
  • alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
  • alkaline earth metal hydride e.g. calcium hydride, etc.
  • alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g.
  • magnesium carbonate calcium carbonate, etc.
  • an alkali metal bicarbonate e.g. sodium bicarbonate, potassium
  • lower alkyllithium e.g. n-butyllithium, etc.
  • a combination of di (lower)alkylamine e.g.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as diethyl ether, pyridine, N,N-dimethylformamide,
  • the reaction temperature is not critical and the
  • reaction is usually carried out under from cooling to
  • the compound (IX) or salts thereof can be prepared by reacting the compound (VII) or salts thereof with the compound (XII).
  • Suitable salts of the compound (IX) may be the same as those for the compound (I-b).
  • This reaction can be carried out in the presence of a suitable base such as those mentioned in the explanation of Method D, in which more preferable base may be a combination of di (lower)alkylamine and lower alkyllithium.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as diethyl ether, pyridine, N,N-dimethylformamide,
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the compound (X) or salts thereof can be prepared by subjecting the compound (IX) or salts thereof to an
  • Suitable salts of the compound (X) may be the same as those for the compound (I-b).
  • the method of alcoholysis may be substantially the same as hydrolysis of Process 2 except that the solvent used in this Method is an alcohol. Accordingly, the base or acid and the reaction temperature therein are the same as those illustrated for Process 2, and therefore are to be referred to said explanation.
  • Suitable alcohol used in this reaction may be lower alkanol such as methanol, ethanol, propanol, butanol, etc.
  • the compound (II) or salts thereof can be prepared by reacting the compound (X) or salts thereof with the compound (XI).
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • the object compound (I) and pharmaceutically acceptable salts thereof of the present invention are potent inhibitors of the enzyme HMG-CoA reductase and are capable of
  • the object compound (I) possessing more potent activity can be represented by the following formula:
  • R 1 , R 2 , R 3 , R 4 , and Y are each as defined above, and
  • Z a is a group of the formula:
  • Test 1 [Assay for rat liver 3-Hydroxy-3- methylglutaryl-Coenzyme A Reductase Activity (in vitro)] Test Method 1 :
  • EDTA ethylenediaminetetraacetic acid
  • 10 mM dithiothreitol with or without the graded concentrations of the test compound.
  • the reaction is started by addition of 10 ⁇ l of 25 mM ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH).
  • NADPH reduced form
  • the mixture is incubated at 37°C for 20 minutes.
  • the reaction is terminated by addition of 10 ⁇ l of 2N hydrochloric acid.
  • a 20 ⁇ l aliquot of the mixture is applied to a Silica Gel 60 F-254 plate (made by Merck & Co., Inc.).
  • the chromatograms are developed in benzene/acetone (1:1). Sections of the thin layer plates where the mevalonolactone is located are scraped and the radioactivity are counted.
  • the object compound (I) and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like. If needed, there may be included in the above
  • auxiliary substances such as lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
  • the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between about 0.1 mg and about 1000 mg or even more, preferably between about 1 mg and about 200 mg per day may be administered to a patient.
  • An average single dose of about 0.1 mg, 1 mg, 10 mg, 20 mg, 30 mg, 50 mg, 100 mg, 200 mg, 250 mg of the object compound (I) of the present invention may be used in treating hypercholesterolaemic and hyperlipoproteinaemic states and associated conditions.
  • diisopropylamide prepared from diisopropylamine (314 mg) and 1.6M n-butyl lithium in hexane (1.94 ml)] in
  • IR (Film) 3400, 2960, 1745, 1710, 1640, 1600,
  • IR (Film) 3400, 2980, 1740, 1710, 1640, 1605, 1550,
  • IR (Film) 3420, 2960, 1745, 1710, 1640, 1605, 1545,
  • Tris (triphenylphosphine)ruthenium(II) chloride (159 mg) was added to a mixture of N-methylmorpholine N-oxide (971 mg) and dry acetone (20 ml) at 20°C under nitrogen. After being stirred at the same temperature for 20 minutes, a solution of 4-(4-fluorophenyl)-2-isopropyl-3-hydroxymethyl- 7-methyl-5-phenylpyrrolo[1,2-b]pyridazine (776 mg) in dry acetone (10 ml) was added dropwise at 15°C over a period of 8 minutes under nitrogen. The reaction mixture was stirred at room temperature for 16 hours and filtered through a thick silica gel pad.
  • the pad was washed with diisopropyl ether (60 ml). The filtrate and washing were combined, washed in turn with 3N hydrochloric acid (40 ml), water (40 ml), saturated aqueous sodium bicarbonate solution (50 ml) and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to a column
  • IR (Film) 3450, 2940, 1745, 1715, 1510, 1250,
  • the mixture was stirred for 20 minutes at -78°C and then 10% aqueous citric acid was added to the mixture below 10°C.
  • the mixture was extracted with ethyl acetate, and the extract was washed with brine, dried and evaporated. The residue was
  • IR (Film) 3400, 2960, 1745, 1720, 1640, 1605, 1550,
  • the diastereomeric excess (d.e.) of the desired (3S)- isomer of the product was 91% according to HPLC analysis.
  • tert-Butyl acetate (67 ml) was added dropwise at -70°C under nitrogen to a solution of lithium diisopropylamide (LDA) that was prepared from a solution of diisopropylamine (77 ml) in dry THF (340 ml) and a 1.6M solution of n-butyllithium in hexane (341 ml).
  • LDA lithium diisopropylamide
  • IR (Film) 3450, 2980, 1740, 1720, 1635, 1605,
  • N-Bromosuccinimide (2.29 g) was added to an ice-cooled solution of ethyl 2-(4-fluorophenyl)-4-isopropylpyrrolo-
  • Acetic anhydride (0.94 ml) was added to an ice-cooled solution of 2-(4-fluorophenyl)-3-hydroxymethyl-4- isopropylpyrrolo[1,2-b]pyridazine (1.42 g) in dry pyridine (15 ml). The mixture was kept stirring overnight at room temperature and then diluted with ethyl acetate. The solution was washed with diluted aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The
  • IR (Film) 3430, 2960, 1740, 1720, 1640, 1600,

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Abstract

Un composé de pyrrolopyridazine correspondant à la formule (I), dans laquelle R1 et R2 sont chacun alkyle inférieur, cycloalkyle(inférieur), cycloalkyle(inférieur)-alkyle(inférieur), aryle ou aryle substitué; R3 et R4 sont chacun hydrogène, alkyle inférieur, alcényle inférieur, alkylthio inférieur, halogène, aryle, aryle substitué, arylthio, arylthio substitué, aralkyle(inférieur), carboxy, carboxy protégé, acyle ou un groupe hétérocyclique à teneur en N pouvant posséder un/des substituant(s) approprié(s); Y est vinylène ou éthylène; et Z est un groupe correspondant à la formule (a) ou (b), dans laquelle R5 est carboxy ou carboxy protégé, et R8 est hydrogène ou un groupe protecteur d'hydroxy; ou ses sels pharmaceutiquement acceptables, est utile en tant qu'inhibiteur de la HMG-CoA réductase.
PCT/JP1991/000678 1990-05-25 1991-05-22 Composes de pyrrolopyridazine WO1991018903A1 (fr)

Applications Claiming Priority (4)

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GB909011837A GB9011837D0 (en) 1990-05-25 1990-05-25 Pyrrolopyridazine compounds
GB9011837.3 1990-05-25
GB909019173A GB9019173D0 (en) 1990-09-03 1990-09-03 Pyrrolopyridazine compounds
GB9019173.5 1990-09-03

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1085021A1 (fr) * 1998-05-21 2001-03-21 Shionogi & Co., Ltd. DERIVES DE LA PYRROLO 1,2-B] PYRIDAZINE, A EFFET INHIBITEUR SUR LE sPLA 2?
WO2004063197A1 (fr) * 2003-01-09 2004-07-29 Fujisawa Pharmaceutical Co., Ltd. Derives de pyrrolopyridazine
WO2004099213A2 (fr) * 2003-05-07 2004-11-18 Pharmacia & Upjohn Company Llc Composes pyrrolo[1,2-b]pyridaziniques
CN100349895C (zh) * 2003-01-09 2007-11-21 安斯泰来制药有限公司 吡咯并哒嗪衍生物
AU2003294183B2 (en) * 2003-01-09 2009-06-18 Astellas Pharma Inc. Pyrrolopyridazine derivatives
US7772366B2 (en) 1994-06-17 2010-08-10 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US7790713B2 (en) 1995-12-20 2010-09-07 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
CN109232575A (zh) * 2017-07-10 2019-01-18 中国科学院上海药物研究所 吡咯[1,2-b]哒嗪类化合物或其可药用盐及它们的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0319330A2 (fr) * 1987-12-03 1989-06-07 May & Baker Limited Pyrrolophtalazines
EP0354418A2 (fr) * 1988-08-06 1990-02-14 Hoechst Aktiengesellschaft Acides 6-fluoro-3,5-dihydroxycarboxyliques et leurs dérivés, procédés pour leur préparation, leur utilisation comme médicaments, préparations pharmaceutiques et composés intermédiaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0319330A2 (fr) * 1987-12-03 1989-06-07 May & Baker Limited Pyrrolophtalazines
EP0354418A2 (fr) * 1988-08-06 1990-02-14 Hoechst Aktiengesellschaft Acides 6-fluoro-3,5-dihydroxycarboxyliques et leurs dérivés, procédés pour leur préparation, leur utilisation comme médicaments, préparations pharmaceutiques et composés intermédiaires

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7772366B2 (en) 1994-06-17 2010-08-10 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US8119631B2 (en) 1995-12-20 2012-02-21 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US7790713B2 (en) 1995-12-20 2010-09-07 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
EP1085021A4 (fr) * 1998-05-21 2003-01-08 Shionogi & Co DERIVES DE LA PYRROLO 1,2-B] PYRIDAZINE, A EFFET INHIBITEUR SUR LE sPLA 2?
EP1085021A1 (fr) * 1998-05-21 2001-03-21 Shionogi & Co., Ltd. DERIVES DE LA PYRROLO 1,2-B] PYRIDAZINE, A EFFET INHIBITEUR SUR LE sPLA 2?
KR101026819B1 (ko) 2003-01-09 2011-04-04 아스테라스 세이야쿠 가부시키가이샤 피롤로피리다진 유도체
US7153854B2 (en) 2003-01-09 2006-12-26 Astellas Pharma Inc. Pyrrolopyridazine derivatives
CN100349895C (zh) * 2003-01-09 2007-11-21 安斯泰来制药有限公司 吡咯并哒嗪衍生物
US7317009B2 (en) 2003-01-09 2008-01-08 Astellas Pharma Inc. Pyrrolopyridazine derivatives
AU2003294183B2 (en) * 2003-01-09 2009-06-18 Astellas Pharma Inc. Pyrrolopyridazine derivatives
JP2006515597A (ja) * 2003-01-09 2006-06-01 アステラス製薬株式会社 ピロロピリダジン誘導体
JP4671104B2 (ja) * 2003-01-09 2011-04-13 アステラス製薬株式会社 ピロロピリダジン誘導体
WO2004063197A1 (fr) * 2003-01-09 2004-07-29 Fujisawa Pharmaceutical Co., Ltd. Derives de pyrrolopyridazine
WO2004099213A3 (fr) * 2003-05-07 2005-04-28 Pharmacia & Upjohn Co Llc Composes pyrrolo[1,2-b]pyridaziniques
WO2004099213A2 (fr) * 2003-05-07 2004-11-18 Pharmacia & Upjohn Company Llc Composes pyrrolo[1,2-b]pyridaziniques
CN109232575A (zh) * 2017-07-10 2019-01-18 中国科学院上海药物研究所 吡咯[1,2-b]哒嗪类化合物或其可药用盐及它们的用途
CN109232575B (zh) * 2017-07-10 2022-01-25 中国科学院上海药物研究所 吡咯[1,2-b]哒嗪类化合物或其可药用盐及它们的用途

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JPH06501918A (ja) 1994-03-03
AU7891891A (en) 1991-12-31

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