WO1993005035A1 - Derives de quinazoline et leur preparation - Google Patents

Derives de quinazoline et leur preparation Download PDF

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Publication number
WO1993005035A1
WO1993005035A1 PCT/JP1992/001117 JP9201117W WO9305035A1 WO 1993005035 A1 WO1993005035 A1 WO 1993005035A1 JP 9201117 W JP9201117 W JP 9201117W WO 9305035 A1 WO9305035 A1 WO 9305035A1
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Prior art keywords
compound
salts
alkyl
formula
hydroxy
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PCT/JP1992/001117
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English (en)
Inventor
Norihiko Shimazaki
Yoshikuni Itoh
Takumi Yatabe
Hitoshi Yamazaki
Masashi Hashimoto
Hirokazu Tanaka
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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.)
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Priority claimed from US07/755,747 external-priority patent/US5296487A/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to EP92918711A priority Critical patent/EP0602125A1/fr
Priority to JP5505101A priority patent/JPH06510538A/ja
Priority to CA002117075A priority patent/CA2117075A1/fr
Publication of WO1993005035A1 publication Critical patent/WO1993005035A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present invention relates to novel quinazoline derivatives and pharmaceutically acceptable salts thereof.
  • novel quinazoline derivatives and pharmaceutically acceptable salts thereof which display effects on the peripheral or central nervous system, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, to a use of the same as a medicament and to a method of the
  • one object of the present invention is to provide novel quinazoline derivatives and
  • Another object of the present invention is to provide processes for the preparation of novel quinazoline
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said quinazoline derivatives and pharmaceutically acceptable salts thereof.
  • Still further object of the present invention is to provide a use of said quinazoline derivatives and
  • salts thereof as a dopamine receptor agonist, 5-HT receptor antagonist, especially 5-HT 2 receptor antagonist; ⁇ 1 receptor antagonist; and the like and a method of the therapeutic treatment of dopamine receptor; 5-HT receptor, especially 5-HT 2 receptor;
  • ⁇ 1 -receptor mediated diseases, particularly hypertension, cardiovascular disorder (e.g. angina pectoris, myocardial infarction, etc.), Parkinsonism, and the like, in a human being or animal.
  • cardiovascular disorder e.g. angina pectoris, myocardial infarction, etc.
  • Parkinsonism e.g. Alzheimer's disease, Parkinsonism, and the like, in a human being or animal.
  • R 1 is substituted heterocyclic-(lower)alkyl
  • R 2 is hydrogen, halogen, nitro, amino
  • R 3 is aryl which may have suitable
  • A is lower alkylene
  • a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt,
  • a base salt such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt,
  • an organic base salt for example, an organic amine salt (e.g. triethylamine salt, pyridine salt
  • dicyclohexylamine salt N,N'-dibenzylethylenediamine salt, etc.
  • a salt with an acid such as inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate,
  • an organic acid addition salt e.g.
  • a salt with a basic or acidic amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • a basic or acidic amino acid e.g. arginine, 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. wherein R 1 , R 2 , R 3 and A are each as defined above, is nitro,
  • w is hydroxyamino or amino
  • R 4 is esterified carboxy
  • X is a leaving group
  • the compounds (II) and (IV) used in the Processes 1 and 4 are new and can be prepared, for example, by the following methods or a conventional manner.
  • R 1 , R 2 , R 3 , R 4 and A are each as defined above.
  • lower is intended to mean 1 to 6 carbon atom(s), preferably 1 to 4 carbon atom(s), unless
  • Suitable “lower alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
  • Suitable "lower alkoxy” may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, trbutoxy, pentyloxy, hexyloxy, and the like.
  • substituent(s) may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like, each of which may be substituted by one or more, preferably one or two
  • substituent(s) such as halogen (e.g. fluorine, chlorine, bromine, iodine), lower alkyl as mentioned above (e.g.
  • halogen and lower alkyl unsubstituted by a group consisting of halogen and lower alkyl, and the most preferred one may be phenyl.
  • Suitable “protected carboxy” may include carbamoyl, esterified carboxy wherein “esterified carboxy” can be referred to the ones as mentioned below, and the like.
  • 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.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy( lower) alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester,
  • 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
  • alkanesulfonyl (lower)alkyl ester e.g. 2-mesylethyl ester, etc.
  • mono(or di or tri)halo(lower) alkyl ester e.g.
  • alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester e.g.
  • lower alkenyl ester e.g. vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g. ethynyl ester, propynyl ester. etc.
  • ar(lower)alkyl ester e.g. mono- or di- or
  • triphenyl(lower)alkyl ester which may have at least one suitable substituent(s) (e.g. lower alkoxy, nitro, hydroxy, lower alkyl, etc.), for example, mono- or di- or triphenyl(lower)alkyl ester which may have (lower)alkoxy [e.g. benzyl ester, benzhydryl ester, trityl ester, phenethyl ester, 4-methoxybenzyl ester,
  • 3,4-dimethoxybenzyl ester bis(methoxyphenyl)methyl ester, etc.], nitrophenyl(lower)alkyl ester (e.g. 4-nitrobenzyl ester, etc.), [hydroxy]-(lower)alkylphenyl(lower)alkyl ester (e.g. 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); 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.
  • 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.
  • protected carboxy thus defined may be carbamoyl and lower alkoxycarbonyl.
  • Suitable "protected amino” may include amino
  • Suitable “amino-protective group” may include acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or
  • heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids is derived from carboxylic, carbonic, sulfonic and carbamic acids.
  • the aliphatic acyl may include saturated or
  • alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
  • alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl
  • alkylsulfonyl such as lower alkylsulfonyl
  • N-alkylcarbamoyl e.g. methylcarbamoyl, ethylcarbamoyl, etc.
  • alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarb ⁇ nyl, propoxycarbonyl,
  • 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, cyclohexanecarbonyl, etc.
  • cyclo( lower)alkanecarbonyl e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.
  • the aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as
  • phenyl(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • phenyl(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.
  • acyl groups may be further substituted with one or more suitable substitueht(s) such as nitro, halogen as mentioned below, and the like, and preferable acyl having such substituent(s) may be nitroaralkoxycarbonyl (e.g.
  • nitrobenzyloxycarbonyl, etc. trihalo(lower)alkyl (e.g. trifluoroacetyl, etc.), and the like.
  • amino-protective group thus defined may be :
  • trihalo(lower)alkanoyl such as trifluoro(lower)- alkanoyl (e.g. trifluoroacetyl, etc.);
  • N-(lower)alkylcarbamoyl e.g. N-ethylcarbamoyl, etc.
  • hydroxy-protective group means a hydroxy group protected by a conventional hydroxy-protective group
  • suitable "hydroxy-protective group” may include lower alkyl as defined above, acyl as defined above, ar( lower)alkyl such as mono-, di- or triphenyl(lower)alkyl (e.g. trityl, etc.), preferably lower alkyl and triphenyl(lower)alkyl.
  • substituted heterocyclic-(lower)alkyl and "substituted heterocyclic-(lower)alkyl” may include 3 to 10, preferably 5 or 6-membered heterocyclic group, preferably
  • heteromonocyclic group containing at least one hetero atom such as oxygen atom, nitrogen atom and sulfur atom (e.g. morpholino, etc.), and the like.
  • heterocyclic group means
  • heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. More preferable heterocyclic group may be
  • heterocyclic group such as :
  • pyrimidyl pyrazinyl
  • pyridazinyl triazolyl (e.g.,
  • tetrazolopyridyl tetrazolopyridazinyl
  • oxazolyl isoxazolyl, oxadiazolyl, (e.g.,
  • heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; wherein said heterocyclic group may be substituted by one or more, preferably one or, two suitable substituent(s) such as lower alkyl as mentioned above, lower alkoxy as mentioned above, in which more preferable example may be saturated 5 or 6-membered heteromonocyclic group
  • (lower)alkyl can be referred to the ones as mentioned above.
  • heterocyclic-(lower)alkyl thus defined may be lower alkylpiperazinyl(lower)alkyl and morpholinyl(lower)alkyl, and the most preferable one may be
  • heterocyclic-carbonyl thus defined may be lower alkylpiperazinylcarbonyl and
  • Suitable "halogen” may be fluorine, chlorine,
  • bromine, iodine, and more preferred example may be
  • Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
  • Suitable “leaving group” may include imidazole, lower alkylimidazole (e.g. 2-methylimidazole, etc.), an acid residue such as halogen as mentioned above (e.g. chlorine, etc.), and the like.
  • Suitable "lower alkylthio” may include straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, pentylthio,
  • Suitable "esterified carboxy” means the same ones as mentioned in the explanation of protected carboxy, in which more preferable example may be lower alkoxycarbonyl.
  • Suitable "hydroxy(lower)alkyl” may include
  • hydroxy-protective group as mentioned in the explanation of "protected hydroxy", in which more preferable example may be lower alkoxy(lower)alkyl and
  • the compound (I) or salts thereof can be prepared by reacting the compound (II) or salts thereof with the compound (III).
  • Suitable salts of the compound (II) may be acid addition salts such as those given for the compound (I).
  • Suitable example of the compound (III) may include N,N'-carbonyldiimidazole, N,N'-carbonylbis (2-methylimidazole), phosgene or its reactive equivalent (e.g.
  • This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
  • the reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
  • the compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to reduction of nitro group of
  • Suitable salts of the compounds (I-a) and (I-b) may be the same as those for the compound (I).
  • the present reaction is usually carried out by a conventional method as mentioned below.
  • the reduction method applicable for this reaction may include conventional ones which are capable of converting a nitro group to a hydroxyamino or amino group, for example, reduction using tin(II) chloride or zinc powder; reduction using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid,
  • a metal e.g. zinc, zinc amalgam, etc.
  • chrome compound e.g. chromous chloride, chromous acetate, etc.
  • organic or inorganic acid e.g. acetic acid, propionic acid
  • hydrochloric acid, sulfuric acid, etc. conventional catalytic reduction in the presence of 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.); reduction using aluminum amalgam, electrolytic reduction; and the like.
  • 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 (
  • the reaction is preferably carried out around neutral
  • This reaction is usually carried out in a
  • the reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
  • the compound (I-d) or salts thereof can be prepared by introducing an amino-protective group into the compound (I-c) or salts thereof. Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I).
  • Suitable introducing agent of the amino-protective group used in this reaction may be a conventional one which is capable of introducing the amino-protective group such as acyl as mentioned before, for example, lower alkyl isocyanate (e.g. ethyl isocyanate, etc.);
  • alkali metal cyanate e.g. potassium cyanate, etc.
  • lower alkyl halo(lower)alkanate e.g. ethyl chloroformate, etc.
  • carboxylic acid, carbonic acid, sulfonic acid and their reactive derivative e.g. an acid halide, an acid anhydride, an activated amide, an activated ester, etc.
  • reactive derivative e.g. an acid halide, an acid anhydride, an activated amide, an activated ester, etc.
  • lower alkanoic acid halide e.g. acetyl chloride, etc.
  • lower alkanesulfonyl halide e.g. mesyl chloride, ethanesulfonyl chloride, etc.
  • a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,
  • halogenated phosphoric acid etc.
  • dialkylphosphorous acid sulfurous acid, thiosulfuric acid, sulfuric acid sulfonic acid (e.g. methanesulfonic acid, toluenesulfonic acid, etc.), mono(lower)alkyl ester of carbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid,
  • trichloroacetic acid etc.
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • a symmetrical acid anhydride such as lower alkanoic anhydride (e.g. acetic anhydride, etc.), trihalo(lower)alkanoic anhydride (e.g.
  • an activated acid amide with a heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole,
  • dimethylpyrazole, triazole and tetrazole e.g. p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester. mesylphenyl ester, phenylazophenyl ester, phenyl
  • thioester p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester with a N-hydroxy
  • Suitable base may include an organic or inorganic base such as alkali metal (e.g. lithium, sodium,
  • alkaline earth metal e.g. calcium, etc.
  • alkali metal hydride e.g. sodium hydride, etc.
  • alkaline earth metal hydride e.g. calcium hydride, etc.
  • alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium
  • alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • alkali metal alkanoic acid e.g. sodium acetate, etc.
  • trialkylamine e.g. triethylamine, etc.
  • pyridine compound e.g. pyridine, lutidine, picoline
  • Suitable acid may include an organic acid (e.g.
  • acetic acid 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.
  • the reaction is preferably carried out in the presence of a condensing agent such as a
  • carbodiimide compound e.g. N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.], a ketenimine compound (e.g.
  • N-hydroxybenzotriazole derivative [e.g., N-hydroxybenzotriazole derivative
  • triphenylphosphine and carbon tetrachloride disulfide or diazenedicarboxylate (e.g. diethyl diazenedicarboxylate, etc.), a phosphorus compound (e.g.
  • ethyl polyphosphate isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.
  • thionyl chloride oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium- 3-sulfonate, a reagent (referred to a so-called "Vilsmeier reagent") formed by the reaction of an amide compound such as N,N-di(lower)alkylformamide (e.g. dimethylformamide, etc.), N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like.
  • amide compound such as N,N-di(lower)alkylformamide (e.g. dimethylformamide, etc.), N-methylformamide or the like
  • a halogen compound such as thionyl chloride,
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g.
  • the compound (I) or salts thereof can be prepared by reacting the compound (IV) or salts thereof with a base.
  • Suitable salts of the compound (IV) may be the same as those for the compound (I).
  • Suitable base used in this reaction may be the same as those given in the explanation of Process 3.
  • This reaction is usually carried out in a
  • the reaction temperature is not critical, and the reaction is usually carried out under from warming to heating.
  • the compound (I-f) or salts thereof can be prepared by subjecting the compound (I-e) or salts thereof to a removal reaction of the hydroxy protective group in
  • Suitable salts of the compounds (I-e) and (I-f) may be the same as those 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
  • 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
  • Suitable acid may include an organic acid (e.g.
  • cation trapping agent e.g. phenol, anisole, etc.
  • This reaction is usually carried out in a
  • a liquid base or acid can be also used as the solvent.
  • the 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.) of a salt of chrome compound (e.g. chromous chloride,
  • chromuos acetate, etc. 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. 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.), and the like.
  • a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulf
  • the reaction is preferably carried out around neutral
  • This reaction is usually carried out in a
  • the reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
  • the removal reaction can be selected according to the kind of hydroxy-protective group to be removed.
  • the compound (I-h) or salts thereof can be prepared by subjecting the compound (I-g) or salts thereof to a removal reaction of the carboxy-protective group in
  • Suitable salts of the compounds (I-g) and (I-h) may be the same as those for the compound (I).
  • This reaction is usually carried out by a
  • reaction conditions e.g. reaction temperature, solvent etc.
  • the object compound (I) obtained according to the Processes 1 to 6 can be isolated and purified in a
  • the compound (II) or salts thereof can be prepared by reacting the compound (V) or salts thereof with the compound (VI) or salts thereof.
  • Suitable salts of the compound (V) may be salts with bases such as those given for the compound (I).
  • Suitable salts of the compound (VI) may be the same acid addition salts as those for the compound (I).
  • This reaction is usually carried out in a
  • the reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
  • the compound (II) or salts thereof can be prepared by reducing the nitro group of the compound (VII) or salts thereof.
  • Suitable salts of the compound (VII) may be the same as those for the compound (I).
  • the compound (IV) or salts thereof can be prepared by reacting the compound (VIII) or its reactive derivative at the carboxy group, or salts thereof with the compound (VI) or salts thereof.
  • Suitable salts of the compound (VIII) may be the same as those for the compound (I).
  • Suitable reactive derivative of the compound (VIII) may include an acid halide, an acid anhydride, an
  • the suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as
  • substituted phosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,
  • dibenzylphosphoric acid halogenated phosphoric acid etc.
  • dialkylphosphorous acid lower alkanesulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, etc.), sulforous acid, thiosulfuric acid, sulfuric acid,
  • alkylcarbonic acid e.g., aliphatic carboxylic acid
  • pivalic acid pentanoic acid, isopentanoic acid,
  • an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole e.g.
  • thioester p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine,
  • N-hydroxyphthalimide 1-hydroxy-6-chloro-1H-benzotriazole, etc.
  • These reactive derivatives can optionally be selected from them according to the kind of the compound (VIII) to be used.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N,N'-diethylcarbodiimide N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • N-cyclohexylimine diphenylketene-N-cyclohexylimine;
  • ethoxyacetylene 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride;
  • triphenylphosphine 2-ethy1-7-hydroxybenzisoxazolium salt
  • the reaction may also be carried out in the presence of an inorganic or organic base such as those given in the explanation of Process 3.
  • the reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
  • the reaction temperature is not critical, and the reaction is usually carried out under warming to heating.
  • the compound (VII) or salts thereof can be prepared by reacting the compound (IX) or its reactive derivative at the carboxy group, or salts thereof with the compound (VI) or salts thereof.
  • Suitable salts and reactive derivative of the compound (IX) may be the same as those for the compound (VIII).
  • reaction conditions e.g. reaction temperature, solvent, etc.
  • quinazoline derivatives (I) stimulate presynaptic(neuronal) and/or postsynaptic(vascular) dopamine receptors that mediate inhibition of neurogenic release of catecholamine and/or dilatation of renal vasculature and remission of Parkinsonism, respectively.
  • Quinazoline derivatives (I) effect on the cardiovascular system as a consequence of its interaction with
  • dopaminergic and adrenergic receptors dopaminergic and adrenergic receptors.
  • acceptable salts thereof of the present invention are novel and display dopamine receptor stimulating effects; 5-HT receptor antagonism, especially 5-HT 2 receptor antagonism; ⁇ - receptor antagonism; and the like, and are useful as a dopamine receptor agonist; 5-HT receptor antagonist, especially 5-HT 2 receptor antagonist; ⁇ 1 receptor antagonist; and the like, for treating or
  • hypertension such as essential hypertension, renal hypertension, pulmonary hypertension, and other cardiovascular disorders (e.g. angina pectoris, congestive heart failure, myocardial infarction, etc.); Parkinsonism; hyperprolactinemia; disorders of peripheral perfusion such as Raynaud's phenomenon, Bruger's diseases, and
  • thrombotic and/or smooth muscle cell proliferative disease such as restenosis after perculaneous transluminal coronary angioplasty;
  • hypercholesterolemia hyperlipemia; urinary disturvance; cardiac hypertrophy; nephropacy such as nephritis, renal failure, etc.; arteriosclerosis obliterans; obstructive thrombus; arterial embolus; Burger-Gr ⁇ ts syndrome;
  • acrocyanosis acrocyanosis; chilblain; frostbite; prolactin-producing ovulation disorder; prolactin-producing pituitary tumor; puerperal galactoschesia; galactorrhea; distal
  • hypertrophy pituitary gigantism
  • mental illness such as melancholia, anxiety, schizophrenia, etc.
  • cerebrovascular diseases such as cerebral infarction, cerebral circulation insufficiency; tachycardia accompanied by sympathetic hypertonia; hyperaldosteronism; diabetic complication such as diabetic hypertriglyceromia, and the like.
  • the object compound (I) has vasodilating activity, blood flow increasing activity such as renal blood flow increasing activity, and the like.
  • the compound (I) and pharmaceutically acceptable salts thereof may be also useful as an adrenolytic, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, hypoglycemic,
  • Test Compound
  • the affinity for DA 2 receptor of a Test Compound was determined following in vitro receptor binding assays.
  • Incubation tubes received 100 ⁇ l of (2-N-[2,3(n)- 3 H]- propyl-N-(2-thiofuranyl)-2'-ethylamino)-5-hydroxy-1,2,3,4- tetrahydronaphthalene, 10 ⁇ l of the Test Compound and 0.89 ml of tissue suspension during binding assays.
  • the concentration of (2-N-[2,3(n)- 3 H]propyl-N-(2-thiofuranyl)- 2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydronaphthalene was 1.5 nM.
  • stratum was 160 ⁇ g/ml.
  • the tubes were incubated at 25°C for 45 minutes, and then filtered under vacuum through Whatman GF/B filters and washed three times with 3 ml of ice-cold buffer. The filters were counted by liquid scintillation counter.
  • the IC 50 value of the Test Compound was calculated from the data of (2-N-[2,3(n)- 3 H]propyl-N-(2- thiofuranyl)-2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydro- naphthalene, binding in the presence of 10 -9 M, 10 -8 M, 10 -7 M and 10 -6 M Test Compound.
  • Rats Male SD rats weighing 300-400 g were used in this test. Rats were pretreated with reserpine (1 mg/kg, S.C.) 17-19 hours before sacrifice and then fasted. Test
  • DOPA was determined as follows; the striatum was homogenized in 9 volumes of 0.1N perchloric acid solution (0.4% EDTA ⁇ 2Na). The homogenate was centrifuged at 10,000 rpm for 1 minute. The supernatant was applied to high performance liquid chromatography.
  • the affinity for Serotonin 2 receptor of a test compound was determined following in vitro receptor binding assays.
  • Tris/HCl 4 mM CaCl 2 , 0.1% Ascorbic acid, 10 ⁇ M pargyline, pH7.7 at 25oC).
  • Incubation tubes received 100 ⁇ l of [ethylen- 3 H]- ketanserin, 10 ⁇ l of the test compound and 0.2 ml of tissue suspension, and 0.69 ml assay buffer during binding assays. The final concentration of [ethylen- 3 H]- ketanserin was 0.05 nM. The tubes were incubated at 37°C for 30 minutes, and then filtered under vacuum through
  • Test Result 3 10 -8 M, 10 -7 M, and 10 -6 M test compound.
  • 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.
  • 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.
  • 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
  • amount between about 0.001 mg and about 300 mg, preferably about 0.1 mg to about 50 mg per day may be administered to a patient.
  • An average single dose of about 0.001 mg, 0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1.0 mg, 3.0 mg, 10.0 mg, 50.0 mg, 100.0 mg, of the object compound (I) of the present invention may be used as adrenolytic, hypotensive, cardiovascular, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, and anti-viral agents.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composé de formule (I), dans laquelle R1 représente un alkyle inférieur hétérocyclique substitué et R2 représente hydrogène, halogène, nitro, amino, amino protégé, hydroxyamino, alkyle inférieur, hydroxy, hydroxy protégé, sulfamoyle, carboxy, carboxy protégé, mercapto, carbonyle hétérocyclique éventuellement substitué, alkyle inférieur hétérocyclique éventuellement substitué, alkylthio inférieur, hydroxyalkyle inférieur ou hydroxyalkyle inférieur protégé; R3 représente aryle pouvant comporter un ou plusieurs substituants adaptés; A est un alkylène inférieur. Ce composé, ainsi que ses sels acceptables en pharmacologie, sont utiles en tant qu'agonistes du récepteur de dopamine, du récepteur 5-HT ou du récepteur α¿1?.
PCT/JP1992/001117 1991-09-06 1992-09-02 Derives de quinazoline et leur preparation WO1993005035A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP92918711A EP0602125A1 (fr) 1991-09-06 1992-09-02 Derives de quinazoline et leur preparation
JP5505101A JPH06510538A (ja) 1991-09-06 1992-09-02 キナゾリン誘導体およびそれらの製造方法
CA002117075A CA2117075A1 (fr) 1991-09-06 1992-09-02 Derives quinazoline et leur preparation

Applications Claiming Priority (3)

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US07/755,747 1991-09-06
US07/755,747 US5296487A (en) 1990-01-02 1991-09-06 Quinazoline derivatives and their preparation
CN93102096A CN1092067A (zh) 1991-09-06 1993-03-05 喹唑啉衍生物及其制备

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AU (1) AU2500992A (fr)
CA (1) CA2117075A1 (fr)
WO (1) WO1993005035A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993018769A2 (fr) * 1992-03-16 1993-09-30 Fujisawa Pharmaceutical Co., Ltd. Nouvelle utilisation d'un derive de quinazoline
EP0828492A1 (fr) * 1995-05-31 1998-03-18 Ergo Science Incorporated Procede permettant de prevenir la stenose associee a une intervention a la suite d'interventions invasives sans pontage
EP1083178A1 (fr) * 1999-08-31 2001-03-14 Pfizer Products Inc. Tétrahydroquinazoline-2,4-dione pour emploi comme médicament

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4769867B2 (ja) * 2005-06-27 2011-09-07 エフ．ホフマン−ラ ロシュ アーゲー ８−アルコキシ−４−メチル−３，４−ジヒドロ−キナゾリン−２−イルアミン及び５−ｈｔ５ａ受容体リガンドとしてのそれらの使用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0436157A1 (fr) * 1990-01-02 1991-07-10 Fujisawa Pharmaceutical Co., Ltd. Dérivés de quinazoline et leur préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0436157A1 (fr) * 1990-01-02 1991-07-10 Fujisawa Pharmaceutical Co., Ltd. Dérivés de quinazoline et leur préparation

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993018769A2 (fr) * 1992-03-16 1993-09-30 Fujisawa Pharmaceutical Co., Ltd. Nouvelle utilisation d'un derive de quinazoline
WO1993018769A3 (fr) * 1992-03-16 1993-11-25 Fujisawa Pharmaceutical Co Nouvelle utilisation d'un derive de quinazoline
EP0828492A1 (fr) * 1995-05-31 1998-03-18 Ergo Science Incorporated Procede permettant de prevenir la stenose associee a une intervention a la suite d'interventions invasives sans pontage
EP0828492A4 (fr) * 1995-05-31 1999-07-07 Ergo Science Inc Procede permettant de prevenir la stenose associee a une intervention a la suite d'interventions invasives sans pontage
EP1661571A2 (fr) * 1995-05-31 2006-05-31 PLIVA d.d. Procédé permettant de prévenir la sténose associée à une intervention à la suite d'interventions invasives sans pontage
EP1661571A3 (fr) * 1995-05-31 2006-08-02 PLIVA d.d. Procédé permettant de prévenir la sténose associée à une intervention à la suite d'interventions invasives sans pontage
EP1083178A1 (fr) * 1999-08-31 2001-03-14 Pfizer Products Inc. Tétrahydroquinazoline-2,4-dione pour emploi comme médicament
US6521630B1 (en) 1999-08-31 2003-02-18 Pfizer Inc. Tetrahydroquinazoline-2,4-diones and therapeutic uses thereof

Also Published As

Publication number Publication date
JPH06510538A (ja) 1994-11-24
CA2117075A1 (fr) 1993-03-18
CN1092067A (zh) 1994-09-14
EP0602125A1 (fr) 1994-06-22
AU2500992A (en) 1993-04-05

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