EP0602125A1 - Quinazoline derivatives and their preparation - Google Patents

Quinazoline derivatives and their preparation

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Publication number
EP0602125A1
EP0602125A1 EP92918711A EP92918711A EP0602125A1 EP 0602125 A1 EP0602125 A1 EP 0602125A1 EP 92918711 A EP92918711 A EP 92918711A EP 92918711 A EP92918711 A EP 92918711A EP 0602125 A1 EP0602125 A1 EP 0602125A1
Authority
EP
European Patent Office
Prior art keywords
compound
salts
formula
alkyl
acid
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92918711A
Other languages
German (de)
French (fr)
Inventor
Norihiko Shimazaki
Yoshikuni Itoh
Takumi Yatabe
Hitoshi Yamazaki
Masashi Hashimoto
Hirokazu Tanaka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
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 US07/755,747 external-priority patent/US5296487A/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0602125A1 publication Critical patent/EP0602125A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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.

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 alpha1.Compound of formula (I), in which R1 represents a substituted heterocyclic lower alkyl and R2 represents hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, carbonyl optionally substituted heterocyclic, optionally substituted heterocyclic lower alkyl, lower alkylthio, lower hydroxyalkyl or protected lower hydroxyalkyl; R3 represents aryl which may contain one or more suitable substituents; A is lower alkylene. This compound, as well as its pharmacologically acceptable salts, are useful as agonists of the dopamine receptor, the 5-HT receptor or the alpha1 receptor.

Description

DESCRIPTION
QUINAZOLINE DERIVATIVES AND THEIR PREPARATION
The present invention relates to novel quinazoline derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to 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
therapeutic treatment of diseases in a human being or animal.
INDUSTRIAL APPLICABILITY Accordingly, one object of the present invention is to provide novel quinazoline derivatives and
pharmaceutically acceptable salts thereof, which display effects on the peripheral or central nervous system, in particular on the peripheral nervous system.
Another object of the present invention is to provide processes for the preparation of novel quinazoline
derivatives and salts thereof. 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
pharmaceutically acceptable salts thereof as a dopamine receptor agonist, 5-HT receptor antagonist, especially 5-HT2 receptor antagonist; α1 receptor antagonist; and the like and a method of the therapeutic treatment of dopamine receptor; 5-HT receptor, especially 5-HT2 receptor;
α1-receptor; mediated diseases, particularly hypertension, cardiovascular disorder (e.g. angina pectoris, myocardial infarction, etc.), Parkinsonism, and the like, in a human being or animal. DISCLOSURE OF INVENTION
The object quinazoline derivatives are novel and can be represented by the following general formula:
in which R1 is substituted heterocyclic-(lower)alkyl, and
R2 is hydrogen, halogen, nitro, amino,
protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R3 is aryl which may have suitable
substituent(s), and
A is lower alkylene,
and pharmaceutically acceptable salts thereof.
Suitable salts of the object compound (I) are
pharmaceutically acceptable, 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, 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,
dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate,
phosphate, etc.), an organic acid addition salt (e.g.
formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.);
a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); and the like.
According to the present invention, the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes. wherein R1, R2, R3 and A are each as defined above, is nitro,
2
w is hydroxyamino or amino,
is amino,
2
t is protected ammo,
is protected hydroxy or protected hydroxy-
( lower)alkyl,
is hydroxy or hydroxy(lower) alkyl,
. is protected carboxy,
is carboxy,
R4 is esterified carboxy, and
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.
Method A :
Method B :
( )
or salts thereof or salts thereof
Method C :
or its reactive derivative or salts thereof at the carboxy group,
or salts thereof
Method D :
or its reactive derivative or salts thereof at the carboxy group,
or salts thereof in which R1, R2, R3, R4 and A are each as defined above.
Some of the starting materials of the above Method A are new and can be prepared, for example, according to the method of Preparation as mentioned below, or in a
conventional manner.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably 1 to 4 carbon atom(s), unless
otherwise indicated.
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.
Suitable "aryl which may have suitable
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.
methyl, etc.), and the like, in which more preferred example may be phenyl which is substituted or
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.
Suitable examples of the 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,
valeryloxymethyl ester, pivaloyloxymethyl ester,
hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-(or 2- or 3- or
4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or
2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or
2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester,
3,3-dimethylbutyryloxymethyl ester, 1-(or
2-)pentanoyloxyethyl ester, etc.], lower
alkanesulfonyl (lower)alkyl ester (e.g. 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 alkoxycarboriyloxy(lower)alkyl ester [e.g.
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester,
t-butoxycarbonyloxymethyl ester, 1-(or
2-)methoxycarbonyloxyethyl ester, 1-(or
2-)ethoxycarbonyloxyethyl ester, 1-(or
2-)isopropoxycarbonyloxyethyl ester, etc.],
phthalidylidene{ lower) alkyl ester, or (5-lower
alkyl-2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester [e.g.
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.];
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, etc.] 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.); phthalidyl ester; and the like.
More preferable example of the protected carboxy thus defined may be carbamoyl and lower alkoxycarbonyl. Suitable "protected amino" may include amino
protected-by a conventional amino-protective group as mentioned below.
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.
The aliphatic acyl may include saturated or
unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl
(e.g. mesyl, ethylsulfonyl, propylsulfonyl,
isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,
pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl. N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbαnyl, propoxycarbonyl,
butoxycarbonyl, t-butoxycarbonyl, etc.),
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.), and the like.
The aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as
phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
These 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.
Preferable example of amino-protective group thus defined may be :
- lower alkanoyl (e.g. acetyl, etc.);
- trihalo(lower)alkanoyl such as trifluoro(lower)- alkanoyl (e.g. trifluoroacetyl, etc.);
- lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.); - carbamoyl;
- N-(lower)alkylcarbamoyl (e.g. N-ethylcarbamoyl, etc.);
- lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, etc.); and the like. "Protected hydroxy" means a hydroxy group protected by a conventional hydroxy-protective group, and 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.
Suitable heterocyclic group in "optionally
substituted heterocyclic-carbonyl", "optionally
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.
Particularly such "heterocyclic group" means
saturated or unsaturated, monocyclic or polycyclic
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 :
-unsaturated 3 to 8-membered, preferably 5 or
6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide,
pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,
2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,
1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-l,2,4-triazinyl,
2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
-saturated 3 to 8-membered, preferably 5 or
6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperrzinyl. etc. ;
-unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,
quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridyl, tetrazolopyridazinyl (e.g.,
tetrazolo[1,5-b]pyridazinyl, etc.),
dihydrotriazolopyridazinyl, etc.;
-unsaturated 3 to 8-membered, preferably 5 or
6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
oxazolyl, isoxazolyl, oxadiazolyl, (e.g.,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
-saturated 3 to 8-membered, preferably 5 or
6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, etc.'
-unsaturated condensed 7 to 12-membered 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
containing 1 to 4 nitrogen atom(s), or containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), optionally substituted by lower alkyl.
Suitable lower alkyl group in "heterocyclic-
(lower)alkyl" can be referred to the ones as mentioned above.
More preferable example of substituted
heterocyclic-(lower)alkyl thus defined may be lower alkylpiperazinyl(lower)alkyl and morpholinyl(lower)alkyl, and the most preferable one may be
4-methylpiperazin-1-ylmethyl.
More preferable example of heterocyclic-carbonyl thus defined may be lower alkylpiperazinylcarbonyl and
morpholinylcarbonyl.
Suitable "halogen" may be fluorine, chlorine,
bromine, iodine, and more preferred example may be
chlorine.
Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
methylmethylene, ethylethylene, propylene, and the like, in which the most preferred one may be tetramethylene.
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,
hexylthio, and the like.
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
hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyhexyl, and the like.
Suitable "protected hydroxy(lower)alkyl" means
hydroxy(lower)alkyl protected by a conventional
hydroxy-protective group as mentioned in the explanation of "protected hydroxy", in which more preferable example may be lower alkoxy(lower)alkyl and
triphenyl(lower)alkoxy{lower)alkyl. The processes for the preparation of the object compound (I) of the present invention are explained in detail in the following. (1) Process 1 :
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.
dimer or trimer thereof, etc.), and the like.
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.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(2) Process 2 :
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.
Reduction method :
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,
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.
In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral
condition.
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.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(3) Process 3 :
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.); and the like. Preferable example of such reactive
derivative may include 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.
trifluoroacetic anhydride, etc.); an activated acid amide with a heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole,
dimethylpyrazole, triazole and tetrazole; an activated ester (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
compound such as N,N-dimethylhydroxylamine,
1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxybenzotriazole,
1-hydroxy-6-chlorobenzotriazole, etc.); and the like. This reaction can be carried out in the presence of a base or an acid according to the introducing agent of the amino-protective group to be used.
Suitable base may include an organic or inorganic base such as alkali metal (e.g. lithium, sodium,
potassium, etc.), 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
bicarbonate, etc.), 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,
4-dimethylaminopyridine, etc.), quinoline, and the like.
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.).
In case that the introducing agent of the
amino-protective group used in a free form or its salt in this reaction, 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,N'-carbonylbis-(2- methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g. ethoxyacetylene,
β-chlorovinylethyl ether), a sulfonic acid ester of
N-hydroxybenzotriazole derivative [e.g.
1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], a combination of trialkylphosphite or
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.
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.
methanol, ethanol, etc.), tetrahydrofuran, pyridine,
N,N-dimethyIformamide, etc., or a mixture thereof, and further in case that the amino-introducing agent is in liquid, it can also be used as a solvent.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating. (4) Process 4 :
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
conventional solvent which does not adversely influence the reaction such as tetrahydrofuran, dioxane, water, methanol, ethanol, etc., or a mixture thereof.
The reaction temperature is not critical, and the reaction is usually carried out under from warming to heating.
(5) Process 5 :
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.
(i) Hydrolysis :
The hydrolysis is preferably carried out in the presence of a base or an acid. 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. sodium carbonate, potassium carbonate, etc.), and alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium
bicarbonate, potassium bicarbonate, etc.), and the like.
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.). The acidic hydrolysis using trifluoroacetic acid is usually
accelerated by addition of 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.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
(ii) Reduction :
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.) 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. 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.
In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral
condition.
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.
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.
(6) Process 6 :
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
conventional method such as hydrolysis, reduction and the like.
The method of hydrolysis and reduction, and the reaction conditions (e.g. reaction temperature, solvent etc.) are substantially the same as those illustrated for removal reaction of the hydroxy-protective group of the compound (I-a) in Process 5, and therefore are to be referred to said explanation.
The object compound (I) obtained according to the Processes 1 to 6 can be isolated and purified in a
conventional manner, for example, extraction,
precipitation, fractional crystallization,
recrystallization, chromatography, and the like.
Methods A to C for preparing the new starting
compounds (II) and (IV) or salts thereof are explained in detail in the following.
(A) Method 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
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.
(B) Method B :
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 method of reduction and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated in Process 2, and therefore are to be referred to said explanation.
(C) Method C :
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
activated amide, an activated ester, and the like.
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, aliphatic carboxylic acid (e.g.
pivalic acid, pentanoic acid, isopentanoic acid,
2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.);
a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.
cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl [(CH3)2N=CH-] ester, vinyl ester, propargyl ester, 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, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine,
1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.), and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (VIII) to be used.
When the compound (VIII) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene-
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;
2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide
intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6- chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychlroide, etc.; or the like.
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,
N,N-dimethylformamide, pyridine, etc. or a mixture thereof.
The reaction temperature is not critical, and the reaction is usually carried out under warming to heating.
(D) Method D :
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).
The method of reaction and the reaction conditions (e.g. reaction temperature, solvent, etc.) are
substantially the same as those illustrated in Method C, and therefore are to be referred to said explanation.
The object 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.
The object compound (I) and pharmaceutically
acceptable salts thereof of the present invention are novel and display dopamine receptor stimulating effects; 5-HT receptor antagonism, especially 5-HT2 receptor antagonism; α- receptor antagonism; and the like, and are useful as a dopamine receptor agonist; 5-HT receptor antagonist, especially 5-HT2 receptor antagonist; α1 receptor antagonist; and the like, for treating or
preventing 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
intermittent claudication; 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-Grϋts syndrome;
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.
And further, 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,
anti-viral agent.
Now in order to show the usefulness of the object compound (I) and pharmaceutically acceptable salts, the pharmacological test data of the representative compound of the compound (I) of this invention are shown in the following. Test Compound :
Compound A [The product of Example 1]
Test 1 Dopamine receptor (DA2 receptor) binding assay
Test Method 1 :
The affinity for DA2 receptor of a Test Compound was determined following in vitro receptor binding assays.
Male rats weighing 150-300g were decapitated and the stratum were dissected from their brains. The tissue was homogenized in 40 volumes of buffer which consisted of 50 mM Tris-HCl (pH 7.5 at 25°C), 1 mM tetraethylenediamine tetraacetic acid, 5 mM potassium chloride, 2 mM calcium chloride, and 1 mM magnesium chloride. The homogenate was centrifuged at 50,000 g for 15 minutes. The pellet was resuspended in 80 volumes of the buffer. The tissue suspension was centrifuged and suspended again in the same way.
Incubation tubes received 100 μl of (2-N-[2,3(n)-3H]- propyl-N-(2-thiofuranyl)-2'-ethylamino)-5-hydroxy-1,2,3,4- tetrahydronaphthalene, 10 μl of the Test Compound and 0.89 ml of tissue suspension during binding assays. The concentration of (2-N-[2,3(n)-3H]propyl-N-(2-thiofuranyl)- 2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydronaphthalene, was 1.5 nM. The final tissue concentration of rat
stratum was 160 μg/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.
Specific binding of the (2-N-[2,3(n)-3H]propyl-(N-(2- thiofuranyl)-2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydronaphthalene was determined in the presence of 1 μM
apomorphine. The IC50 value of the Test Compound was calculated from the data of (2-N-[2,3(n)-3H]propyl-N-(2- thiofuranyl)-2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydro- naphthalene, binding in the presence of 10-9M, 10-8M, 10-7M and 10-6M Test Compound.
Test Result 1 :
Test 2 [Inhibition of reserpine-induced DOPA
accumulation]
Test Method 2 :
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
Compound was given orally to the rats 2 hours before sacrifice. [m-Hydroxybenzylhydrazine (100 mg/kg, i.p.) was given 30 minutes before sacrifice.] Each rat was exposed to microwaves using a head-focus microwave applicator for 1.5 seconds. The whole brain was removed and further separated into the striatum.
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.
Test Result 2
Test 3 [5-HT2 Binding Assay]
Test Method 3 :
The affinity for Serotonin 2 receptor of a test compound was determined following in vitro receptor binding assays.
Male Wistar rats weighing 150-300 g were decapitated and the frontal cortex were dissected from their brains. The tissue was homogenized in 15 volumes of ice-cold buffer which consisted of 0.32 M Sucrose, 50 mM Tris-HCl
(pH 7.5 at 25°C). The homogenate was centrifuged at 3,300 rpm at 4ºC for 10 minutes. The supernatant was
centrifuged at 20,000 rpm for 20 minutes. The pellet was resuspended again in the same way, and incubated at 37ºC for 15 minutes. The tissue suspension was centrifuged at
20,000 rpm for 20 minutes. The final pellet was
resuspended in 15 volumes of ice-cold assay buffer (50 mM
Tris/HCl, 4 mM CaCl2, 0.1% Ascorbic acid, 10 μM pargyline, pH7.7 at 25ºC).
Incubation tubes received 100 μl of [ethylen-3H]- ketanserin, 10 μl 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-3H]- ketanserin was 0.05 nM. The tubes were incubated at 37°C for 30 minutes, and then filtered under vacuum through
Whatman GF/B filters and washed three times with 3 ml of ice-cold buffer (50 mM tris/HCl, pH 7.5 at 25°C). The filters were counted by liquid scintillation counter.
Specific binding of [ethylen-3H]-ketanserin was determined in the presence of 1 μM mianserin. The IC50 value of the test compound was calculated from the data of
[ethylen-3H]-ketanserin binding in the presence of 10-9M,
10-8M, 10-7M, and 10-6M test compound. Test Result 3 :
For therapeutic administration, 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.
If needed, there may be included in the above
preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives 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.
While 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 0.001 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.
The following Preparations and Examples are given for the purpose of illustrating this invention in more detail.
Preparation 1-1)
To a stirred mixture of 4-(4-methylpiperazin-1- ylmethyl)-2-nitrobenzoic acid (0.28 g),
hydroxybenzotriazole (0.14 g) and dry dimethylformamide (5 ml) was added dicyclohexylcarbodiimide (0.21 g), and the mixture was stirred for 1 hour at room temperature. Then 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamine hydrochloride (0.27 g) and triethylamine (0.20 g) were added and the stirring was continued for additional 1 hour. 1N Hydrochloric acid (2 ml) and water (20 ml) were added and the mixture was washed with ethyl acetate, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (x2). The combined organic extracts were dried over magnesium sulfate and solvent was evaporated to give 4-(4-methylpiperazin-1- ylmethyl)-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydro- pyridin-1-yl)butyl]benzamide (0.21 g).
NMR (CDCI3, δ) t 1.78 (4H, m), 2.23 (2H, m), 2.30 (3H, s), 2.43 (8H, m), 2.52 (2H, m), 2.62 (2H, m), 3.00 (2H, m), 3.28 (2H, s), 3.49 (2H, m), 5.75 (1H, m), 7.1-7.4 (7H, m), 7.75 (1H, s), 8-78 (1H, m)
Preparation 1-2)
To a stirred mixture of 4-(4-methylpiperazin-1- ylmethyl)-2-nitro-N-[4-(4-phenyl-1,2,3,6- tetrahydropyridin-1-yl)butyl]benzamide (0.21 g), ethanol (5 ml) and dry tetrahydrofuran (10 ml) was added tin (II) chloride (0.33 g) and the mixture was refluxed for 1 hour. After cooling, chloroform (15 ml) and IN sodium hydroxide (25 ml) were added and the mixture was stirred. The organic layer was separated and the remained aqueous layer was extracted with chloroform. The organic layer and extract were combined and dried over magnesium sulfate and evaporated to give 2-amino-4-(4-methylpiperazin-1- ylmethyl)-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)- butyl]benzamide (0.25 g) .
NMR (CDCI3, δ ) : 1.72 (4H, m), 2.31 (3H, s), 2.50
(10H, m), 2.71 (2H, m), 3.15 (2H, m), 3.33 (2H, s), 3.45 (2H, m), 3.75 (2H, m), 5.50 (2H, br s), 6.03 (1H, m), 6.49 (1H, dd, J=8, 1Hz), 6.65 (1H, d, J=1Hz), 6.41 (1H, m), 7.2-7.45 (6H, m)
Example 1
A mixture of 2-amino-4-(4-methylpiperazin-1- ylmethyl)-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1- yl)butyl]benzamide (0.25 g), carbonyldiimidazole (0.45 g) and dry tetrahydrofuran (10 ml) was stirred under reflux for 14 hours. After evaporation of the solvent, the crude residue was taken up with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to give crystals. Recrystallization from ethanol afforded
7-(4-methylpiperazin-1-ylmethyl)-3-[4-(4-phenyl-1,2,3,6- tetrahydropyridin-1-yl)butyl]-1,2,3,4- tetrahydroquinazoline-2,4-dione (0.16 g).
mp : 167-168ºC
IR (Nujol) : 1700, 1660, 1620, 1590 cm-1
NMR (CDCI3, δ ) : 1.75 (4H, m), 2.30 (3H, s), 2.50
(12H, m), 2.72 (2H, m), 3.18 (2H, m), 3.56 (2H, s), 4.12 (2H, m), 6.05 (1H, m), 7.00 (1H, s), 7.15-7.40 (6H, m), 8.03 (1H, d, J=8Hz), 9.28 (1H, br s)

Claims

CLAIM
1. A compound of the formula :
in which R1 is substituted heterocyclic-(lower)alkyl, and
R2is hydrogen, halogen, nitro, amino,
protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R3 is aryl which may have suitable
substituent(s), and
A is lower alkylene,
or pharmaceutically acceptable salts thereof.
2. The compound of Claim 1, wherein
R2 is hydrogen.
3. The compound of Claim 2, wherein
R1 is unsaturated 3 to 8 membered heteromonocyclic
group containing 1 to 4 nitrogen atoms, which is substituted by lower alkyl or lower alkoxy, and R3 is phenyl optionally substituted by halogen or lower alkyl.
4. The compound of Claim 3, wherein
R1 is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl or dihydrotriazinyl, each of which is substituted by lower alkyl or lower alkoxy.
5. The compound of Claim 4, wherein
R1 is lower alkylpiperazinyl(lower)alkyl, and
R3 is phenyl.
6. The compound of Claim 5, which is
7-(4-methylpiperazin-1-ylmethyl)-3-[4-(4-phenyl- 1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4- tetrahydroquinazoline-2,4-dione. 7. A process for the preparation of a compound of the formula :
in which R1, R2, R3 and A are each as defined in Claim 1, or salts thereof,
which comprises
(a) reacting a compound of the formula : or salts thereof, with a compound of the formula :
CO(X)2
to give a compound of the formula :
or salts thereof; or
(b) reducing the nitro group of of a compound of the
formula :
or salts thereof, to give a compound of the formula :
or salts thereof; or (c) introducing the amino-protective group into a
compound of the formula :
or salts thereof, to give a compound of the formula :
or salts thereof; or
(d) reacting a compound of the formula : or salts thereof, with a base to give a compound of the formula :
or salts thereof; or
(e) subjecting a compound of the formula :
or salts thereof, to a removal reaction of the hydroxy-protective group in to give a compound of the formula :
or salts thereof; or
(f) subjecting a compound of the formula :
or salts thereof, to a removal reaction of the carboxy-protective group in to give a compound of the formula :
or salts thereof;
wherein R1, R2, R3 and A are each as defined above, is nitro,
is hydroxyamino or amino, is amino,
is protected amino.
is protecred hydroxy or protected hydroxy- (lower)alkyl,
is hydroxy or hydroxy(lower)alkyl, is protected carboxy,
is carboxy,
is esterified carboxy, and
X is a leaving group.
8. A pharmaceutical composition comprising, as an active ingredient, a compound of Claim 1 in admixture with a pharmaceutically acceptable carrier or excipient.
9. Use of a compound of Claim 1 as a medicament.
10. Use of a compound of Claim 1 as a dopamine receptor agonist, 5-HT receptor antagonist or α1 receptor antagonist.
11. A method for the treatment of dopamine receptor
mediated diseases, 5-HT receptor mediated diseases or α1 receptor mediated diseases which comprises
administering a compound of Claim 1 to a human being or animal.
EP92918711A 1991-09-06 1992-09-02 Quinazoline derivatives and their preparation Withdrawn EP0602125A1 (en)

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US07/755,747 US5296487A (en) 1990-01-02 1991-09-06 Quinazoline derivatives and their preparation
PCT/JP1992/001117 WO1993005035A1 (en) 1991-09-06 1992-09-02 Quinazoline derivatives and their preparation
CN93102096A CN1092067A (en) 1991-09-06 1993-03-05 Quinazoline derivant and preparation thereof

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GB9205702D0 (en) * 1992-03-16 1992-04-29 Fujisawa Pharmaceutical Co A new use of a quinazoline derivative
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JPH06510538A (en) 1994-11-24
WO1993005035A1 (en) 1993-03-18
AU2500992A (en) 1993-04-05
CN1092067A (en) 1994-09-14

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