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WO1998033792A1 - Derives de la piperidine - Google Patents

Derives de la piperidine Download PDF

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Publication number
WO1998033792A1
WO1998033792A1 PCT/JP1998/000387 JP9800387W WO9833792A1 WO 1998033792 A1 WO1998033792 A1 WO 1998033792A1 JP 9800387 W JP9800387 W JP 9800387W WO 9833792 A1 WO9833792 A1 WO 9833792A1
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Prior art keywords
compound
substituted
unsubstituted
solvent
yield
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PCT/JP1998/000387
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English (en)
Japanese (ja)
Inventor
Shigeki Fujiwara
Yuko Okamura
Haruki Takai
Hiromi Nonaka
Kozo Yao
Akira Karasawa
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Kyowa Hakko Kogyo Co., Ltd.
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Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU56793/98A priority Critical patent/AU5679398A/en
Publication of WO1998033792A1 publication Critical patent/WO1998033792A1/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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the present invention relates to 4 (3H) -quinazolinone and 4 (3H) _1,2,3-benzotriazinone derivatives having an adenosine uptake inhibitory activity and useful for cardioprotection and prevention or treatment of inflammation such as foot edema. It relates to its pharmacologically acceptable salts.
  • An object of the present invention is to inhibit myocardial injury from anoxia or hypoxia such as ischemia and reperfusion injury by inhibiting nucleoside uptake into cells and increasing extracellular adenosine concentration.
  • An object of the present invention is to provide a piperidine derivative or a pharmaceutically acceptable salt thereof, which is useful for preventing or treating inflammation such as paw edema.
  • the present invention provides a compound of the formula (I)
  • R 2 , R 3 , R 4 and R 5 are the same or different and are each a hydrogen atom, a halogen, an amino, a mono- or di-lower alkylamino, a lower alkanoylamino, nitro, cyano, a substituted or unsubstituted lower alkyl, , Hydroxy, lower alkoxy, lower alkylthio, alkoxy, lower alkoxycarbonyl, lower alkanoyl, aralkyloxy or lower alkanoyloxy, wherein R 6 , R 7 , R 8 and R 9 are the same or different and are a hydrogen atom, lower Represents alkyl, hydroxy, substituted or unsubstituted lower alkoxy or aralkyloxy, or two adjacent groups represent methylenedioxy or ethylenedioxy, R 1Q represents a hydrogen atom, lower alkyl or halogen, and n is 0, 1 or X represents N or C-R 1 (where R 1 represents
  • Examples of 1 to 8 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl and the like.
  • Alkenyl includes straight-chain or branched-chain C 2-6, for example, bier, aryl, methyl acryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl And so on.
  • cycloalkyl examples include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aralkyl moiety of aralkyl and aralkyloxy examples include benzyl, phenethyl, benzhydryl, and naphthylmethyl having 7 to 13 carbon atoms.
  • heterocyclic group examples include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, and homopiperazinyl.
  • aryl portion of aryl and arylsulfonyloxy examples include phenyl, naphthyl, biphenyl, anthryl and the like.
  • Halogen means fluorine, chlorine, bromine and iodine atoms.
  • Substituents of the substituted lower alkyl, substituted lower alkylthio and substituted lower alkoxy may be the same or different and have 1 to 3 substituents such as halogen, nitro, cyano, hydroxy, lower alkoxy, lower alkoxy, lower alkoxycarbonyl, lower alkoxyl. Examples include noyl, cycloalkyl, amino, mono- or di-lower alkylamino, and phthalimide.
  • Substituted aryl, substituted arylsulfonyloxy and substituted aralkyl may have the same or different substituents of 1 to 3 halogen atoms, lower alkyl, nitro, cyano, amino, mono- or di-lower alkylamino, hydroxy. , Lower alkoxy, carboxy, lower alkoxy , Lower alkanol, methylenedioxy, trifluoromethyl, etc. ).
  • Substituents of the substituted heterocyclic groups may be the same or different and have 1 to 3 substituents such as halogen, lower alkyl, amino, mono- or di-lower alkylamino, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, trifluoromethyl , Phenyl, aralkyl and the like.
  • halogen lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, cycloalkyl, mono- or di-lower alkylamino, lower alkyl and aralkyl have the same meanings as above.
  • Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, quer Organic salts such as carboxylate and methanesulfonate are exemplified.
  • examples of pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkali salts such as magnesium salt and calcium salt.
  • pharmacologically acceptable ammonium salts include, for example, salts of ammonium, tetramethylammonium, etc .
  • pharmacologically acceptable organic Amine addition salts include addition salts such as morpholine and piperidine, and pharmacologically acceptable amino acid addition salts include lysine, glycine, phenylalanine and the like. With salting, and the like.
  • the methods for introducing and removing protecting groups commonly used in organic synthetic chemistry can be used to obtain the desired compound.
  • the order of reaction steps such as introduction of a substituent can be changed as necessary.
  • Production method 1 Compound (I) can be produced according to the following reaction steps.
  • X is C-R la wherein R la represents a hydrogen atom, a substituted or unsubstituted lower alkyl, alkenyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl
  • R la represents a hydrogen atom, a substituted or unsubstituted lower alkyl, alkenyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl
  • the compound represented by the formula (1) is obtained by converting the compound (II) into an aromatic hydrocarbon such as benzene or toluene or in the absence of a solvent, and a corresponding orthoester such as triethyl orthoformate, trimethyl orthoformate, or triethyl orthoformate.
  • Acetate, triethyl orthopropionate, triethyl orthobenzoate, etc. should be used in an amount of 1 equivalent to the amount of
  • the compound in which X is represented by C—R la (where R la has the same meaning as described above) is obtained by acylating the amino group of the compound (II) with a corresponding acylating agent. After that, it can also be produced by performing a ring closure reaction under basic conditions.
  • the acylation is carried out using a corresponding acylating agent, for example, an acid anhydride such as acetic anhydride or propionic anhydride, or an acid halide such as acetyl chloride, and, if necessary, pyridine, triethylamine, an alkyl metal hydroxide, an alkyl metal carbonate.
  • a solvent such as chloroform, dichloromethane, tetrahydrofuran (THF), 1,4-dioxane or the like, or without a solvent, within a range of 0 ° C. to the boiling point of the solvent used.
  • the ring closure reaction with a base is carried out in the presence of an alkyl metal hydroxide, for example, sodium hydroxide, potassium hydroxide, or the like, in a suitable solvent, for example, a lower alcohol such as methanol, ethanol, or isopropanol, THF, 1,4-dioxane, or the like. It is obtained by reacting a cyclic ether or a mixed solvent thereof at room temperature to the boiling point of the solvent used. These reactions are usually carried out for 1 to 48 hours.
  • an alkyl metal hydroxide for example, sodium hydroxide, potassium hydroxide, or the like
  • a suitable solvent for example, a lower alcohol such as methanol, ethanol, or isopropanol, THF, 1,4-dioxane, or the like. It is obtained by reacting a cyclic ether or a mixed solvent thereof at room temperature to the boiling point of the solvent used. These reactions are usually carried out for 1 to 48 hours.
  • X is C one R lb compound represented by the benzene compound (II), aromatic hydrocarbons such as toluene, main evening Bruno - In a lower alcohol such as toluene, ethanol, or isopropanol, a cyclic ether such as THF, 1,4-dioxane, or a mixed solvent thereof, or in the absence of a solvent, from 1 equivalent to 1 equivalent of carbon disulfide. It can be obtained by heating from room temperature to about the boiling point of the solvent with a solvent amount of an organic base such as pyridine or triethylamine, and reacting for 1 to 48 hours.
  • aromatic hydrocarbons such as toluene, main evening Bruno -
  • a lower alcohol such as toluene, ethanol, or isopropanol
  • a cyclic ether such as THF, 1,4-dioxane, or a mixed solvent thereof, or in the absence of a solvent, from 1 equivalent to 1 equivalent of carbon dis
  • this compound can be prepared using a conventional alkylating agent (eg, an alkyl halide such as methyl iodide or ethyl iodide), and a base such as pyridine, triethylamine, an alkyl hydroxide metal, or an alkyl carbonate, Dichloromethane, By reacting at 0 ° C to the boiling point of the solvent used in the presence of a solvent such as THF, 1,4-dioxane, etc., in compound (I), X is C—R lc (where R lc may be substituted). Or represents an unsubstituted lower alkylthio) c (Steps 1-4)
  • a conventional alkylating agent eg, an alkyl halide such as methyl iodide or ethyl iodide
  • a base such as pyridine, triethylamine, an alkyl hydroxide metal, or an alkyl carbonate,
  • compounds in which X is represented by N can be obtained by subjecting compound (II) to the usual diazotization method (dropping an aqueous solution of sodium nitrite into a concentrated hydrochloric acid solution under ice-cooling). Can be manufactured.
  • Production method 2 Compound (I) can also be produced according to the following reaction steps,
  • n, R 2 to R 1G , X, Y and Z have the same meanings as above, Q represents ethoxycarbonyl or benzyl, R 14 is chlorine, bromine, iodine, methanesulfonyloxy, benzenesulfonyloxy Or represents toluenesulfonyloxy)
  • Compound (III) is prepared by converting compound (Ilia) in which Q represents ethoxycarbonyl in the presence of an acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid, in a suitable solvent, for example, water, methanol, ethanol, Lower alcohols such as sopropanol; cyclic ethers such as THF and 1,4-dioxane; or compounds that undergo acid hydrolysis in a mixed solvent of these at room temperature to the boiling point of the solvent used, or Q represents benzyl (Illb) To a catalytic reduction reaction.
  • an acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid
  • a suitable solvent for example, water, methanol, ethanol, Lower alcohols such as sopropanol; cyclic ethers such as THF and 1,4-dioxane; or compounds that undergo acid hydrolysis in a mixed solvent of these at room temperature to the boiling point of the solvent used, or Q represents benzyl (
  • the reaction can be carried out usually at room temperature and normal pressure in the presence of a catalyst such as Raney nickel, palladium carbon, platinum oxide and the like in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, acetic acid. .
  • a catalyst such as Raney nickel, palladium carbon, platinum oxide and the like
  • a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, acetic acid.
  • the compound (I) is obtained by converting the compound (III) obtained in the step 2-1 into a compound described in Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), Vol. 38, pp. 1591-1595 (1990). According to the method, compound (IV) [South African Patent 6 706512 (1968) or Journal of Medicinal Chemistry (J. Med. Chem.), 11, 130-136, (1968), Chemish Berichte ( Chem. Ber.) 102, 3666 (1969) or Chemical and Pharmaceutical Bulletin (Chem. Pharm.
  • a suitable solvent for example, a lower alcohol such as methanol, ethanol, or isopropanol, or a cyclic compound such as THF or 1,4-dioxane.
  • ether Dimethylformamide (DMF), dimethylsulfoxide (DM SO) or a mixed solvent thereof can be obtained by reacting 30 minutes to 48 hours at the boiling point of Solvent Using room temperature to.
  • n, R 2 to R 1 () , R 12 , R 13 and X have the same meanings as described above, and W is chlorine, bromine, iodine, methanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyl Represents oxy
  • Compound (Ia) can be obtained by combining compound (Iaa) with 1 equivalent to solvent amount of compound (V), if necessary, with a tertiary amine such as triethylamine or pyridine or an alkali metal carbonate such as sodium carbonate or potassium carbonate.
  • a suitable solvent for example, lower alcohols such as methanol, ethanol and isopropanol, cyclic ethers such as THF and 1,4-dioxane, DMF, dimethylacetamide (DMA), N-methylpyrrolidinone, DMSO Or in a mixed solvent thereof, if necessary, in a sealed tube at room temperature to the boiling point of the used solvent for 10 minutes to 72 hours.
  • Compound (I c) may be from compound (I cc), also it is produced according to the method of Step 3.
  • n, R 2 to R 1 (1 and X have the same meanings as described above, and Wa represents chlorine, bromine, and iodine
  • Compound (Id) can be produced by subjecting compound (Id) to a catalytic reduction reaction.
  • Catalytic reduction is usually carried out at room temperature and atmospheric pressure in the presence of a catalyst such as Raney nickel, palladium carbon, platinum oxide, etc. in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, acetic acid. it can.
  • Production method 7 Of compound (I), compound (Ie) wherein Y is C-H and Z is C--H is to be produced from compound (Iee) according to the method of step 6. Can also.
  • Production method 8 Compound (I) wherein Y is N and Z is C-H (I f) can also be produced from compound (Iff) according to the method of Step 6.
  • n, R 2 to R 1Q , Wa and X represent the same meaning as described above.
  • Production method 9 Compound (II) in production method 1 can be produced according to the following reaction steps.
  • n, R 2 to R 1G , Y and Z represent the same meaning as described above.
  • Compound (XII) is obtained by the method described in Compound (VI) and Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), Vol. 38, pp. 3014-30 19 (1990) and the references cited therein.
  • a base for example, triethylamine, pyridine, potassium carbonate, cesium carbonate and the like, halogenated hydrocarbons such as chloroform, dichloromethane, etc. It can be obtained by reacting in an aromatic hydrocarbon such as toluene or toluene, or an ether solvent such as THF at 0 ° C. and at the boiling point of the solvent for 10 minutes to 24 hours.
  • Compound (II) can be obtained by reducing the nitro group of compound (XII) obtained in step 911 (for example, catalytic reduction or reduction using a metal).
  • the catalytic reduction is usually performed at room temperature and atmospheric pressure in the presence of a catalyst such as Raney nickel, palladium carbon, or platinum oxide in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, or acetic acid. it can.
  • the reduction using a metal is carried out, for example, under conditions of zinc monoacetic acid, iron monoacetic acid, iron ferric chloride monoethanol monohydrate, iron monohydrochloric acid, tin monohydrochloric acid, and the like, from room temperature to the boiling point of the used solvent.
  • Compound (II) can be obtained from compound (VIII) and compound (VII) from Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), Vol. 34, pp. 1907-1916 (1) 986 years) It can also be manufactured according to the method described.
  • Production method 10 Compound (II) in Production method 1 can also be produced according to the following reaction steps.
  • Compound ( ⁇ ) is obtained by obtaining compound (Xb) from compound (VI) and compound (IXb) according to the method of step 9-11, and then selectively deprotecting the benzyl group to obtain compound (XI). After condensation with compound (IV) according to the method of Step 2-2, follow the method of Step 9-12 To reduce the nitro group.
  • -As a method for selective deprotection of the benzyl group a method using vinyl chloroformate described in the literature [Tetrahedron Lett., Vol. 18, pp. 1567–1570 (1985)] is preferable. .
  • Production method 11 1 a compound in which Y is C—NR 12 R 13 (wherein R 12 and R 13 have the same meanings as described above) and Z is N among the compounds (II) in Production method 1.
  • (Ila) can also be produced according to the following reaction steps.
  • Compound (Ila) is obtained by reacting compound (X Ila) obtained by production method 9 or production method 10 with compound (V) according to the method of step 3, and then reacting it by the method of step 9-1-2. It can be obtained by reducing the nitro group.
  • Production method 12 In compound (II) in production method 1, Y is C—NR 12 R 13 (where R 12 and R 13 have the same meanings as described above), and Z is C—H Compound (lib) can also be produced from compound (Xllb) according to the method of Step 11.
  • Production method 13 In the compound ( ⁇ ) in production method 1, Y is N; A compound (lie) wherein Z is C—NR 12 R 13 (wherein R 12 and R 13 have the same meanings as described above) can be produced from the compound (XIIc) according to the method of Step 11 Can also.
  • Production method 15 In compounds (Ilia) and (Illb) in production method 2, X is C-R la (Wherein R la has the same meaning as described above), compound (nic) and compound (md) can also be produced according to the following reaction steps.
  • Production method 16 In compounds (Ilia) and (Illb) in production method 2, 'R 2 , R 4 and R 5 are hydrogen atoms, and compounds having various substituents in R 3 are prepared according to the following reaction method
  • n, R 1G , Q and X represent the same meaning as described above.
  • a compound (Illf) in which R 3 is a nitro group and R 2 , R 4 and R 5 are hydrogen atoms is a compound (Iile) in which R 2 to R 5 are all hydrogen atoms, and acetic acid, sulfuric acid, etc.
  • it can be obtained by reacting an equivalent or excessive amount of nitric acid or a nitrating agent such as fuming nitric acid without a solvent. The reaction is usually performed at -30 to 100 ° C for 1 minute to 24 hours.
  • Compounds (Illg) in which R 3 is bromine and R 2 , R 4 and R 5 are hydrogen atoms can be obtained by converting the compound (Iile) to an acid such as acetic acid or sulfuric acid or a halogen such as carbon tetrachloride or chloroform. It can be obtained by reacting an equivalent amount or an excess amount of a brominating agent such as bromine with a benzene hydrocarbon or the like as a solvent.
  • a metal salt preferably a silver salt such as silver sulfate or silver acetate may be added in a catalytic amount to an excess amount, if necessary, and it is usually from about -30 ° C to 100 ° C for 1 minute to 24 hours. Done in time.
  • the compound (Illh) in which R 3 is acetyl and R 2 , R 4 and R 5 are hydrogen can be obtained by reacting the compound (Illg) obtained in step 6 with an organotin compound in the presence of a transition metal catalyst It can also be obtained by hydrolyzing a vinyl ether intermediate.
  • Transition metal catalysts used in the reaction with organotin compounds include dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichlorobis [tri (O-tolyl) phosphine] palladium, tris (dibenzylideneacetone) di Palladium catalysts such as palladium and black form are mentioned.
  • Tin compounds include (11-ethoxyvinyl) triptyltin.
  • aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and THF, DMF, DMSO and the like are used.
  • Lithium chloride may be appropriately added according to the reaction.
  • the reaction is completed at 0 to 120 ° C in 0.5 to 24 hours.
  • the obtained vinyl ether intermediate is hydrolyzed in the presence of a suitable acid to obtain a compound (Illh).
  • the acid used include a protic acid such as hydrochloric acid and P-toluenesulfonic acid.
  • reaction solvent alcohols such as methanol and ethanol, ethers such as dioxane and THF, ketones such as acetone and 2-butanone, DMF, DMSO, pyridine or water are mixed as necessary. .
  • the reaction is 0-: 120 and is completed in 0.5-24 hours.
  • Production method 17 Compound (Ih) in which R 3 is acetyl and R 2 , R 4 , and R 5 are hydrogen atoms in compound (I), R 3 is bromine, and R 2 , R 4 , and R 5 are hydrogen
  • the compound can also be produced from an atomic compound (Ig) according to the method of Step 16-3.
  • the intermediates and the target compound in the above production method are isolated and purified by a purification method commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, drying, concentration, recrystallization, various types of chromatography, and the like. be able to.
  • the intermediate can be subjected to the next reaction without purification.
  • compound (I) when it is desired to obtain a salt of compound (I), if compound (I) can be obtained in the form of a salt, it can be purified as it is, and if it can be obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, the salt may be formed by suspending and adding an acid.
  • Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various soots, and these adducts are also included in the present invention. Although some of the compounds (I) may have optical isomers, the present invention also includes all possible stereoisomers and mixtures thereof.
  • Test example 2 [ 3 H] 12-Trobenzylthioinosine (NB I) binding inhibitory activity (an indicator of adenosine binding inhibitory activity)
  • Compound (I) or a pharmaceutically acceptable salt thereof may be used as it is or in various pharmaceuticals. Can be used in form.
  • the pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier as an active ingredient. Desirably, these pharmaceutical compositions are in unit dosage form suitable for oral or injection administration.
  • any useful pharmaceutically acceptable carrier can be used.
  • oral liquid preparations such as suspensions and capsules include water, sugars such as sucrose, sorbitan, glycerol, polyethylene glycol, glycerols such as propylene glycol, and sesame oil. And oils such as olive oil and soybean oil, preservatives such as P-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint.
  • Powders, pills, capsules and tablets are made of excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch, sodium alginate, lubricants such as magnesium stearate, talc, and polyvinyl.
  • Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration.
  • Disintegrants When manufacturing capsules, solid pharmaceutical carriers are used.
  • the injection can be prepared using a carrier comprising distilled water, a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. At this time, it is prepared as a solution, suspension or dispersion using an appropriate auxiliary according to a conventional method.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection in the above-mentioned pharmaceutical form. Although it depends on the age, weight, symptoms, etc., 1 to 900 mg Z60 kg / day is appropriate.
  • Example 8 6-clo mouth—3_ [1— (2-clo mouth—6,7-dimethoxy-4-quinazolinyl) -14-piberidinyl] _3,4-dihydro-4-oxoquinazolin (compound 8)
  • Example 2 was repeated except that the compound d obtained in Reference Example 4 was used instead of the compound c, and that 2,4-dichloro-6,7-dimethoxyquinazoline was used instead of 4-chloro-6,7-dimethoxyquinazoline.
  • the title compound was obtained as white crystals according to the method (yield 81%).
  • Example 2 was repeated except that the compound f obtained in Reference Example 6 was used instead of the compound c, and that 2,4-dichloro-6,7-dimethoxyquinazoline was used instead of 4-monochloro-6,7-dimethoxyquinazoline.
  • the title compound was obtained as white crystals according to the method (87% yield).
  • Example 1 9 3,4-Dihydro-3- [1- (6,7-dimethoxy-2-morpholinor-4-quinazolinyl) —4-piberidinyl] methyl-6-methyl-4-oxoquinazoline / 2 methanesulfonate (Compound 1 9)
  • Example 2 7 3 _ [1-(2-black mouth-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-3,4-dihydro-1-methyl-4-oxo-1-phenyl Quinazoline (Compound 27)
  • Example 1 was repeated except that the compound n obtained in Reference Example 13 was used in place of the compound c, and that 2,4-dichloro-6,7-dimethoxyquinazoline was used instead of 4,4-dichloro-6,7-dimethoxyquinazoline. According to the method of 2, the title compound was obtained as white crystals (yield: 64%).
  • Example 2 8 3,4-Dihydro-3- [1- (6,7-dimethoxy-2-morpholino-4-quinazolinyl) -1-4-piperidinyl] _6-methyl-4-oxo-1-2-phenylquinazoline (Compound 28)
  • the title compound was obtained as white crystals according to the method of Example 18 except that the compound j obtained in Reference Example 9 was used instead of the compound h (yield 31%).
  • Example 1 was repeated except that the compound j obtained in Reference Example 19 was used in place of the compound h, and that 2,4-dichloro-6,7-dimethoxyquinazoline was used instead of 4-monochloro-6,7-dimethoxyquinazoline. According to the method of 18, the title compound was obtained as white crystals (yield: 71%).
  • Example 36 3- (1-) [2-bis (2-hydroxyethyl) amino-6,7-dimethoxy-4-quinazolinyl] -14-piperidinyl ⁇ methyl_3,4-dihydro-2,6-dimethyl-4 _Oxoquinazoline (Compound 36)
  • Example 3 8 3,4-Dihydro-3- (1- (6,7-dimethoxy-2-morpholinor-4-quinazolinyl) _4-piperidinyl) ethyl-2,6-dimethyl-4-oxoquinazoline (compound 38)
  • the title compound was obtained as white crystals (two-step yield: 48%) according to the method of Example 37 except that the compound r obtained in Reference Example 17 was used instead of the compound P.
  • Example 3 9 3— ⁇ 1 -— [2-bis (2-hydroxyethyl) amino-6,7-dimethoxy-4-quinazolinyl] -1-piperidinyl ⁇ ethyl-3,4-dihydro2,6-dimethyl-4-oxoquinazoline ( Compound 39) ⁇
  • Example 4 2 6-Acetyl-3— [1— (6,7-Jetoxy-4-quinazolinyl) —4-piberidinyl] -13,4-dihydro-4-oxoquinazoline (Example 42)
  • Example 2 was repeated except that the compound g obtained in Reference Example 7 was used instead of the compound c and 4-chloro-6,7-dimethoxyquinazoline was used instead of 4-chloro-6,7-dimethoxyquinazoline.
  • the title compound was obtained as white crystals (yield 18%).
  • Example 4 3 3— [1_ (2_chloro-6,7-diethoxy-4-quinazolinyl) —4-piperidinyl] -13,4-dihydro-6-methyl-4-oxoquinazoline (compound 43)
  • Example 2 was repeated except that the compound b obtained in Reference Example 2 was used in place of the compound c, and that 2,4-diclo- mouth-6,7-diethoxyquinazoline was used instead of 4-chloro-6,7-dimethoxyquinazoline.
  • the title compound was obtained as white crystals according to the method (88% yield).
  • Example 47 1.0 g (1.63 mmol) of the compound 47 obtained in Example 47 was dissolved in 20 ml of methanol, 5 ml of a 2N aqueous sodium hydroxide solution was added thereto, and the mixture was heated under reflux for 2 hours. After cooling, the solvent was distilled off, water and hydrochloric acid were added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with ether to give the free base of the title compound, and then the title compound was obtained as white crystals according to the method of the second step of Example 11 (two-step yield: 68% ).
  • Example 4 9 3- ⁇ 1_ [2-bis (2-hydroxyethyl) amino-6,7-diethoxy_4-quinazolinyl] _4-piperidinyl ⁇ -3,4 dihydro-6-methyl-4-oxoquinazoline-2methane Sulfonate (Compound 49)
  • the title compound was obtained as white crystals according to the method of Example 11 except that Compound 43 was used instead of Compound 7 and diethanolamine was used instead of morpholine.
  • Example 50 3,4-dihydro-3- [1- (6,7-dimethoxy-2-propylamino-4-quinazolinyl) -1-piperidinyl] -16-methyl-4-oxo Soquinazoline dimethanesulfonate (Compound 50) 1
  • the title compound was white in accordance with the method of Example 11 except that Compound 43 was used instead of Compound 7 and propylamine was used instead of morpholine. Obtained as crystals (yield 40%)
  • Example 51 1 6-Bromo_3— [1- (6,7-Jetoxy-2-morpholino-4-quinazolinyl) -14-piberidinyl] _3,4-dihydro-4-oxoquinazoline (Compound 51)
  • Example 5 2 3 _ ⁇ 1— [2-bis (2-hydroxyethyl) amino-1,6,7-diethoxy-4-quinazolinyl] -1-piperidinyl ⁇ — 6-bromo-3,4-dihydro-4-oxoquinazoline (compound 5 2)
  • Example 2 The procedure of Example 2 was repeated, except that compound b was used in place of compound c, and 4-chloro-6-methoxy-7-methylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. The title compound was obtained as white crystals (yield 26%).
  • Example 2 was repeated except that compound b was used in place of compound c and 2,4-dichloro-6,7-methylenedioxyquinazoline was used in place of 4,6,7-dimethoxyquinazoline.
  • the title compound was obtained as white crystals according to the method (yield: 72%
  • Tsu ⁇ (% 9 umbrella 3 ⁇ 4i) S ⁇ u , ⁇ ⁇ ⁇ so).
  • Example 6 4 3, 4-dihydro-3-[1-(6, 7-diisopropoxy-2-morpholino-4-quinazolinyl)-4-piberidinyl] _ 6-methyl-4 years old oxoquinazoline hydrochloride (compound 6) Four )
  • Example 65 3_ [1- (7-benzyloxy-2-chloro-6-methoxy-4-quinazolinyl) -4-piperidinyl] —3,4-dihydro-6-methyl_4-oxoquinazoline (compound 65)
  • Example 2 The procedure of Example 2 was repeated except that compound b was used instead of compound c and 7-benzyloxy_2,4-dichloro-16-methoxyquinazoline was used instead of 4-chloro-6,7-dimethoxyquinazoline. According to the above, the title compound was obtained as white crystals (yield: 77%). ⁇
  • Example 6 6 3- [1- (7-benzyloxy-6-methoxy-2_morpholino-4-quinazolinyl) -1-4-piperidinyl] —3,4-dihydro-6-methyl is one
  • the temperature of the reaction solution was raised to room temperature over 30 minutes, and left as it was for 1 hour. 800 ml of water was added to the reaction solution, and the mixture was separated. The organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure, and ether was added to the residue. The resulting crystals were collected by filtration, and 84.9 g of 1-ethoxycarbonyl-4- (5-methyl-2-nitrobenzoylamino) piperidine (compound ba) was collected. (91%) as white crystals.
  • Second step 84.8 g (0.25 mol) of compound ba obtained in the first step is dissolved in 700 ml of ethanol, 8.4 g of 10% Pd-C is suspended in 20 ml of water, and the mixture is added under a hydrogen atmosphere at room temperature. And stirred vigorously for 12 hours. The reaction solution was filtered using a filter aid, washed with ethanol, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitated crystals were collected by filtration and 73.6 g of 4- (21-amino-5-methylbenzoylamino) -1-ethoxycarbonylpiperidine (compound bb) was obtained (97% yield). As pale yellow crystals.
  • the crushed silver sulfate of I) was added little by little while suppressing heat generation with ice. After stirring at room temperature for 1 hour, the reaction solution was poured into ice water, neutralized with a 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed successively with 2N aqueous sodium hydroxide solution and saturated saline, then dried and concentrated, and the resulting residue was subjected to silica gel column chromatography.
  • Reference Example 1 1 3 _ (1 -ethoxycarbinyl 4-piberidinyl)-3,4-dihydro-6 _ methyl _ 4 -oxo-2- propylquinazoline (compound) Triethyl orthobutyrate instead of triethyl orthopropionate The title compound was obtained as white crystals (yield: 20%) according to the method of Reference Example 10 except that the compound was used.
  • Reference Example 1 2 2-butyl-3-(1-ethoxycarbonyl 4-piberidinyl)-3,4-dihydro-6-methyl _ 4-oxoquinazoline (compound m) Orthodoxy instead of triethyl orthopropionate
  • the title compound was obtained as white crystals according to the method of Reference Example 10 except that triethyl valerate was used (yield: 64%) '.
  • 4- (2-Methoxy-2-nitrobenzoylamino) ethyl] piperidine (compound rb) was obtained as white crystals, followed by the method of the fourth step in Reference Example 1. The title compound was obtained as white crystals (two-step yield: 68%).
  • the title compound was obtained as white crystals (yield 46%) according to the method of Reference Example 17 except that diethanolamine was used instead of morpholine.
  • the present invention provides a piperidine derivative or a pharmacologically acceptable salt thereof, which has an adenosine uptake inhibitory activity and is useful for protecting myocardium and preventing or treating inflammation such as paw edema.

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Abstract

L'invention concerne des dérivés de la pipéridine, de formule générale (I) (composé I), dans laquelle R?2, R3, R4 et R5¿, identiques ou différents, représentent hydrogène, halogéno, amino, mono ou di(alkyle inférieur)amino, etc.; R?6, R7, R8 et R9¿, identiques ou différents, représentent hydrogène, alkyle inférieur, hydroxy, alcoxy inférieur éventuellement substitué, etc., ou bien deux d'entre eux, adjacents et associés, représentent méthylène-dioxy ou éthylène-dioxy; R10 représente hydrogène, alkyle inférieur ou halogéno; n est 0, 1 ou 2; X représente N ou C-R1; Y représente N ou C-R11; et Z représente N ou C-R11a; ainsi que leurs sels pharmacologiquement acceptables.
PCT/JP1998/000387 1997-01-31 1998-01-30 Derives de la piperidine WO1998033792A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999053924A1 (fr) * 1998-04-17 1999-10-28 Kyowa Hakko Kogyo Co., Ltd. Agent analgesique
WO2006012577A3 (fr) * 2004-07-22 2006-09-28 Bayer Pharmaceuticals Corp Derives de la quinazolinone utiles pour la regulation de l'homeostasie du glucose et de prise d'aliments
US9040533B2 (en) 2012-12-27 2015-05-26 Purdue Pharma L.P. Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators
JP2022503821A (ja) * 2018-10-22 2022-01-12 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド Ｕｓｐ７の阻害

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0578349A (ja) * 1990-01-02 1993-03-30 Fujisawa Pharmaceut Co Ltd キナゾリン誘導体およびそれらの製造法
WO1994019342A1 (fr) * 1993-02-18 1994-09-01 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de l'incorporation d'adenosine
WO1996006841A1 (fr) * 1994-08-26 1996-03-07 Kyowa Hakko Kogyo Co., Ltd. Derive de quinazoline

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0578349A (ja) * 1990-01-02 1993-03-30 Fujisawa Pharmaceut Co Ltd キナゾリン誘導体およびそれらの製造法
WO1994019342A1 (fr) * 1993-02-18 1994-09-01 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de l'incorporation d'adenosine
WO1996006841A1 (fr) * 1994-08-26 1996-03-07 Kyowa Hakko Kogyo Co., Ltd. Derive de quinazoline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NOMOTO Y., ET AL.: "STUDIES ON CARDIOTONIC AGENTS. I. SYNTHESIS OF SOME QUINAZOLINE DERIVATIVES.", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 38., no. 06., 1 January 1990 (1990-01-01), JP, pages 1591 - 1595., XP002912326, ISSN: 0009-2363 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999053924A1 (fr) * 1998-04-17 1999-10-28 Kyowa Hakko Kogyo Co., Ltd. Agent analgesique
WO2006012577A3 (fr) * 2004-07-22 2006-09-28 Bayer Pharmaceuticals Corp Derives de la quinazolinone utiles pour la regulation de l'homeostasie du glucose et de prise d'aliments
US9040533B2 (en) 2012-12-27 2015-05-26 Purdue Pharma L.P. Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators
JP2022503821A (ja) * 2018-10-22 2022-01-12 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド Ｕｓｐ７の阻害
AU2019368263B2 (en) * 2018-10-22 2025-01-23 Dana-Farber Cancer Institute, Inc. USP7 inhibition

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