WO1999019326A1 - Derives de piperidine - Google Patents

Derives de piperidine Download PDF

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Publication number
WO1999019326A1
WO1999019326A1 PCT/JP1998/004664 JP9804664W WO9919326A1 WO 1999019326 A1 WO1999019326 A1 WO 1999019326A1 JP 9804664 W JP9804664 W JP 9804664W WO 9919326 A1 WO9919326 A1 WO 9919326A1
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Prior art keywords
compound
substituted
unsubstituted
imidazo
unsubstituted lower
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PCT/JP1998/004664
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English (en)
Japanese (ja)
Inventor
Yuko Okamura
Shigeki Fujiwara
Shin-Ichi Sasaki
Kozo Yao
Hiromi Nonaka
Akira Karasawa
Koji Suzuki
Original Assignee
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 AU94620/98A priority Critical patent/AU9462098A/en
Publication of WO1999019326A1 publication Critical patent/WO1999019326A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a piperidine derivative or a pharmacology thereof, which has an adenosine uptake inhibitory activity and is useful as a drug for preventing or treating inflammation such as myocardial protection, renal diseases (nephritis, diabetic nephropathy, etc.), tengitis, and foot edema. Permissible salts.
  • An object of the present invention is to protect myocardium from myocardial injury due to anoxia such as ischemia and reperfusion injury or hypoxia by inhibiting nucleoside uptake into cells and increasing extracellular adenosine concentration.
  • Another object of the present invention is to provide a piperidine derivative or a pharmacologically acceptable salt thereof useful as an agent for preventing or treating inflammation such as renal disease (nephritis, diabetic nephropathy), inflammation or foot edema.
  • the present invention provides a compound of the formula (I)
  • Ri represents hydrogen, substituted or unsubstituted lower alkyl or halogen
  • R 2 , R 3 , R 4 and R 5 are the same or different and are hydrogen, halogen, amino, mono or di-lower alkylamino, substituted or Unsubstituted lower alkanoylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or Represents an unsubstituted lower alkanol, substituted or unsubstituted aralkyloxy or substituted or unsubstituted lower alkanoyloxy, n represents 0, 1 or 2, and X—Y represents the formula (a) or the formula (b )
  • R 6 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl
  • R 7 represents hydrogen, hydroxy
  • R 8 and R 9 are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.
  • Rio is hydrogen, substituted or unsubstituted lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, halogen or NR12R13 (wherein R12 and
  • Ri 3 is the same or different and represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or R 12 and R 13 represents represents) a substituted or unsubstituted heterocyclic group formed by including a together a connexion N
  • Rii is hydrogen, substituted or unsubstituted lower alkyl, Shiano, carboxy or substituted or unsubstituted Represents a lower alkoxycarbonyl, and Z represents 0 or S]] or a pharmacologically acceptable salt thereof.
  • the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds having other formula numbers.
  • the moiety may be a linear or branched C1-C8, e.g., methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, etc.
  • the lower alkenyl is a straight-chain or branched carbon atom having 2 to 2 carbon atoms.
  • aralkyl portion of aralkyl and aralkyloxy includes 7 to 15 carbon atoms, such as benzyl, phenethyl, Benzhydryl, naphthylmethyl and the like.
  • heterocyclic group examples include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, hexamethyleneimino and the like.
  • aryl examples include phenyl, naphthyl, biphenyl, anthryl and the like.
  • Halogen means fluorine, chlorine, bromine and iodine atoms.
  • Substituted lower alkyl, substituted lower alkylthio, substituted lower alkoxy, substituted lower alkanoylamino, substituted alkoxycarbonyl, substituted lower alkanoyl, substituted lower alkanoyloxy and substituted lower alkenyl have the same or different substituents.
  • substituents 1-3 halogen, nitro, cyano, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanol, cycloalkyl, amino, mono- or di-lower alkylamino, phthalimid and the like.
  • Substituents of substituted aryl, substituted aralkyl, substituted aralkyloxy and substituted cycloalkyl may be the same or different and have 1 to 3 halogen atoms, lower alkyl, nitro, cyano, amino, mono- or di-lower alkylamino, hydroxy, Lower alkoxy, carbonyl, lower alkoxycarbonyl, lower alkanol, methylenedioxy, trifluoromethyl and the like.
  • 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 alkoxyl ponyl, lower alkanol, and lower alkanol.
  • substituents such as halogen, lower alkyl, amino, mono- or di-lower alkylamino, hydroxy, lower alkoxy, carboxy, lower alkoxyl ponyl, lower alkanol, and lower alkanol.
  • halogen lower alkoxy, lower alkoxycarbonyl, lower alkanol, cycloalkyl, mono- or di-lower alkylamino, lower alkyl, aryl and aralkyl have the same meanings as described above.
  • Examples of the pharmacologically acceptable salt 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 acid salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, quencher And pharmaceutically acceptable metal salts, for example, alkali metal salts such as sodium salt and potassium salt, and alkaline earth salts such as magnesium salt and calcium salt.
  • Metal salts, aluminum salts, zinc salts, and the like, and pharmacologically acceptable ammonium salts include, for example, salts of ammonium, tetramethylammonium, and the like, and pharmacologically acceptable organic salts.
  • Examples of amine addition salts include addition salts of morpholine and piperidine, and examples of pharmacologically acceptable amino acid addition salts include lysine, glycine, and phenylalanine. Addition salts, and the like.
  • Compound (I) is obtained by combining compound (II) (for example, it can be synthesized according to the method disclosed in International Publication W094 / 19342 or JP-A-8-151377) with 1-2 equivalents of compound (III). If necessary, 1-3 equivalents of amines such as triethylamine and pyridin, and salts of alkali metals such as sodium carbonate and potassium carbonate, etc., and a suitable solvent, for example, lower alcohols such as methanol, ethanol, isopropanol, etc.
  • Cyclic ethers such as tetrahydrofuran (THF) and 1,4-dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidinone, dimethylsulfoxide (DMSO) and the like or a mixed solvent thereof
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMSO dimethylsulfoxide
  • Compound (V-a) is composed of compound (II) and compound (IV) (for example,
  • Compound (Vb) can be obtained by subjecting the nitro group of compound (Va) to, for example, catalytic reduction or reduction using a metal.
  • Catalytic reduction is usually carried out at room temperature and normal pressure in the presence of a catalyst such as a catalytic amount of 10 to 10 equivalents of Raney nickel, palladium carbon, platinum oxide, etc., and a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, and acetic acid. It can be performed in water or the like.
  • Reduction using a metal is, for example, 1 to
  • the reaction is carried out at a temperature from room temperature to the boiling point of the solvent used under conditions such as 100 equivalents of zinc monoacetic acid, iron monoacetic acid, iron-ferric chloride-ethanol monohydrate, iron monohydrochloride, and tin monohydrochloride.
  • the compound in which Z is 0 is the compound (Vb) and one or more equivalents of ⁇ , ⁇ ′-carbonyldiimidazole, phosgene, etc., and a catalytic amount as necessary: L0 equivalent of triethylamine
  • a base such as amines such as pyridine and pyridine
  • a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol
  • cyclic ethers such as THF and 1,4-dioxane
  • halogenation such as dichloromethane and chloroform.
  • those in which Z is represented by S are compound (Vb) and at least one equivalent of ⁇ , ⁇ '-thiocarbonyldiimidazole, carbon disulfide, tiophosgene, etc.
  • a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol; cyclic ethers such as THF and 1,4-dioxane; dichloromethane , In ethyl acetate, ether, acetonitrile, DMF, DMSO, etc., or a mixture thereof, at a temperature from 0 ° C to the boiling point of the solvent used, for 10 minutes to It can be obtained by reacting for 48 hours.
  • a base such as amines such as triethylamine and pyridine
  • a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol; cyclic ethers such as THF and 1,4-dioxane; dichloromethane , In ethyl acetate, ether, acetonitrile, DMF, DMSO, etc., or a mixture thereof, at a temperature from 0 ° C to the
  • Compound (Ib) is obtained by combining compound (Ia) with 1-2 equivalents of a compound represented by R 8 aL (wherein and L have the same meanings as described above), and 1-2 equivalents of a base such as water. 10 minutes in a suitable solvent, for example, THF, DMF, acetone, methyl ethyl ketone, etc., in the presence of sodium iodide, potassium carbonate, cesium carbonate, etc., at a temperature between 0 ° C and the boiling point of the solvent used It can be obtained by reacting for up to 24 hours.
  • a suitable solvent for example, THF, DMF, acetone, methyl ethyl ketone, etc.
  • sodium iodide, potassium carbonate, cesium carbonate, etc. at a temperature between 0 ° C and the boiling point of the solvent used It can be obtained by reacting for up to 24 hours.
  • Production method 4 In compound (I), Q is a compound of formula (ic)
  • R9, R12, R13 and n have the same meanings as above, and RlOa represents chlorine, bromine or iodine in the definition of R10)
  • the compound (Id) is the same as the compound (Ic) in which Rio is chlorine, bromine or iodine of the compound (Ib) but in an amount of 1 equivalent to a solvent amount of the formula R 12 R 13 NH (where Ri 2 and Ri 3 are An amine represented by the following formula) is optionally used in the presence of a base such as an amine such as triethylamine, pyridine or an alkali metal carbonate such as sodium carbonate or potassium carbonate in an amount of 10 to 10 equivalents of a catalyst, if necessary.
  • a base such as an amine such as triethylamine, pyridine or an alkali metal carbonate such as sodium carbonate or potassium carbonate in an amount of 10 to 10 equivalents of a catalyst, if necessary.
  • Solvents for example, lower alcohols such as methanol, ethanol, and isopropanol; cyclic ethers such as THF and 1,4-dioxane; DMF, DMA, N-methylpyrrolidinone, DMSO, etc .; or a mixed solvent of these, if necessary, in a sealed tube At a temperature from room temperature to the boiling point of the solvent used for 10 minutes to 72 hours.
  • a catalytic amount of iodinated lime, sodium iodide or the like may be appropriately added during the reaction ⁇ Ri 2 Ri 3 NH (wherein Ri 2 and Ri 3 represent the same meaning as described above.)
  • Ri 2 and Ri 3 represent the same meaning as described above.
  • Compound (I-f) can be obtained from compound (I-e) according to the method of Step 4.
  • Compound (I-j) can be obtained from compound (I-i) according to the method of Step 4.
  • Compound (1-1) can be obtained by dehydrogenating compound (I-k) obtained in Production Method 1.
  • the dehydrogenation reaction is usually carried out using 1 to 100 equivalents of potassium permanganate, palladium on carbon, etc., in a suitable solvent such as water, acetone, nitrobenzene, or a mixed solvent thereof at room temperature to the boiling point of the solvent used. At temperatures up to 1 ⁇ : done in 168 hours.
  • Production method 9 In compound (III) in production method 1, Q is a compound of the formula (id)
  • Compound (VII) is obtained by subjecting compound (VI) (for example, which can be synthesized according to the method disclosed in JP-A-61-207388) to alkylation according to the method of Step 3, and then adding acetic acid Using a solvent such as sulfuric acid, sulfuric acid or the like, or without a solvent, reducing the nitrous body obtained by the action of an equivalent or excessive amount of a nitrifying agent such as nitric acid or fuming nitric acid according to the method of Step 2-2 Can be obtained.
  • the nitration reaction is usually performed at -30 to: 1 OCTC for 1 minute to 24 hours.
  • Compound (VIII) can be obtained by reacting compound (VII) with a large excess of formamide in the absence of a solvent at room temperature to the boiling point of formamide for 1 to 24 hours.
  • Compound ( ⁇ -a) is obtained by reacting compound (VIII) with a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride or phosphorus tribromide in an amount of 1 equivalent to solvent without solvent or dichloromethane or 1,2-dichloromethane. It can be obtained by reacting in an inert solvent such as a solvent at room temperature to the boiling point of the solvent used, or in the absence of solvent at a temperature from room temperature to the boiling point of the halogenating agent used for 1 to 24 hours it can.
  • a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride or phosphorus tribromide
  • Production method 10 Of compound (III) in production method 1, Q is a compound represented by the formula (i-e)
  • Compound (IX) is obtained by reacting compound (VII) obtained in step 911 with a large excess of urea in the absence of a solvent at room temperature to the boiling point of urea for 1 to 24 hours. Can be.
  • Compound ( ⁇ -b) can be obtained by halogenating compound (IX) according to the method of Steps 9-13.
  • Production method 1 1 In compound (III) in production method 1, Q is a compound of formula (ii-b)
  • Compound (XI) can be synthesized according to the method described in compound (X) [for example, Journal of Heterocycl. Chem., 10, 891 (1973). Is cyclized according to the method of Step 2-3, and then alkylated according to the method of Step 3.
  • Compound (XII) can be obtained by converting compound (XI) with 1 equivalent to a solvent amount of hydrazine, if necessary, in the presence of a 1 equivalent to a solvent amount of a suitable base such as triethylamine, in a suitable solvent, for example, a lower solvent such as methanol or ethanol. It can be obtained by reacting in an alcohol at a temperature from room temperature to the boiling point of the solvent used for 1 to 24 hours. Compound (XII) can also be obtained according to the following method.
  • the compound (XIV) can be synthesized from the compound (XIII) according to the method described in Step 3 (for example, the compound can be synthesized according to the method described in Tetrahedron Lett., Vol. 28, p. 1389 (1987)). After alkylation according to And can be obtained by Oxidation is carried out, for example, with 1 to 10 equivalents of an appropriate oxidizing agent such as potassium permanganate, chromium trioxide, sodium dichromate, etc.
  • an appropriate oxidizing agent such as potassium permanganate, chromium trioxide, sodium dichromate, etc.
  • a suitable base such as sodium hydroxide
  • a suitable solvent for example, water, acetone, acetic acid, sulfuric acid, t-butyl alcohol, etc.
  • Compound (XII) can also be obtained according to the method of Step 111, except that compound (XIV) is used instead of compound (XI).
  • Compound (III-c) can be obtained by halogenating compound (XII) according to the method of Step 9-13.
  • Production method 1 2 Of compound (III) in production method 1, Q is a compound of formula (iii-b)
  • Compound (Illd) can be synthesized according to the method disclosed in compound (XV) (for example, JP-A-54-154797, JP-A-56-7784). ) Can be obtained by halogenating according to the method of Step 9_3.
  • Production method 13 Of compound (III) in production method 1, Q is represented by formula (iii-c)
  • Compound ( ⁇ -e) can be obtained by converting compound (XVI) (for example, which can be synthesized according to the method disclosed in JP-A-54-154797) with halogen according to the method of Steps 9-1-3. Can be obtained.
  • Production method 14 Of compound (III) in production method 1, Q is a compound of formula (iv-c)
  • the compound (XVIII) is the same as the compound (XVII) [for example, J. Heterocycl. Chem., 18, 85, 1981, Tetrahedron Lett ), P. 79 (1976) or a method analogous thereto], and, for example, 1-2 equivalents of 3-chloropropionyl chloride and the like, and 1-2 equivalents of aluminum chloride and zinc chloride.
  • a suitable solvent for example, nitrobenzene, carbon disulfide, dichloromethane, at a temperature from 0 to the boiling point of the used solvent for 1 to 24 hours, and then 1 equivalent to a solvent amount of sulfuric acid, etc. Under the temperature of 0 ° C. to the boiling point of the solvent used for 10 minutes to 24 hours.
  • Compound ( ⁇ -f) is prepared by combining compound (XVIII) with 1 equivalent to a solvent amount of isoamyl nitrite or the like in the presence of a suitable acid such as hydrochloric acid in a suitable solvent such as a lower alcohol such as methanol or ethanol. After reacting at -20 to the boiling point of the solvent used for 1 to 24 hours to obtain an oxime compound, 1 equivalent to the solvent amount of halogen such as phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, etc.
  • a suitable acid such as hydrochloric acid
  • a suitable solvent such as a lower alcohol such as methanol or ethanol.
  • Production method 15 Of compound (III) in production method 1, Q is a compound of formula (iv-b) (iv-b)
  • Compound (XX) is synthesized according to the method described in Compound (XIX) [for example, the method described in the journal “Job Med.”, J. Med. Chem., 23, 506 (1980)). Can be obtained according to the method of Step 8.
  • Compound (III-g) can be obtained by halogenating compound (XX) according to the method of Step 9-3.
  • Production method 16 Of compound (III) in production method 1, Q is a compound of formula (v-a)
  • Compound (Ill-h) can be obtained from compound (XX) in Production Method 15 by halogenation according to the method of Steps 9-13.
  • a compound having at least one amino group, mono- or di-lower alkylamino group or a lower alkanoyloxy noisy Rua amino group R 2 to R 5 are the corresponding R 2 ⁇ ! It can also be produced by reducing the compound (I) having a nitro group at 5 , and further alkylating or acylating the compound if necessary.
  • the reduction can be performed by a conventional method using, for example, catalytic reduction or a metal.
  • Contact reduction is usually carried out at room temperature and atmospheric pressure in the presence of a catalyst such as a catalytic amount of 10 equivalents of Raney Nickel Palladium Carbon, Platinum Oxide, etc., and a suitable solvent such as methanol, ethanol, ethyl acetate.
  • the reduction using a metal can be carried out under the conditions of, for example, 1 to 100 equivalents of zinc monoacetic acid, iron-acetic acid, iron monoferric chloride monoethanol monohydrate, iron monohydrochloric acid, tin monohydrochloric acid, and the like. It takes 10 minutes to 48 hours at the boiling point.
  • Alkylation and acylation of the reduction product can be carried out by using 1 to 2 equivalents of a conventional alkylating agent (eg, an alkyl octide such as methyl iodide) or an acylating agent (eg, an acid anhydride such as acetic anhydride).
  • the reduction is performed using a reducing agent such as lithium aluminum hydride or sodium borohydride in a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane, THF, etc., usually at -78: to room temperature. It can take 10 minutes to 48 hours.
  • Alkylation is carried out using a conventional organometallic reagent, for example, a Grignard reagent such as methylmagnesium amide, ethylmagnesium chloride, or the like, an organic lithium reagent such as methyllithium, butyllithium, or the like, using a suitable solvent, for example, dioxane, It is usually carried out in ether, THF, etc. at -78 to room temperature for 10 minutes to 48 hours.
  • a reducing agent such as lithium aluminum hydride or sodium borohydride in a suitable solvent
  • a suitable solvent such as methanol, ethanol, ethyl acetate, dioxane,
  • R 2 ⁇ ! Compounds having at least one carboxy group in I 5 can be cowpea in subjecting the corresponding compounds having a Asechiru group R 2 to R 5 (I) is in the haloform reaction can be produced.
  • the haloform reaction is carried out according to the method described in Journal of American's Chemical Society (J. Am. Chem. Soc .;), Vol. 72, p. 1642 (1950), etc., by chlorine or bromine and water. This is performed using a sodium hypohalite solution prepared from an aqueous sodium oxide solution.
  • the compound having at least one hydroxy group in R 2 to R 5 corresponds to the corresponding R 2 to!
  • the compound (I) having a lower alkoxy group in 5 can also be produced by dealkylation.
  • the dealkylation is carried out, for example, in the presence of 1 equivalent to a solvent amount of an acid such as hydrobromic acid or hydroiodic acid, in the absence of a solvent or in a solvent such as water, acetic acid, methanol, or a lower alcohol such as ethanol, or Force in a solvent such as DMF, DMSO, etc.
  • reaction in the presence of one or more equivalents of a thiol, such as ethanethiol or thiophenol, in the presence of a metal salt (sodium salt, potassium salt, etc.), or 1 to: L0 equivalent of trichloride
  • a thiol such as ethanethiol or thiophenol
  • metal salt sodium salt, potassium salt, etc.
  • the reaction can be carried out in a solvent such as dichloromethane in the presence of a Lewis acid such as hydrogen, boron tribromide or aluminum trichloride.
  • the reaction is room
  • the reaction is carried out at a temperature from the boiling point of the solvent used and ends in 30 minutes to 48 hours.
  • the compound having at least one lower alkoxy group in R 2 to R 5 corresponds to the corresponding R 2 to! 5 to 1 to 2 equivalents of a lower alkyl halide from a compound (I) having a hydroxy group in an inert solvent such as 1 to 2 equivalents of a base such as sodium hydride, potassium carbonate, cesium carbonate, etc. It can also be produced by reacting in THF, DMF, acetone, methyl ethyl ketone or the like at 0 to the boiling point of the used solvent for 10 minutes to 24 hours.
  • a compound having at least one carboxy sheet group R2 ⁇ R5 or Rii the corresponding R 2 ⁇ ; R 5 or a compound having a lower Arukokishikaru Boniru group R 11 (I) hydrolyzes It can also be manufactured.
  • the hydrolysis is carried out, for example, in the presence of 1 equivalent to a solvent amount of an acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid, or 1 to 10 equivalents of a base such as sodium hydroxide or hydroxylic lime, a suitable solvent such as water or methanol.
  • the reaction can be carried out in a lower alcohol such as ethanol, ethanol or isopropanol, a cyclic ether such as THF or 1,4-dioxane, or a mixed solvent thereof.
  • a lower alcohol such as ethanol, ethanol or isopropanol
  • a cyclic ether such as THF or 1,4-dioxane
  • the reaction is carried out at room temperature to the boiling point of the solvent used, and is completed in 10 minutes to 48 hours.
  • compound (I) compounds having a lower alkyl group R 6, the corresponding compound having hydrogen in R 6 and lower alkyl payment de 1-2 equivalents from (I), 1 to 2 equivalents of a base, for example,
  • the reaction is carried out in the presence of sodium hydride, potassium carbonate, cesium carbonate, etc. in an inert solvent such as THF, DMF, acetone, methyl ethyl ketone, etc. at 0 to the boiling point of the used solvent for 10 minutes to 24 hours.
  • an inert solvent such as THF, DMF, acetone, methyl ethyl ketone, etc.
  • a compound having hydrogen at Rio can also be produced by subjecting compound (I) having a corresponding halogen at Rio to the above-mentioned catalytic reduction reaction.
  • the intermediates and target compounds in the above production method are isolated and purified by purification methods commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, drying, concentration, recrystallization, various chromatographies can do. In the case of intermediates, It can be used for the next reaction without purification.
  • compound (I) when it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, and if it can be obtained in the free form, it can be purified with an appropriate organic solvent.
  • the salt may be formed by dissolving or suspending and adding an acid or a base.
  • Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents. These adducts may also be used as the drug of the present invention. it can.
  • Some of the compounds (I) may have stereoisomers such as optical isomers, cis-trans isomers, and diastereoisomers, but the present invention relates to all possible stereoisomers and Also included are mixtures thereof.
  • Table 1 Table 2, Table 3, Table 4, and Table 5 show specific examples of the compound (I) obtained by the above production method.
  • Test Example 1 [ 3 H] —adenosine uptake inhibitory action
  • Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms.
  • the pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier as an active ingredient.
  • these pharmaceutical compositions are in unit dosage form suitable for administration orally or by injection.
  • any useful pharmacologically acceptable carrier can be used.
  • oral liquid preparations such as suspensions and mouthwashes include water, sugars such as sucrose, sorbitol, fructose, daricols such as polyethylene glycol and propylene glycol, sesame oil, olive oil, It can be produced using oils such as soybean oil, preservatives such as P-hydroxybenzoic acid esters, and flavors such as stove belly flavor and peppermint.
  • Powders, pills, capsules and tablets include lactose, glucose, sucrose, mannitol, etc., excipients, starch, sodium alginate, etc., disintegrants, magnesium stearate, talc, etc., polyvinyl alcohol, hydroxy It can be produced using a binder such as propylcellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unitary oral dosage forms because of their ease of administration. When producing tablets and capsules, solid pharmaceutical carriers are used.
  • Injectables are distilled water, salt solution, glucose solution or saline and glucose It can be prepared using a carrier consisting of a mixture of solutions. 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.
  • Second step 3- [1- (6-amino-7-ethylaminoquinazoline-4-yl) -4-piperidinyl] -1,2,3,4-tetrahydro-1 obtained in the first step , 6-Dimethyl-2,4-dioxoquinazoline 298 mg (0.65 mmol) was dissolved in acetonitrile 40 ml, ⁇ , ⁇ -carbonyldiimidazole 317 mg (1.95 mmol) was added, and the mixture was heated with stirring at 60 for 2 hours. .
  • Second step The compound bb obtained in the first step is dissolved in 20 ml of methanol, and 0.4 ml (3.00 mmol) of triethylamine and 1,2,3,4- can be synthesized by the method described in International Publication W094 / 19342.
  • Add 354 mg (l.OO mmol) of tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-pyridinyl) quinazoline hydrobromide heat the mixture for 1 hour, and depressurize the solvent. After evaporation, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed, dried, and the solvent was distilled off.
  • Example 1 1,3-Getyl-2,3-dihydro-8- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -6-morpholino-1H-imidazo [4,5-g] quinazolin-2-one (Compound 12)
  • Example 11 except that Compound 9 obtained in Example 9 was used instead of Compound 8 OM 13d7 ⁇ K
  • Example 15 The title compound was obtained as white crystals according to the method of Example 3 except that the compound 15 obtained in Example 15 was used instead of the compound 1 and that methyl iodide was used instead of methyl iodide. (Yield 28%).
  • Example 3 The title compound was obtained as white crystals according to the method of Example 3 except that the compound 15 obtained in Example 15 was used instead of the compound 1 and propyl iodide was used instead of methyl iodide. (Yield 26%).
  • Second step Dissolve 710 mg (2.50 mmol) of the compound obtained in the first step in 20 ml of DMF 890 mg (2.50 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3- (4-piperidinyl) quinazoline hydrobromide and potassium carbonate 1.04g
  • Example 2 8-chloro-1,3-getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo Quinazoline-3-yl) -1-piperidinyl] -1,3-dimethyl-1H-imidazo [4,5-g] phthalazin-2-one (compound 26)
  • Example 2 4 1,3-Dibutyl-8-cyclo-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo Quinazoline-3-yl) -1-piperidinyl] -1 ⁇ -imidazo [4,5-g] phthalazin-2-one (compound 29) 1,3-Dibutyl-2,3,5,6,7,8-hexahydro-1H, 6H, 7H-imidazo [4,5-g] phthalazine- obtained in Reference Example 13 in place of compound j The title compound was obtained as white crystals according to the method of Example 20 except that 2,5,8-trione (compound o) was used.
  • Example 28 The title compound was obtained as white crystals (yield: 22%) according to the method of Example 28 except that the compound 29 obtained in Example 24 was used instead of the compound 25.
  • Second step 1.05 g (1.75 mmol) of the free base obtained in the first step was dissolved in 20 ml of ethyl acetate, and an excess amount of a saturated hydrogen chloride / monoethyl acetate solution was added dropwise at room temperature and stirred for 10 minutes. . The precipitated crystals were collected by filtration, washed with ethyl acetate, and recrystallized from ethanol to give 0.93 g (yield 84%) of the title compound as white crystals.
  • the title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 25 obtained in Example 20 was used instead of the compound 26 (44% yield). .
  • Example 36 1, 3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-piperidinyl] -8- (4-methyl-1-piperazinyl) -1H-imidazo [4,5-g] phthalazin-2-one dihydrochloride (Compound 36)
  • the title compound was obtained as white crystals (two-step yield: 46%) according to the method of Example 33 except that hexamethyleneimine was used instead of morpholine.
  • Example 4 1 1,3-Getyl-2,3-dihydro-5- [4- (l, 2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline-3- Yl) -1-Piperidinyl] -8-dimethylamino-1H-imidazo [4,5-g] phthalazin-2-one hydrochloride
  • the title compound was obtained as white crystals according to the method of Example 33 except that propylamine was used instead of morpholine and DMF was used instead of N-methylpyrrolidinone (two-step yield: 29%).
  • the title compound was obtained as white crystals according to the method of Example 33 except that dipropylamine was used instead of morpholine (two-step yield: 13%).
  • the title compound was obtained as white crystals (two-step yield: 65%) according to the method of Example 33 except that propylamine was used instead of morpholine.
  • the title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 30 obtained in Example 25 was used instead of the compound 26 (yield: 50%). .
  • the title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 31 obtained in Example 26 was used instead of the compound 26 (37% yield). .
  • the title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 32 obtained in Example 27 was used instead of the compound 26 (46% yield). .
  • the title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 60 obtained in Example 60 was used instead of the compound 26 (yield: 39%). .
  • the title compound was obtained as white crystals according to the method of the first step of Example 33, except that the compound 63 obtained in Example 62 was used instead of the compound 26 (yield: 12%). .
  • Second step 4.4 g (20.0 mmol) of the compound obtained in the first step was dissolved in 10 ml of acetic anhydride, and 1.02 ml (25.0 mmol) of fuming nitric acid was added dropwise, followed by stirring at room temperature for 20 minutes. Ice water was added thereto, and the precipitated crystals were filtered off and washed with water to give 2,3-dihydro-1,3-dimethyl-6-dito-2-oxo-1H-benzoimidazole-5. -A crude product of methyl carboxylate 4.0 g was obtained (yield 75%).
  • Second step The title compound was obtained as white crystals (yield 79%) according to the method of the first step of Example 2, except that the compound obtained in the first step was used.
  • the title compound was converted into white crystals according to the method of Reference Example 5, except that methyl mino-1,3-getyl-2,3-dihydro-2-oxo-1H-benzimidazol-5-carboxylate was used. (Two-step yield 70%).
  • 6-Amino-2,3-dihydro-1,3-dimethyl-2-oxo-1H-benzimidazole-5-force obtained in accordance with the method of the second step of Reference Example 2 in place of methyl rubonate 6 According to the method of Reference Example 5, except that methyl 2-amino-1,3-dimethyl-2,3-dihydro-2-oxo-1,3-dipropyl-1H-benzimidazole-5-carboxylate was used. Thus, the title compound was obtained as white crystals (two-step yield: 55%).
  • First step can be synthesized by a known method [for example, the method described in J. Heterocycl. Chem., 10, 891 (1973)]. Dissolve 9.24 g (41.2 mmol) of dimethyl 5-diaminofurate in 100 ml of acetonitrile, and add 10.4 g of ⁇ , ⁇ -carbonyldiimidazole
  • Second step 2.50 g (10.0 mmol) of the compound obtained in the first step was suspended in 45 ml of DMF, 0.88 g (22.0 mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes.
  • Second step Dissolve 1.00 g (4.58 mmol) of the compound obtained in the first step in a mixed solvent of 10 ml of 2-methyl-1-propanol and 15 ml of water. 3.62 g (22.9 mmol) of lithium was gradually added. After heating and stirring at 110 for 1 hour, 1.45 g (9.16 mmol) of potassium permanganate was further added gradually,
  • the title compound was obtained as white crystals according to the method of Reference Example 9 except that propyl iodide was used instead of methyl iodide (three-step yield: 57%).
  • the title compound was obtained as white crystals according to the method of Reference Example 10 except that isopropyl iodide was used in place of iodinated chill (three-step yield: 19%).
  • the title compound was obtained as white crystals (33% yield) according to the method of Reference Example 10 except that butyl iodide was used instead of iodinated chill.
  • the title compound was obtained as white crystals according to the method of Reference Example 10 except that isobutyl iodide was used instead of iodide tyl (three-step yield: 20%).
  • the title compound was obtained as white crystals according to the method of Reference Example 9 except that aryl bromide was used instead of methyl iodide (three-step yield: 46%).
  • 1,3-Jetyl-2,3,5,6-tetra can be synthesized by the method described in JP-A-56-7784. Using hydro-2,5-dioxo-1H-imidazo [4,5-g] quinoline-7-carboxylate, according to the method described in New Experimental Chemistry, Vol. 14, p. 2075 (Maruzen, 1978). To give the title compound.
  • Example 2 was repeated except that ethyl 1,3-getyl-2,3,5,6-tetrahydro-2,5-dioxo-1H-imidazo [4,5-g] quinolin-7-carboxylate was used.
  • the title compound was obtained according to a one-step procedure (95% yield).
  • the title compound was obtained according to the method described in JP-A-54-154797, except that getyl malonate was used in place of ethyl acetate.
  • First step Commercially available 2-hydroxybenzimidazole is used in place of methyl 2,3-dihydro-2-oxo-1H-benzimidazol-5-carboxylate, and methyl iodide is used instead of methyl iodide.
  • methyl iodide is used instead of methyl iodide.
  • Second step 875 mg (6.56 mmol) of aluminum chloride are suspended in 3 ml of carbon disulfide, and 1.04 g (5.46 mmol) of the compound obtained in the first step and 0.55 ml (5.76 mmol) of 3-chloropropionyl chloride are obtained.
  • Drop 5 ml of carbon disulfide solution over 5 minutes under ice-cooling The mixture was stirred at 50 for 4 hours. After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure, and 15 ml of sulfuric acid was added dropwise to the obtained residue under ice-cooling, and the mixture was heated and stirred at 100 for 1.5 hours.
  • First step Using 5-amino-1,3-dimethyl-2,3-hydroxy-1H-benzimidazol-2-one, which can be synthesized by a known method, using the journal 'OB' Medicinal Chemistry (J. Med. Chem.), 23, p. 506 (1980), based on the method described in 1,3-Getyl-2,3,5,6,7,8-hexahydro-1H, 6H- The imidazo [4,5-g] quinoline-2,7-dione was obtained.
  • Second step The title compound was obtained as white crystals according to the method of the first step of Example 2 except that the compound obtained in the first step was used (yield: 88%).
  • a piperidine derivative or a drug having adenosine uptake inhibitory activity and useful for preventing or treating inflammation such as myocardial protection, renal diseases (nephritis, diabetic nephropathy, etc.), tengitis, or foot edema
  • inflammation such as myocardial protection, renal diseases (nephritis, diabetic nephropathy, etc.), tengitis, or foot edema
  • a physically acceptable salt is provided.

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Abstract

L'invention concerne des dérivés de pipéridine, qui correspondent à la formule générale (I), ou leurs sels pharmaceutiquement acceptables. Dans cette formule (I) R1 représente hydrogène, alkyle inférieur (non)substitué, etc.; R?2, R3, R4 et R5¿ peuvent être identiques ou différents, chacun représentant halogéno, amino, mono- ou di(alkyle inférieur)amino, alcanoylamino inférieur (non)substitué, etc.; n correspond à 0, à 1 ou à 2; X-Y correspond soit à la formule (a), soit à la formule (b) et Q correspond à la formule (i), (ii), (iii), (iv) ou (v).
PCT/JP1998/004664 1997-10-15 1998-10-15 Derives de piperidine WO1999019326A1 (fr)

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JP28176997 1997-10-15
JP9/281769 1997-10-15

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003057254A1 (fr) * 2001-12-28 2003-07-17 Takeda Chemical Industries, Ltd. Produits preventifs/remedes contre les troubles urinaires
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
US9040533B2 (en) 2012-12-27 2015-05-26 Purdue Pharma L.P. Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08151377A (ja) * 1994-11-25 1996-06-11 Kyowa Hakko Kogyo Co Ltd キナゾリン誘導体
JPH09165385A (ja) * 1994-08-26 1997-06-24 Kyowa Hakko Kogyo Co Ltd キナゾリン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09165385A (ja) * 1994-08-26 1997-06-24 Kyowa Hakko Kogyo Co Ltd キナゾリン誘導体
JPH08151377A (ja) * 1994-11-25 1996-06-11 Kyowa Hakko Kogyo Co Ltd キナゾリン誘導体

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
WO2003057254A1 (fr) * 2001-12-28 2003-07-17 Takeda Chemical Industries, Ltd. Produits preventifs/remedes contre les troubles urinaires
US7132547B2 (en) 2001-12-28 2006-11-07 Takeda Pharmaceutical Company Limited Preventives/remedies for urinary disturbance
US7138533B2 (en) 2001-12-28 2006-11-21 Takeda Pharmaceutical Company Limited Preventives/remedies for urinary disturbance
US7462628B2 (en) 2001-12-28 2008-12-09 Takeda Pharmaceutical Company Limited Preventives/remedies for urinary disturbance
US9040533B2 (en) 2012-12-27 2015-05-26 Purdue Pharma L.P. Oxime-substituted-quinoxaline-type piperidine compounds as ORL-1 modulators

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