EP0000485A1 - Pipéridino-propanols, leur préparation et compositions pharmaceutiques les contenant - Google Patents

Pipéridino-propanols, leur préparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0000485A1
EP0000485A1 EP78100308A EP78100308A EP0000485A1 EP 0000485 A1 EP0000485 A1 EP 0000485A1 EP 78100308 A EP78100308 A EP 78100308A EP 78100308 A EP78100308 A EP 78100308A EP 0000485 A1 EP0000485 A1 EP 0000485A1
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Prior art keywords
formula
lower alkyl
optionally substituted
hydroxy
compound
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German (de)
English (en)
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Kurt Dr. Eichenberger
Hans Dr. Kühnis
Franz Dr. Ostermayer
Herbert Dr. Schröter
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Novartis AG
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Ciba Geigy AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • the invention relates to new piperidino-propanols, in particular ⁇ 1- (3-heterocyclyloxy-2-hydroxypropanol) -4- (N-diazacyclyl) piperidines of the formula wherein R 1 represents an optionally substituted heteroaryl radical, R 2 represents hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical or an acyl radical, and alk represents lower alkylene which separates the two nitrogen atoms from one another by 2 or 3 carbon atoms, or stands for an optionally substituted 1,2-phenylene radical, and their salts, and processes for their preparation, furthermore pharmaceutical preparations containing these compounds and their use, preferably in the form of pharmaceutical preparations.
  • a heteroaryl radical R 1 is an optionally substituted, preferably monccyclic and bicyclic, heteroaryl radical, Line one if necessary, eg simple, substituted, preferably monocyclic azaaryl radical having 5 to 6 ring members and 1 to 2 ring nitrogen atoms, such as optionally substituted pyridyl, for example 2-, 3- or 4-pyridyl, imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, pyridazinyl , for example 2-pyridazinyl, or pyrazinyl, for example 2-pyrazinyl; an optionally substituted bicyclic azaaryl radical, in particular benzoazaaryl radical, having 5 to 6 ring members and 1 to 2 ring nitrogen atoms in the azaaryl radical; as optionally substituted indolyl, for example 4-indolyl, quinolinyl, for example 4-quinolinyl, or is
  • Optionally substituted aliphatic hydrocarbon radicals R 2 are corresponding lower alkyl, and lower alkenyl or lower alkynyl, substituents, in particular lower alkyl, being primarily etherified or esterified hydroxy or mercapto, acyl or optionally substituted amino.
  • Optionally substituted cycloaliphatic and cycloaliphatic-aliphatic hydrocarbon radicals R 2 are cycloalkyl, preferably with 3-8, in particular 5-7 ring carbon atoms, or cycloalkenyl, preferably with 5-8, in particular 6 or 7 ring carbon atoms. also cycloalkyl-lower alkyl, and cycloalkenyl-lower alkyl, in which cycloalkyl or cycloalkenyl have the meanings given above.
  • Substituents of cycloaliphatic and cycloaliphatic-aliphatic hydrocarbon radicals are primarily optionally substi tuiert aliphatic hydrocarbon residues, optionally etherified or esterified hydroxy or oxo.
  • Araliphatic hydrocarbon radicals R 2 are primarily substituted phenyl-lower alkyl, in which phenyl may contain substituents, for example optionally substituted aliphatic hydrocarbon radicals, optionally etherified hydroxy or mercapto, acyl, nitro or optionally substituted amino.
  • Optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents of a heteroaryl radical R 1 or of cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radicals R 2 contain, inter alia, optionally etherified or esterified hydroxyl groups or optionally substituted amino as substituents.
  • Etherified hydroxy is, in particular, lower alkoxy or phenyl-lower alkoxy, furthermore lower alkenyloxy or lower alkynyloxy, and also hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylthione-lower alkoxy or lower alkanoyl-lower alkoxy, while esterified hydroxy is especially halogen, furthermore lower alkanoyloxy.
  • Etherified mercapto is primarily lower alkylthio, while esterified mercapto is e.g. Niederalkanoylthio is.
  • Acyl is preferably the corresponding residue of an organic carboxylic acid and in particular represents lower alkanoyl.
  • Acyl also stands for. the corresponding radical of a carbonic acid derivative, such as for lower alkoxycarbonyl or optionally substituted carbamoyl.
  • An acyl radical in the broadest sense of the definition is also cyan.
  • Optionally substituted amino is acyl amino, in particular lower alkanoylamino or lower alkoxycarbonylamino, furthermore optionally substituted ureido.
  • Substituted amino is also lower alkylamino or di-lower alkylamino, as well as lower alkylene amino, lower oxaalkylene amino or lower azaalkylene amino, the latter in which the aza nitrogen is preferably substituted, for example by lower alkyl.
  • Niederalky.len alk is preferably unbranched lower alkylene and primarily ethylene, and 1,3-propylene, but can also be branched lower alkylene, such as 1,2-propylene, 1,2- or 2,3-butylene.
  • alk represents the 1,2-phenyl.en radical, this can be substituted by lower alkyl, lower alkoxy or halogen.
  • radicals and compounds designated "lower" in connection with the present description preferably contain up to 7 and primarily up to 4 carbon atoms.
  • Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; Substituted lower alkyl is in particular corresponding methyl or 1- or 2-ethyl.
  • Lower alkenyl is e.g. Vinyl, allyl, 2- or 3-methallyl or 3,3-dimethylallyl.
  • Lower alkynyl is especially propargyl.
  • Cycloalkyl is primarily cyclopentyl,. Cyclohexyl or cycloheptyl, also cyclopropyl or cyclooctyl.
  • Cycloalkenyl is e.g. 1- or 3-cyclohexenyl or 1-cycloheptenyl.
  • Cycloalkyl-lower alkyl is, for example, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cyclo heptylmethyl.
  • Cycloalkenyl-lower alkyl is e.g. for 1-cyclohexenylmethyl, 2- (1-cyclohexenyl) ethyl or 1-cycloheptenylmethyl.
  • Phenyl lower alkyl is i.a. Benzyl, 1- or 2-phenylethyl or 3-phenylpropyl.
  • Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy.
  • Phenyl lower alkoxy is e.g. Benzyloxy or 1- or 2-phenylethoxy.
  • Hydroxy lower alkoxy is e.g. 2-hydroxyethoxy, also 2- or 3-hydroxypropyloxy.
  • Lower alkoxy lower alkoxy includes Lower alkoxymethoxy or 1- and especially 2-lower alkoxy-ethoxy, e.g. Methoxy-methoxy, 2-methoxy-ethoxy or 2-ethoxy-ethoxy.
  • Lower alkylthione lower alkoxy is especially lower alkylthiomethoxy or 1- and primarily 2-lower alkylthioethoxy, e.g. 2-methylthio-ethoxy or 2-ethylthio-ethoxy.
  • Lower alkanoyl lower alkoxy is especially acetonyloxy.
  • Lower alkenyloxy is e.g. Allyloxy, 2- or 3-methallyloxy or 3,3-dimethylallyloxy.
  • Lower alkynyloxy is especially propargyloxy.
  • Halogen is preferably halogen with an atomic number up to 35, i.e. Fluorine, chlorine or bromine.
  • Lower alkanoyloxy is e.g. for acetyloxy, propionyloxy or pivaloyloxy.
  • Lower alkylthio is e.g. Methylthio, ethylthio, n-propylthio or isopropylthio.
  • Niederalkanoylthio is i.a. Acetylthio or propionylthio.
  • Lower alkanoyl is e.g. Acetyl, .propionyl or butyryl.
  • Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl.
  • Optionally substituted carbamoyl is e.g. Carbamoyl, or N-lower alkyl or N, N-di-lower alkyl carbamoyl, such as N-methyl-carbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl or N, N-diathylcarbamoyl.
  • Niederalkanoylamino is e.g. Acetylamino or propionylamino.
  • Lower alkoxycarbonylamino is e.g. Methoxycarbonylamino or ethoxycarbonylamino.
  • Optionally substituted ureido is e.g. Ureido or 3-lower alkyl or 3-cycloalkyl-ureido, in which cycloalkyl e.g. Has 5-7 ring links, e.g. 3-methylureido, 3-ethylureido or 3-cyclohexylureido.
  • N-lower alkylamino and N, N-di-lower alkylamino are e.g. Methylamino, ethylamino, dimethylamino or diethylamino.
  • Lower alkylene amino preferably contains 5-7 ring carbon atoms and is e.g. Pyrrolidino or Piperidino.
  • Niederoxaalkylenamino is primarily morpholino, while Niederazaalkylenamino in particular corresponding N-Niederalkyl-Niederazaalkylenamino, e.g. 4-methyl-1-piperazino.
  • the substituted lower alkyl groups include, for example, hydroxy lower alkyl, lower alkoxy lower alkyl, halogen lower alkyl, lower alkanoylamino lower alkyl or Lower alkoxymethyl or 1- and primarily 2-lower alkoxyethyl, for example methoxymethyl, ethoxymethyl, 2-methoxyethyl or 2-ethoxyethyl.
  • Halogen lower alkyl is preferably halomethyl, e.g. Trifluoromethyl.
  • Lower alkanoylamino lower alkyl is especially lower alkanoylaminomethyl or 1- and primarily 2-lower alkanoylamino-ethyl, e.g. Acetylaminomethyl, 2-acetylamino-ethyl or 2-propionylamino-ethyl.
  • Lower alkoxycarbonylamino-lower alkyl is especially lower alkoxycarbonylaminomethyl, or 1- and primarily 2-lower alkoxycarbonylamino-ethyl, e.g. Methoxycarbonylaminomethyl, 2-methoxycarbonylamino-ethyl or 2-Aethoxycarbonylamino-ethyl.
  • the new compounds can be in the form of their salts, such as their acid addition salts and primarily their pharmaceutically usable, non-toxic acid addition salts.
  • Suitable salts are e.g. those with inorganic acids such as hydrohalic acids e.g. Hydrochloric acid or hydrobromic acid, sulfuric acids, e.g. Sulfuric acid, or phosphoric acids, or with organic acids such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, e.g.
  • Ant vinegar, propion, amber, glycol, milk, apple, wine, lemon, ascorbic, maleic, hydroxymalein, pyruvic, fumaric, benzoic, 4-aminobenzoic, Anthranil, 4-hydroxybenzoic, salicyl, 4-aminosalicyl, embon, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethylenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid.
  • the new compounds of the present invention can be in the form of mixtures of isomers, such as racemates, or of pure isomers, for example optically active Antipodes.
  • the new compounds have valuable pharmacological properties. So they show an antihypertensive effect, as shown in animal experiments, e.g. when administered intravenously in doses of approximately 0.1 to approximately 30 mg / kg on the anesthetized cat. '
  • the new compounds cause antitachycardia, as can also be shown in animal experiments, for example in in vitro experiments at concentrations of about 1 to about 100 y / ml in guinea pig hearts (Langendorff preparation), and an a-sympathicolysis, for example in in vitro experiments at concentrations of about 0.01 to about 10 ⁇ / ml in the rat (isolated perfused mesenteric artery preparation; according to a modification of the method by McGregor, J.
  • the new compounds can therefore be used as antihypertensives, antitachycardica and a-sympathicolytica. Furthermore, the new compounds can serve as starting or intermediate products for the production of other, in particular therapeutically active, compounds.
  • the invention relates first and foremost to compounds of the formula I in which R, optionally substituted monocyclic heteroaryl or benzoheteroaryl having 5 to 6 ring members and 1 or 2 ring nitrogen atoms in the radical R 1 , where substituents of the heterocyclic aryl radical optionally substituted lower alkyl, for example lower alkyl, lower alkoxy lower alkyl , Lower alkanoylamino lower alkyl or lower alkoxycarbonylamino Is hydrogen or optionally substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or phenyl-lower alkyl, where substituents of these radicals are, for example, optionally substituted lower alkyl, for example lower alkyl, or optionally etherified or esterified hydroxy or mercapto, for example lower alkoxy, lower alkylthio and / or halogen, or further for lower alkanoyl or lower alkoxycarbonyl, and alk has
  • R 1 is monocyclic monoazaaryl or diazaaryl with six ring gliders, optionally substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio or ethylthio, halogen with an atom number of up to 35, for example chlorine or bromine, and / or nitro, such as pyridyl, for example 2-, 3- or 4-pyridyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, pyrazinyl, for example 2-pyrazinyl or indolyl, for example 4-indolyl, R 2 for hydrogen, lower alkyl, for example methyl, ethyl or isopropyl, cycloalkyl, for example cyclopentyl or optionally substituted in the phenyl part by lower alkyl, for example methyl, lower alkoxy, for
  • the invention relates in particular to compounds of the formula I in which R 1 is optionally lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio or ethylthio, halogen with atom numbers up to 35, for example chlorine or bromine, and / or nitro, substituted 2-pyrazinyl, and for optionally appropriately substituted pyridyl, for example 2- , or 3-pyridyl, where substituents can have any position, but at least one, preferably the ortho position to the linking ring carbon atom and / or nitrogen atom of the heteroaryl radical, and 4-indolyl, and R 2 is hydrogen, lower alkyl, for example methyl, ethyl or isopropyl, or phenyl-lower alkyl, for example benzyl or 1- or 2-phenylethyl, and alk means lower alkylene with 2-3 carbon atoms, which separates the two nitrogen atoms by
  • the invention relates primarily to compounds of the formula I in which R 1 is 2-pyrazinyl, furthermore pyridyl, for example 2- or 3-pyridyl, and 4-indolyl, preferably in the ortho position to the linking carbon atom and / or nitrogen atom is substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio or ethylthio, halogen with an atom number of up to 35, for example chlorine or bromine, or nitro, and may optionally contain further substituents of this type, R 2 in particular for hydrogen, furthermore represents lower alkyl, for example methyl, or phenyl-lower alkyl, for example benzyl, and alk represents ethylene, and salts, in particular acid addition salts, primarily pharmaceutically usable, non-toxic acid addition salts thereof.
  • R 1 is 2-pyrazinyl, furthermore pyridyl, for example 2- or 3-
  • the invention relates first and foremost to compounds of the formula I in which R 1 is 4-indolyl, 2-pyrazinyl or pyridyl, which is ortho to the linkage carbon atom and / or nitrogen atom, preferably by lower alkyl, for example methyl, lower alkoxy, for example Methoxy, lower alkylthio, for example methylthio or ethylthio, halogen with an atom number of up to 35, for example chlorine or bromine, or nitro is substituted, R 2 is hydrogen, furthermore lower alkyl, for example methyl, and alk is ethylene, and salts, in particular acid addition salts, in primarily pharmaceutically usable, non-toxic acid addition salts thereof.
  • R 1 is 4-indolyl, 2-pyrazinyl or pyridyl, which is ortho to the linkage carbon atom and / or nitrogen atom, preferably by lower alkyl, for example methyl, lower alkoxy, for example Methoxy, lower alkyl
  • the invention relates primarily to the compounds described in the examples; in particular those of the formula I which have a preferably substituted 2-pyrazinyl radical as the radical R 1 .
  • the new compounds are obtained by methods known per se. For example, you can combine the formula or a salt thereof with a compound of the formula or a salt thereof, in which one of the radicals X 1 and X 2 is hydrogen and the other the rest of the formula corresponds in which X 3 is a free hydroxyl group, and X 4 be a reactive esterified hydroxyl group or where X 3 and X 4 together form an epoxy group and, if desired, convert an available compound into another compound of formula I and / or, if desired, convert an available free compound into a salt, and / or , if desired, convert an available salt into the free compound or another salt, and / or, if desired, separate an available mixture of isomers into the isomers.
  • the reactive esterified hydroxyl group X 4 is a strong, inorganic or organic acid, especially a hydrohalic acid, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, furthermore sulfuric acid or hydroxyl group esterified by an organic sulfonic acid, such as an aromatic sulfonic acid, for example benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid.
  • X 4 stands in particular for chlorine or bromine, also iodine, if it does not form an epoxy group together with X 3 .
  • the above implementation is carried out in the usual way. If a reactive ester is used as the starting material of the formula IIa, the reaction is preferably carried out in the presence of a basic condensing agent and / or with an excess of the basic compound of the formula IIIa.
  • the compound of formula IIIb is preferably in the form of a salt, such as a metal, especially an alkali metal, e.g. Sodium or potassium salt used, or one works in the presence of an acid-binding agent, in particular a condensing agent, which is able to form a salt with the compound of formula IIIb, such as an alkali metal lower alkoxide.
  • a salt such as a metal, especially an alkali metal, e.g. Sodium or potassium salt used, or one works in the presence of an acid-binding agent, in particular a condensing agent, which is able to form a salt with the compound of formula IIIb, such as an alkali metal lower alkoxide.
  • the above reaction is carried out in the absence or, preferably, in the presence of a, usually inert, solvent or diluent and, if necessary, with cooling or heating, e.g. in a temperature range from about 0 ° C to about 150 ° C, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere performed.
  • a, usually inert, solvent or diluent e.g., a temperature range from about 0 ° C to about 150 ° C
  • an inert gas e.g. Nitrogen atmosphere performed.
  • the starting materials are known or can be obtained in a manner known per se.
  • piperidin-4-one in which the secondary amino group may be in a manner known per se, for example by a benzyl firmly or an easily removable acyl radical can be protected, - react with a diamine of the formula HZ 2 0N-alk-HN-R 2 (V) and at the same time or subsequently with a suitable reducing agent, such as catalytically activated hydrogen or a hydride reducing agent, for example sodium cyanoborohydride, to treat.
  • a suitable reducing agent such as catalytically activated hydrogen or a hydride reducing agent, for example sodium cyanoborohydride
  • the 2-oxo-1,3-diazacycloalkane radical is formed, for example by treatment with a suitable reactive carbonic acid derivative, such as di-lower alkyl carbonate or phosgene; if necessary, an N-protecting group can be replaced by hydrogen in a manner known per se.
  • a starting material of the formula IIIa thus obtainable can be prepared in a manner known per se, for example by treatment with a reactive ester of a 2,3-epoxy-1-propanol, such as a 2,3-epoxy-1-propyl halide, and, if desired, by subsequent reaction with a strong acid, such as a hydrohalic acid, can be converted into a starting material of the formula IIb.
  • the new compounds can also be obtained by using a compound of the formula wherein X 5 is a hydroxyl-convertible radical, X 5 is converted to hydroxyl and, if desired, carries out the additional process steps.
  • X 5 is in particular an esterified hydroxyl group and primarily acyloxy, in which acyl is the corresponding radical of an organic carboxylic acid, such as a lower alkane carboxylic acid, for example acetyl, propionyl or pivaloyl, or an aromatic carboxylic acid, for example benzoyl.
  • acyl is the corresponding radical of an organic carboxylic acid, such as a lower alkane carboxylic acid, for example acetyl, propionyl or pivaloyl, or an aromatic carboxylic acid, for example benzoyl.
  • the conversion of X 5 into hydroxy can be carried out by means of solvolysis, in particular by hydrolysis, it being possible to work with water in an alkaline or acidic medium, or by alltolysis (transesterification), for example using a lower alkanol, for example methanol or ethanol, optionally in the presence of a transesterification catalyst, such as an alkali metal lower alkanolate, for example sodium or potassium methoxide, ethanolate or butoxide.
  • the reaction is carried out in the absence or presence of solvents or diluents and, if necessary, with cooling or heating, for example in a temperature range from about 0 ° C. to about 120 ° C., in a closed vessel and / or in an inert gas atmosphere .
  • the starting materials of the formula VI can be obtained, for example, by converting X 3 into a esterified hydroxyl group which can be converted to hydroxyl, for example by acylation with a compound of the formula IIa in which X 3 is hydroxyl and X 4 is a reactive esterified hydroxyl group reactive derivative, such as an optionally mixed anhydride, an organic carboxylic acid, converted into acyloxy and the intermediate thus obtainable, preferably in excess, reacted with a compound of formula IIIa.
  • the new compounds can also be obtained if one is in a compound of the formula wherein X ⁇ represents an anion, reduces the pyridinium ring to the piperidine ring, and, if desired, carries out the additional process steps.
  • An anion X ⁇ is in particular that of an acid, preferably a mineral, such as hydrohalic, for example hydrochloric or hydrobromic acid, or a suitable organic carbon or sulfonic acid.
  • an acid preferably a mineral, such as hydrohalic, for example hydrochloric or hydrobromic acid, or a suitable organic carbon or sulfonic acid.
  • the above reduction can be carried out in a conventional manner, preferably by means of catalytic hydrogenation, such as with hydrogen in the presence of a suitable hydrogenation catalyst, e.g. a heavy metal e.g. Palladium, platinum or Raney nickel catalyst, or by treatment with nascent hydrogen, such as by treatment with an alkali metal, e.g. Sodium or potassium, in the presence of an alcohol, such as lower alkanol, for example ethanol or n-butanol.
  • a suitable hydrogenation catalyst e.g. a heavy metal e.g. Palladium, platinum or Raney nickel catalyst
  • nascent hydrogen such as by treatment with an alkali metal, e.g. Sodium or potassium
  • an alcohol such as lower alkanol, for example ethanol or n-butanol.
  • the carbonyl group is reduced to the methylene group, for example by treatment with lithium aluminum hydride, and the 2-oxc-1,3-diazacycloalkane ring is formed, for example by treatment with phosgene.
  • the 4- (2-oxo-3-R 2 -1, 3-diazacycloalkyl-1-yl) pyridine compound obtainable in this way is then reacted with a compound of the formula IIa in which X 3 is hydroxyl and X 4 is a reactive esterified hydroxyl group, especially halogen, are implemented.
  • Die.new compounds of formula I can also be obtained by in a compound of formula wherein one of X 6 and X 7 is hydrogen and the other is the acyl radical of a carbonic acid half-derivative which forms the 2-oxo-1,3-diazacycloalkane ring by ring closure and, if desired, carries out the additional process steps.
  • the acyl residue of a carbonic acid half derivative means the corresponding residue of a carbonic acid half ester such as lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl, a carbonic acid halide, i.e. Halocarbonyl, e.g. Chlorocarbonyl or bromocarbonyl, or a carbonic acid halamide, e.g. Carbamoyl.
  • a carbonic acid half ester such as lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl
  • a carbonic acid halide i.e. Halocarbonyl, e.g. Chlorocarbonyl or bromocarbonyl
  • a carbonic acid halamide e.g. Carbamoyl.
  • the ring closure is carried out in the absence or presence of a solvent or diluent and, if necessary, in the presence of a, preferably basic, condensing agent, such as an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate or lower alkanoate, and an organic base, such as a tertiary amine or a base of the pyridine type, with cooling or preferably heating, for example in a temperature range from about + 20 ° C to about 150 ° C, in a closed vessel and / or in an inert gas atmosphere. carried out.
  • a, preferably basic, condensing agent such as an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate or lower alkanoate
  • an organic base such as a tertiary amine or a base of the pyridine type
  • the starting material of the formula XII is prepared by methods known per se and preferably in situ by reacting a compound of the formula XII, in which X 6 and X 7 are hydrogen, with a reactive derivative of carbonic acid.
  • Reactive derivatives of carbonic acid are corresponding esters, such as di-lower alkyl carbonate, for example diethyl carbonate, or , for example phosgene, furthermore amides, for example urea or carbonyldimidazole, and also halocarbonic acid esters, such as lower alkyl chlorocarbonic acid, for example isobutyl chlorocarbonate, or halo carbamate genides, e.g. chloride.
  • the reaction is carried out in a conventional manner, normally in the presence of an inert solvent, preferably an optionally halogenated aliphatic or aromatic hydrocarbon, e.g. Chloroform or toluene, also an amide or nitrile, e.g. Dimethylformamide, dimethylacetamide or acetonitrile, or a cycloaliphatic ether such as dioxane and tetrahydrofuran.
  • a condensing agent especially a basic condensing agent such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g.
  • an alkali metal lower alkanoate e.g. Sodium acetate
  • an alkali metal lower alkanolate e.g. Sodium methoxide or potassium tert-butoxide
  • organic tertiary nitrogen base such as a tri-lower alkylamine, e.g. Trimethylamine or triethylamine, or pyridine.
  • a compound of the formula XII in which X 6 and X 7 are hydrogen can be obtained, for example, by using piperidin-4-one with a compound of the formula IIa in which X 3 is hydroxy and X 4 is a reactive esterified hydroxyl group, in particular halogen, is reacted, and then the intermediate can be reacted with a diamine of the formula V with simultaneous or subsequent treatment with a reducing agent, such as catalytically activated hydrogen or a suitable hydride reducing agent, for example sodium cyanoborohydride.
  • a reducing agent such as catalytically activated hydrogen or a suitable hydride reducing agent, for example sodium cyanoborohydride.
  • the new compounds of formula I can also be obtained if one in a compound of formula wherein X s represents an imino residue convertible to oxo, X 8 converts to oxo and, if desired, carries out the additional process steps.
  • the imino radical X 8 can be substituted, for example by lower alkyl or phenyl.
  • a corresponding starting material of the formula XIII can be obtained by hydrolysis, preferably in the presence of an acidic agent, such as. convert a mineral acid, for example hydrochloric acid, into the corresponding compound of formula I.
  • the above reaction is carried out in the absence or, preferably, in the presence of a solvent or diluent and, if necessary, with cooling or heating, e.g. in a temperature range from about 0 ° C to about 150 ° C, optionally in a closed vessel and / or in an inert gas atmosphere.
  • the starting materials of the formula XIII can be obtained in a manner known per se, for example by treating a compound of the formula XII, in which each of the radicals X 6 and X 7 is hydrogen, with a cyanogen halogen, for example cyanogen bromide, preferably in the presence of a suitable, for example basic condensing agent, with simultaneous or subsequent ring closure to the 2-imino-1,3-diazacycloalkane ring of the starting material of the formula XIII.
  • a cyanogen halogen for example cyanogen bromide
  • Residual halogen such as bromine or iodine
  • a suitable aprotic solvent such as pyridine, dimethylformamide or acetonitrile
  • a compound of formula I which contains hydroxy or mercapto in the form of a primary carbinol or a phenolic hydroxyl group as a substituent, this, optionally in salt, for example alkali metal salt form, by treatment with a reactive ester of an alcohol such as a optionally substituted lower alkyl halide, in etherified Convert hydroxy or mercapto, eg lower alkoxy or lower alkylthio.
  • hydroxy in a hydroxy-lower alkyl or hydroxy-lower alkoxy substituent usually in the form of a reactive esterified hydroxy group, such as halogen, for example chlorine, with an alcohol, for example lower alkanol, or a mercaptan, for example lower alkyl mercaptan, preferably in the presence of a basic agent, for example can convert an alcohol or a mercaptan into a metal compound, react and thus arrive at compounds of the formula I which have correspondingly etherified hydroxy or mercapto-lower alkyl or lower alkoxy.
  • a reactive esterified hydroxy group such as halogen, for example chlorine
  • a reactive esterified hydroxyl group such as halogen, for example chlorine
  • halogen for example chlorine
  • an alcoholate or thiolate compound such as an alkali metal, for example sodium - or potassium lower alkanolate or thio lower alkanolate
  • esterified hydroxy or mercapto group for example into lower alkoxy or lower alkylthio.
  • a propargyloxy group e.g. by hydration in an acidic medium and in the presence of a mercury II salt, e.g. by treatment with an aqueous mineral acid, e.g. Convert dilute hydrochloric or sulfuric acid into the acetonyloxy group in the presence of mercury-II chloride.
  • Substituents esterified carboxyl or Nie contains, this, for example by treatment with ammonia or an amine, preferably with an excess thereof and at elevated temperature, in transfer amidated carboxyl or ureido if necessary.
  • a compound of the formula I which contains primary amino as a substituent; you can use amino, e.g. by treating the amino compound with a suitable acid derivative, such as an optionally mixed anhydride, e.g. acylate an appropriate chloride, if necessary in the presence of a basic agent.
  • a suitable acid derivative such as an optionally mixed anhydride, e.g. acylate an appropriate chloride, if necessary in the presence of a basic agent.
  • the reactions described above can optionally be carried out simultaneously or in succession and in any order and in a conventional manner, e.g. in the presence or absence of solvents or diluents, if necessary, in the presence of condensation and / or catalytic agents, with cooling or heating, in a closed vessel and / or in an inert gas atmosphere.
  • the end products are obtained in free form or in the form of their salts, in particular their acid addition salts, which is also encompassed by the invention.
  • Salts obtained can be converted into the free compounds in a manner known per se, acid addition salts e.g. by treatment with basic agents, including suitable ion exchangers.
  • acid addition salts e.g. by treatment with basic agents, including suitable ion exchangers.
  • free compounds obtained e.g. by treatment with organic or inorganic acids, form salts.
  • acid addition salts e.g. converted to other salts by treatment with suitable heavy metal salts or anion exchangers.
  • the abovementioned salts or other salts of the new compounds of the formula I can also be used to purify the free bases obtained serve by converting the free bases into salts, separating them and again freeing the bases from the salts.
  • the free compounds are also to be understood as meaningful and expedient, if appropriate, the corresponding salts.
  • the new compounds can be in the form of the racemates or the optical antipodes.
  • Racemates obtained can be separated into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction with an optically active acid which forms salts with the racemic compound and separation of the salts obtained in this way, e.g. due to their different solubilities, in the diastereomeric salts, from which the free antipodes can be released by the action of suitable agents.
  • Particularly suitable, optically active acids are e.g. the D and L forms of tartaric acid, di-toluic tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid.
  • the invention also relates to those embodiments of the process according to which one at which one forms a starting material under the reaction conditions of one, starting at any stage of the process as an intermediate compound obtainable and the remaining process steps or the process at any stage terminates, or ' , or in which a reaction component is optionally in the form of a derivative, for example a salt.
  • the new compounds can be used, for example, in the form of pharmaceutical preparations which contain a pharmacologically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral, for example oral or parenteral administration.
  • tablets or gelatin capsules which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or Calcium stearate, and / or polyethylene glycol.
  • Tablets can also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. starches, agar, alginic acid or a salt of which, such as sodium alginate, and / or effervescent mixtures, or have adsorbents, colorants, flavors and sweeteners.
  • binders e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone
  • disintegrants e.g. starches, agar, alginic acid or a salt of which, such as sodium alginate, and / or effervescent mixtures, or have
  • Such solutions are preferably isotnic aqueous solutions or suspensions, these being, for example, in the case of lyophilized preparations which contain the active substance alone or together with a carrier material, such as mannitol, can be prepared before use.
  • the pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.
  • the present pharmaceutical preparations which, if desired, can contain further pharmacologically active substances, are produced in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain about 0.1% up to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active substance.
  • the dosage can depend on various factors, such as the type of application, species, age and / or individual condition.
  • the daily doses for oral administration are between approximately 5 mg and approximately 50 mg for warm-blooded animals weighing approximately 70 kg.
  • a mixture of 10.66 g of 1- ⁇ 1- [3- (3-chloro-2-pyrazinyloxy) -2-hydroxypropyl] -4-piperidyl ⁇ imidazoline-2-one and 1.78 g of sodium methylate in 150 ml of methanol is refluxed for 10 hours with stirring.
  • the reaction mixture is totally evaporated in a water jet vacuum.
  • the residue is dissolved in ethyl acetate and washed with water.
  • the organic solution is dried over sodium sulfate and evaporated in a water jet vacuum.
  • the 1- ⁇ 1- [2-hydroxy-3- (3-methoxy-2-pyrazinyloxy) propyl] -4-piperidyl ⁇ -lmidazolidin-2-one is thus obtained as oil. That with a methanolic hydrochloride produced crystallized Mixture of methanol and diet ether and melts at 222 ° - 223 ° (with decomposition).
  • the 1- ⁇ 1- [2- [hydroxy 3- (2-chloro-3-pyridyloxy) propyl] -4-piperidyl is obtained in an analogous manner using 1- (4-piperidyl) imidazolidin-2-one ⁇ -imidazoli- xy) -propyl] -4-piperidyl ⁇ -im din-2-one with mp. 163-166 °.
  • the 2-chloro-3- (2,3-epoxypropyloxy) -6-methyl-pyridine used as the starting material is obtained by boiling 2-chloro-6-methyl-3-pyridinol with epichlorohydrin and potassium carbonate for 2 hours. It is used raw.
  • a mixture of 7.1 g of 2-methyl-4- (2,3-epoxypropyl) indole and 5.9 g of 1- (4-piperidyl) -2-imidazolidinone is dissolved in 125 ml of isopropyl alcohol and refluxed for 6 hours cooked. The mixture is then cooled in an ice bath and filtered off. The crystals are dissolved in isopropanol and possibly recrystallized with the addition of animal charcoal.
  • the 4- ⁇ 3- [4- (2-oxo-3-imidazolidinyl) -1-piperidyl] -2-hydroxy-1-propyloxy ⁇ -2-methyl-1H-indole has an mp of 208-210 °.
  • the reaction product is chromatographed on 2 kg of basic aluminum oxide, a mixture of chloroform-methanol (85:15) being used as the elution mixture. In this way, the viscous oil obtained is 3- (2-hydroxyethyl) -1- (4rpiperidyl) imidazolidin-2-one, which is used without additional purification.
  • the 4- ⁇ 3- [4- (1-benzyl-2-oxo-3-imidazolidinyl) -1-piperidyl] -2-hydroxy-1-propyloxy ⁇ -2-methyl-JH-indole has an mp of 97 -100 ° C.
  • (4-piperidyl) imidazolidin-2-one can be prepared in the following manner.
  • a mixture of 42.8 g of benzylamine and 120 ml of methyl ethyl ketone is introduced with stirring and with ice bath cooling.
  • 41 g of 2-bromoethylamine hydrobromide are added in portions and the mixture is boiled under reflux for 16 hours.
  • the mixture is then cooled in an ice bath and the precipitate formed is filtered off.
  • the crystals are dissolved in 150 ml water and washed twice with 50 ml diethyl ether.
  • the water phase is set with conc.
  • the combined chloroform extracts are dried and evaporated to dryness under reduced pressure.
  • a solution of 29.25 g of 1-benzyl-ethylenediamine and 36.85 g of 1-benzyl-4-piperidone in 100 ml of absolute methyl alcohol is with the addition of 2 g of a 5% platinum-carbon catalyst and 0.49 g of conc .
  • chemically pure sulfuric acid is hydrogenated at room temperature and normal pressure until 1 mol equivalent of hydrogen is taken up.
  • the catalyst is then filtered off and the filtrate is evaporated to dryness.
  • the residue is dissolved in 2N hydrochloric acid and extracted three times with 75 ml of diethyl ether each time. with conc. Ammonia solution made alkaline and extracted five times with 75 ml of chloroform.
  • the residue is dissolved in 150 ml of ethyl acetate and the solution is extracted four times with 50 ml of 2N sodium hydroxide solution.
  • the organic phase is dried and evaporated.
  • the remaining oil is mixed with 60 ml of ethyl alcohol and 25 ml conc.
  • the aqueous phase is separated off and the organic phase is extracted three times with 30 ml of 2N sodium hydroxide solution each.
  • the ethyl acetate phase is then dried and evaporated.
  • a mixture of 12 g of 1-benzyl-3- (I-benzyl-4-piperidyl) imidazolidin-2-one, 120 ml of 70% aqueous methyl alcohol solution and 3.39 g of conc. chem. pure hydrochloric acid is hydrogenated with the addition of 2.4 g of a 5% palladium-carbon catalyst until 1 molar equivalent of hydrogen is taken up at room temperature and normal pressure. The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. The residue is set with conc. aqueous ammonia solution alkaline and extracted five times with 50 ml of chloroform. The combined chloroform extracts are dried and evaporated under reduced pressure.
  • the 4- ⁇ 3- [4- (2-oxo-3-imidazolidinyl) -1-piperidyl] -2-hydroxy-1-propyloxy ⁇ -2-phenyl-1H-indole has an mp of 166-168 ° C ..
  • the 2-phenyl-4-hydroxy-indole was synthesized from the 4-oxo-2-phenyl-4.5.6.7-tetrahydroindole by aromatization with palladium-carbon in diphenyl ether and has a melting point of 120 ° -123 ° C.
  • the 4- ⁇ 3- [4- (2-oxo-3-imidazolidinyl) -1-piperidyl] -2-hydroxy-1-propyloxy ⁇ -2-methyl-1H-indole has an mp of 208-210 ° C .
  • the quaternary starting material is prepared by heating 3- (2-methyl-4-indolyloxy) -2-hydroxy-1-bromopropane with 1- (4-pyridyl) -2-imidazolidinone in dimethylformamide at 100 °.
  • the ethyl acetate phase is then dried and evaporated. The residue is recrystallized from isopropanol with the addition of animal charcoal.
  • the 4- ⁇ 3- [4- (2-oxo-3-imidazolidinyl) -1-piperidyl] -2-hydroxy-1-propyloxy ⁇ -2-methyl-1H-indole has an mp of 208-210 °.
  • the starting material is prepared by reductive alkylation of 1- ⁇ 3- (2-methyl-4-indolyloxy) -2-hydroxy-1-propyl] -4-piperidone with ethylenediamine with palladium-carbon catalysis in methanol.
  • Tablets containing 20 mg of 4- ⁇ 3- [4- (2-oxo-3-imidazolidinyl) -1-piperidyl] -2-hydroxy-1-propyloxy ⁇ -2-methyl-1H-indole hydrochloride can e.g. can be produced as follows:
  • composition for 5000 tablets
  • the 4- ⁇ 3- [4- (2-oxo-3-imidazolidinyl) -1-piperidyl] -2-hydroxy-1-prepyloxy ⁇ -2-methyl-1H-indole hydrochloride is mixed with the lactose, the colloidal silica and mixed part of the weixen starch and the mixture was passed through a sieve. Another part of the wheat starch is pasted with five times the amount of water on the water bath and the powder mixture is kneaded with this paste until a weak plastic mass is formed. The mass is passed through a sieve, dried and the dry granules are sieved again. Then the remaining wheat starch, the talc and the magnesium stearate are mixed in and the mixture is compressed into tablets (with a break groove) of 0.1 g weight.

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EP78100308A 1977-07-08 1978-07-05 Pipéridino-propanols, leur préparation et compositions pharmaceutiques les contenant Withdrawn EP0000485A1 (fr)

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CH648878 1978-06-14

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2433526A1 (fr) * 1978-07-28 1980-03-14 Chimosa Chimica Organica Spa Nouveaux composes de la piperidine, procede pour leur preparation et leur utilisation comme stabilisants pour polymeres synthetiques
JPS5632455A (en) * 1979-08-10 1981-04-01 Sandoz Ag 33aminopropoxyaryl derivative
EP0035374A3 (en) * 1980-03-01 1981-11-11 John Wyeth & Brother Limited Piperidyl - urea, - thiourea and - guanidine derivatives, and intermediates therefor, processes for preparing them and pharmaceutical compositions containing the derivatives
US5576321A (en) * 1995-01-17 1996-11-19 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5614523A (en) * 1995-01-17 1997-03-25 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5627196A (en) * 1995-01-17 1997-05-06 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5741789A (en) * 1995-01-17 1998-04-21 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5789402A (en) * 1995-01-17 1998-08-04 Eli Lilly Company Compounds having effects on serotonin-related systems
WO2005121122A1 (fr) * 2004-06-09 2005-12-22 Glaxo Group Limited Composes d'imidazol-2-one utiles dans le traitement de divers troubles
EP2208726A1 (fr) 2004-05-21 2010-07-21 Takeda Pharmaceutical Company Limited Dérivés d'amides cycliques et leur production et utilisation comme agents antithrombotiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7311514A (fr) * 1972-08-24 1974-02-26
NL7700530A (nl) * 1976-01-21 1977-07-25 Ciba Geigy Geoxigeneerde n-acryldiazacyclische ver- bindingen.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7311514A (fr) * 1972-08-24 1974-02-26
NL7700530A (nl) * 1976-01-21 1977-07-25 Ciba Geigy Geoxigeneerde n-acryldiazacyclische ver- bindingen.

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2433526A1 (fr) * 1978-07-28 1980-03-14 Chimosa Chimica Organica Spa Nouveaux composes de la piperidine, procede pour leur preparation et leur utilisation comme stabilisants pour polymeres synthetiques
JPS5632455A (en) * 1979-08-10 1981-04-01 Sandoz Ag 33aminopropoxyaryl derivative
EP0035374A3 (en) * 1980-03-01 1981-11-11 John Wyeth & Brother Limited Piperidyl - urea, - thiourea and - guanidine derivatives, and intermediates therefor, processes for preparing them and pharmaceutical compositions containing the derivatives
US5576321A (en) * 1995-01-17 1996-11-19 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5614523A (en) * 1995-01-17 1997-03-25 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5627196A (en) * 1995-01-17 1997-05-06 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5741789A (en) * 1995-01-17 1998-04-21 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5789402A (en) * 1995-01-17 1998-08-04 Eli Lilly Company Compounds having effects on serotonin-related systems
US6172073B1 (en) 1995-01-17 2001-01-09 Eli Lilly And Company Compounds having effects on serotonin-related systems
EP2208726A1 (fr) 2004-05-21 2010-07-21 Takeda Pharmaceutical Company Limited Dérivés d'amides cycliques et leur production et utilisation comme agents antithrombotiques
WO2005121122A1 (fr) * 2004-06-09 2005-12-22 Glaxo Group Limited Composes d'imidazol-2-one utiles dans le traitement de divers troubles
US7534893B2 (en) 2004-06-09 2009-05-19 Glaxo Group Limited Imidazol-2-one compounds useful in the treatment of various disorders

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