US3770748A - Substituted phenylalkanol derivatives - Google Patents

Substituted phenylalkanol derivatives Download PDF

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US3770748A
US3770748A US00237879A US3770748DA US3770748A US 3770748 A US3770748 A US 3770748A US 00237879 A US00237879 A US 00237879A US 3770748D A US3770748D A US 3770748DA US 3770748 A US3770748 A US 3770748A
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acid
formula
carbon atoms
phenyl
compounds
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J Borck
J Dahm
A Wild
J Hovy
J Kramer
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5

Definitions

  • This invention relates to novel substituted phenylalkanol derivatives, to processes for the preparation thereof, pharmaceutical compositions comprising them and methods of use thereof.
  • novel compounds of this invention are phenylalkanol derivatives of the general Formula I wherein R is OH, alkoxy of up to 6 carbon atoms, cycloalkoxy of up to 6 carbon atoms, aryloxy of 6-12 carbon atoms, aralkoxy of 7-12 carbon atoms, or acyloxy of up to 18, preferably up to 6 carbon atoms; R is H, alkyl of up to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl of 612 carbon atoms, aralkyl of 7-12 carbon atoms, or acyl of up to 18, preferably up to 6 carbon atoms, R, is H or CH R is Cl, Br or CH and n is 2 or 3; and the physiologically acceptable acid addition salts and quaternary ammonium salts thereof, and mixtures thereof.
  • Compounds of Formula I and the physiologically acceptable acid addition and quaternary ammonium salts thereof possess, with good compatibility, an excellent antiphlogistic effect, usually accompanied by analgesic and antipyretic effects. They also possess one or more of bacteriostatic, bactericidal, antiprotozoal, diuretic, bloodsugar-lowering, choleretic, cholesterol-level-lowering and radiation-protective activity.
  • the compounds of Formula I and their physiologically acceptable salts can thus be employed as drugs as well as intermediates for the production of other drugs.
  • IbR acyloXy of up to 18 carbon atoms
  • IdR acyloxy of up to 18 carbon atoms and n is 3;
  • IfR acyl of up to 18 carbon atoms
  • Ih-R acyl of up to 18 carbon atoms and n is 3;
  • acyloxy and acyl in each instance preferably containing up to 6 carbon atoms, e.g., alkanoyloxy and alkanoyl.
  • this invention relates to a process for the preparation of substituted phenylalkanol derivatives of the general Formula I which comprises any one of the following:
  • This invention also relates to pharmaceutical preparations comprising at least one compound of the general Formula I in suitable unit dosage form, in admixture with at least'one solid, liquid or semiliquid auxiliary agent or vehicle, and optionally at least one further active compound, preferably those containing 0.1400 mg. of a compound of Formula I per unit dosage.
  • This invention also relates to a method for obtaining antiphlogistic, analgesic and/or antipyretic effects in living beings, by the administration thereto of a composition of this invention.
  • R in addition to a free OH group can also be an etherified or esterified OH group.
  • etherified OH groups are alkoxy, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec.- butoxy, isobutoxy, tert.-butoxy, amyloxy, isoamyloxy, hexyloxy and isohexyloxy; cycloalkoxy groups, e.g., cyclobutyloxy, cyclopentyloxy and cyclohexyloxy; heterocycloalkoxy, e.g., tetrahydrofuran-2-yloxy, tetrahydropyran- 2'-yloxy and 4-alkoxytetrahydropyran-4'-yloxy; aryloxy, e.g., phenoxy, p-tolyloxy, xylyloxy and naph
  • esterified OH groups are those esterified with a saturated or unsaturated aliphatic, cycloaliphatic, aromatic, araliphatic, or heterocyclic, substituted or unsubstituted carboxylic acid or sulfonic acid.
  • Preferred carboxylic acids are fatty acids, preferably alkanoic acids, of 1-18, particularly 1-6 carbon atoms, e.g., formic, acetic, propionic, butyric, isobutyric, valeric, isovaleric, caproic, isocaproic, enanthic, caprylic, capric, lauric, myristic, palmitic and stearic acid; and other carboxylic acids, e.g., pivalic acid, diethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, acrylic acid, fumari acid, maleic acid, cyclohexanecarboxylic acid, benzoic acid, phenylacetic acid, phenylpropionic acid, gluconic acid, furan-Z-carboxylic acid, nicotinic acid and isonicotinic acid.
  • carboxylic acids e.g., pivalic acid, diethylacetic
  • the OH groups can also be esterified with a sulfonic acid including aliphatic and arylsulfonic acids, e.g., methanesulfonic acid, ethanedisulofnic acid, fi-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, naphthalene-monoand -disulfonic acids, or camphorsulfonic acid, or with an inorganic acid, preferably sulfuric acid or a phosphoric acid, e.g., orthophosphoric acid.
  • a sulfonic acid including aliphatic and arylsulfonic acids, e.g., methanesulfonic acid, ethanedisulofnic acid, fi-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid,
  • R in addition to H can also be alkyl of up to 6 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl and isohexyl, or the acyl radical of an acid of up to 18, preferably up to 6 carbon atoms, e.g., an acid named above.
  • X is a group which can be converted into a group of Formula Z
  • examples of such groups are those of the formula -CHR -A, wherein A is a group which can be converted into a moiety of the formula -CH R by reaction with a reducing agent.
  • A can, for example, be an aldehyde group, in free or functionally modified form, for example as an acetal, e.g., a dialkylacetal group, preferably a dimethylor diethylacetal group; an alkyleneacetal group, preferably an ethyleneacetal of 1,2-propyleneacetal group; or a free or optionally a functionally modified carboxyl group, preferably an alkoxycarbonyl group of up to 7 carbon atoms, especially methoxycarbonyl, ethoxycarbonyl, or isopropoxycarbonyl, or an aralkoxy carbonyl group of up to 9 carbon atoms, especially benzyloxycarbonyl.
  • an acetal e.g., a dialkylacetal group, preferably a dimethylor diethylacetal group
  • an alkyleneacetal group preferably an ethyleneacetal of 1,2-propyleneacetal group
  • a free or optionally a functionally modified carboxyl group preferably an al
  • a carboxylic acid halogenide preferably a carboxylic acid chloride or bromide; a carboxylic acid anhydride group of up to 16 carbon atoms, preferably an acetoxycarbonyl group; a carboxylic acid azide or amide group; or a nitrile group.
  • X can also be an oxiran-Z-yl or a Z-methyl-oxiran-Z-yl group.
  • X is a group which can be converted into a group of the Formula W which is preferably one of the followwherein U is Y(CH CH (OR )-CH YCH CH 0R (CH 7 0 H(CH2) n or (CEzZyCH-C Hr- Nz l (W3) wherein Y is C1 or Br;
  • an aprotic-dipolar solvent e.g., dimethylformamide, acetonitrile, dimethyl sulfoxide, tetramethylurea, tetrahydrothiophene 1,1-dioxide (sulfolane), propylene carbonate and hexamethylphosphoric triamide (hernpa); and mixtures of one or more thereof.
  • the starting compounds can also be the corresponding acids substituted in the 3-position of the phenyl ring by Br or CH in place of C1, or the aboveindicated functional derivatives thereof.
  • the amides of Formula II are obtained by pouring the corresponding carboxylic acid chlorides or bromides into an excess aqueous ammonia solution.
  • These corresponding carboxylic acid chlorides and bromides can be obtained by treating the free acids with an inorganic acid chloride or bromide, e.g., SOClg, SO CI PCl PCl POCl PBr or POBr If, in place of ammonia, a monoor dialkylamine is used, then the corresponding monoor dialkylamides are obtained.
  • the anhydrides of Formula II i.e.,
  • R is any desired organic residue, preferably, however, CH or ((FHzh-IITQ-CHMY R20CH CH2 by reaction with an inorganic cyanide, preferably NaCN or KCN.
  • the enol acetates are employed which are obtained from the aldehydes of Formula II by heating with acetic anhydride/sodium acetate.
  • diazotization can also be achieved by the addition of an organic nitrite, such as n-butyl nitrite, n-amyl nitrite, o-r isoamyl nitrite, preferably in the presence of HCl or HBr.
  • organic nitrite such as n-butyl nitrite, n-amyl nitrite, o-r isoamyl nitrite, preferably in the presence of HCl or HBr.
  • R4 by bromination, preferably with a bromoimide, e.g., N- bromosuccinimide, in one of the customary solvents at temperatures of between 20 and C., preferably at the boiling temperature of the solvent, optionally under simultaneous irradiation, preferably with short-wave light, and subsequent solvolysis.
  • a bromoimide e.g., N- bromosuccinimide
  • R represents, for example, (H, Br)
  • the corresponding compounds of Formula III are obtained by the bromination of compounds of Formula X followed by hydrogenation.
  • a reducing preferably hydrogen-evolving agent, e.g., a complex metal hydride.
  • reducing agents catalytically activated hydrogen, hydrogen in the nascent state and chemical reducing agents can also be employed.
  • suitable catalysts are, for example, noble metal, nickel and cobalt catalysts, for the reduction of carboxylic acid derivatives, mixed catalysts e.g., copper chromium oxide can also be employed.
  • the noble metal catalysts can be employed on supports, e.g., platinum on carbon, palladium on calcium carbonate or strontium carbonate, as oxide catalysts, e.g., platinum oxide, or as finely divided metal catalysts.
  • Nickel and cobalt catalysts are suitably used as Raney metals nickel on kieselguhr or pumice as the support can also be employed.
  • the hydrogenation can be effected at room temperature and normal pressure or also at an elevated temperature and/or an elevated pressure.
  • the reaction is conducted under pressures of between 1 and 100 atmospheres, occasionally, as in the hydrogenation of esters with, for example Co(II) acetate, also under higher pressures, and at temperatures of between 80 C. and 200 C., especially between room temperature and +l C.
  • the reaction is suitably effected in the presence of one of the usual solvents.
  • the free compounds or the corresponding salts can be utilized, e.g., the hydrochlorides or sodium salts.
  • the reaction is preferably conducted under normal pressure and by terminating the hydrogenation after absorption of the stoichiometric amount of hydrogen. Basically, it is possible to hydrogenate at an acidic, neutral or basic pH.
  • Another generally suitable reduction method is the reaction with nascent hydrogen.
  • the latter can be produced, for example, by treating a metal with an acid or base, e.g., a mixture of zinc and acid or alkaline solution, iron and hydrochloric acid or acetic acid, or tin and hydrochloric acid.
  • an acid or base e.g., a mixture of zinc and acid or alkaline solution, iron and hydrochloric acid or acetic acid, or tin and hydrochloric acid.
  • sodium or another alkali metal in an alcohol, e.g., ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol or phenyl.
  • the method of Bouveault-Blanc can be employed, preferably at the boiling temperature of the alcohols used.
  • an aluminum-nickel alloy can be utilized in an alkaline-aqueous solution, optionally with the addition of ethanol.
  • Sodium amalgam or aluminum amalgam in an aqueous-alcoholic or aqueous solution is also suitable for producing nascent hydrogen.
  • the reaction can also be effected in a heterogeneous phase, wherein suitably an aqueous phase and a benzene or toluene phase are used.
  • the reaction temperatures employed range between room temperature and the boiling point of the solvent used.
  • a complex metal hydride e.g., LiAlH NaAlH (OCH CH OCH or NaBH optionally with the addition of a catalyst, e.g., BF AlCl or LiBr
  • the process is advantageously conducted in the presence of one of the usual solvents, preferably in an ether, e.g., diethyl ether, tetrahydrofuran or dioxane.
  • ether e.g., diethyl ether, tetrahydrofuran or dioxane.
  • the reactions are advantageously conducted between 80 C. and the boiling point of the solvent.
  • the decomposition of the thus-formed metal complexes can be done in the usual manner, e.g., with moist ether or an aqueous ammonium chloride solution.
  • a particularly preferred reducing agent is NaAlH (OCH CH OCI-I)
  • reducing agents preferably agents evolving hydrogen, e.g., sodium amalgam or catalytically activated hydrogen.
  • a solvolyzing agent e.g., an alcohol, an acid, or H O
  • bases or basic salts are generally employed, preferably alkalines, e.g., NaOH or KOH. It is also possible to use slurries of Ca( OH) Pb(OH) or AgOH.
  • the saponification is ordinarily conducted at an elevated temperature, for example at the boiling temperature of the solvent.
  • the OH group in the heterocyclic ring is usually first masked, and the masking group is then split ofl after the reaction.
  • an inert solvent preferably toluene or xylene.
  • a small amount of KI can be added.
  • the reaction mixture is then refluxed until it becomes neutral.
  • Phenyl ethers are obtained by mixing the alcoholic alkali alcoholate solution with an equivalent of the respective phenol, and then continuing the procedure as described for the alkyl ethers.
  • a silver salt of the corresponding acid a silver salt of the corresponding acid.
  • the OH group in the heterocycle generally is first masked and the masking group is then split olf after the reaction.
  • Compounds of Formula I can be produced from starting materials of Formula II wherein X is an oxiran-Z-yl or 2-methyloxiran-2-yl group, by treatment with a hydrogen-evolving agent, preferably a hydride, e.g., B H or LiAlI-I in the presence of a Lewis acid, e.g., BF or AlCl
  • a hydrogen-evolving agent preferably a hydride, e.g., B H or LiAlI-I
  • a Lewis acid e.g., BF or AlCl
  • the reaction is carried out in one of the usual solvents, preferably an ether, e.g., diethyl ether or tetrahydrofuran, at temperatures of between -20 C. and +30 C., preferably between 5 C. and +5 C.
  • compounds of Formula I are obtained in accordance with conventional methods, by reacting with a cyclizing agent, preferably by heating in an aqueous solution or suspension, optionally in the presence of an acidic or basic catalyst, or in one of the usual organic solvents, preferably in an organic acid, e.g., formic acid, acetic acid or propionic acid, especially in the presence of an acidic catalyst, e.g., HCl.
  • a cyclizing agent preferably by heating in an aqueous solution or suspension, optionally in the presence of an acidic or basic catalyst, or in one of the usual organic solvents, preferably in an organic acid, e.g., formic acid, acetic acid or propionic acid, especially in the presence of an acidic catalyst, e.g., HCl.
  • the process is conducted at low temperatures, e.g., room temperature, or at elevated temperatures, preferably at the boiling temperature of the solvent employed. In some cases, it may be necessary to conduct the reaction under pressure (up to 200 atmospheres) and/or at an elevated temperature (up to 300 C.).
  • a catalyst e.g., a base, such as NaOH, KOH or sodium or potassium carbonate can be used but is not absolutely necessary.
  • Compounds of Formula I are also obtained by exchanging, in the diazonium compounds of Formula III the diazonium group for a C1 or Br atom according to methods described in the literature.
  • the exchange for chlorine is preferably effected in an aqueous solution in the presence of Cu Cl by the Sandmeyer method.
  • the exchange for bromine can be conducted, for example, in an aqueous solution in the presence of Cu Br according to Sandmeyer, or by reaction with bromine to form the diazonium perbromide, and subsequent refluxing in a suitable solvent, e.g., water or a lower alcohol.
  • a suitable solvent e.g., water or a lower alcohol.
  • the diazonium bromides can also be converted into the diazonium mercury bromides with HgBr and these can be thermally dissociated to the desired bromine compounds.
  • Chlorination is effected, for example, by the direct reaction with elemental chlorine in an inert solvent, e.g., water, CCl acetic acid, without or with the addition of specific catalysts, e.g., FeCl AlCl SbCl or SnCl preferably between 10 C.
  • an inert solvent e.g., water, CCl acetic acid
  • specific catalysts e.g., FeCl AlCl SbCl or SnCl preferably between 10 C.
  • Bromination can be achieved, for example, in a particularly simple manner by direct reaction with elemental bromine in an inert solvent, e.g., CS acetic acid, or CCl especially with the addition of a catalyst which act as bromine transfer agents, e.g., iron filings, AlCl AlBr FeCl iodine or pyridine, preferably between 30 C.
  • an inert solvent e.g., CS acetic acid
  • CCl especially with the addition of a catalyst which act as bromine transfer agents, e.g., iron filings, AlCl AlBr FeCl iodine or pyridine, preferably between 30 C.
  • a catalyst which act as bromine transfer agents e.g., iron filings, AlCl AlBr FeCl iodine or pyridine, preferably between 30 C.
  • hypobromous acid an acyl hypobromite, N- bromoimide, e.g., N-bromosuccinimide, N-bromophthalimide or other bromine-yielding agent, e.g., 1,3-dibromo- 5,5-dimethylhydantoin, in an inert solvent, e.g., nitrobenzone or CS preferably at l0 C. to C.; or by reaction with NOBr or NO Br in CS or cyclohexane.
  • an inert solvent e.g., nitrobenzone or CS preferably at l0 C. to C.
  • a solvolyzing agent e.g., alcohols, acids, or with H O, preferably in the presence of an acidic or basic catalyst, in accordance with known methods or by reaction with a metallic salt or metallic alcoholate.
  • a reducing, preferably hydrogen-evolving agent preferably a complex metal hydride.
  • the reaction conditions must be selected so that the phenyl ring is not reduced, for example by using NaBH in methanol, optionally in the presence of aluminum chloride or lithium bromide.
  • the reaction is advantageously carried out in the presence of one of the usual solvents, preferably lower alcohol, ether, tetrahydrofuran or ethylene glycol dimethyl ether.
  • the reaction is advantageously terminated by refluxing the reaction mixture.
  • the decomposition of the thusformed metal complexes can be accomplished in the usual way, for example with the use of an aqueous ammonium chloride solution.
  • a compound of Formula I can be converted into the associated acid addition salt with the use of an acid.
  • Suitable acids for such a reaction are those yielding physiologically acceptable salts.
  • organic and inorganic acids can be utilized, including aliphatic, alicyclic, araliphatic, aromatic and heterocyclic mono or polybasic carboxylic or sulfonic acids, e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, oxalic acid, malonic acid, snccinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanedisulfonic acid,
  • compounds of Formula I can be liberated from the acid addition salts thereof by treatment with strong bases, e.g., sodium or potassium hydroxide, sodium or potassium carbonate, or from the metallic and ammonium salts thereof by treatment with acids, especially mineral acids, e.g., hydrochloric or sulfuric acid.
  • strong bases e.g., sodium or potassium hydroxide, sodium or potassium carbonate
  • acids especially mineral acids, e.g., hydrochloric or sulfuric acid.
  • the compounds of Formula I When the compounds of Formula I contain a center of asymmetry, they are ordinarily produced in their racemic form. When they exhibit two centers of asymmetry, they are generally obtained in the synthesis as mixtures of two racemates, from which the individual racemates can be isolated in a conventional manner, for example by repeated recrystallization from suitable solvents, and can thus be obtained in the pure form.
  • racemates can be separated into their optical antipodes in accordance with a large number of known methods.
  • selective precipitation is also possible, chemical separation is preferred.
  • diastereomers are formed from the racemic mixture by reaction with an optically active auxiliary agent.
  • an optically active acid can optionally be reacted with the amino group of a compound of Formula I.
  • diastereomeric salts of compounds of Formula I can be formed with an optically active acid, e.g., and tartaric acid, dibenzoyl-( and -()-tartaric acid, diacetyl-(+)- and -()-tartaric acid, camphoric acid, p-camphorsulfonic acid, (I)- and (-)-mandelic acid, and (-)-dinitrodiphenic acid and/or and ()-lactic acid.
  • the desired enantiomer of Formula I is then obtained by separating the optically active auxiliary agent in accordance with known methods.
  • the optically active compounds of Formula I are in each case obtained by saponification of the pure diastereomer.
  • the acidic phthalic acid or succinic acid esters e.g., by reaction respectively, with phthalic and/ or succinic anhydride, and convert the thusproduced dibasic acids into their diastereomeric salts, by reaction with an optically active base, e.g., quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindarnine, morphine, l-phenylethylamine, l-uaphthylethylamine, phenyloxynaphthylmethylamine, quinidine and/or strychnine, from which the pure enantiomers can be obtained.
  • an optically active base e.g., quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindarnine, morphine, l-phenylethylamine, l-uaphthylethylamine, phenyloxynaphthylmethylamine
  • optically active substrate materials such as, for example, tartaric acid, starch, cane sugar, cellulose, or cellulose acetate, and optically inactive and/or optically active eluents, for purposes of separation into the pure enantiomers, or an optically inactive substrate material, e.g., silica gel or aluminum oxide, in combination with an optically active eluent.
  • optically active substrate materials such as, for example, tartaric acid, starch
  • optically inactive and/or optically active eluents for purposes of separation into the pure enantiomers, or an optically inactive substrate material, e.g., silica gel or aluminum oxide, in combination with an optically active eluent.
  • the optical antipodes can also be separated biochemically by a selective enzymatic reaction. For example, using a hydrolase and racemic ester, one of the enantiomers is selectively saponified and the other remains unchanged, which permits their separation because of their different
  • optically active compounds in accordance with the above-described methods by using starting substances which are already optically active.
  • the novel compounds can be employed in a mixture with solid, liquid and/ or semiliquid excipients as drugs in the human or veterinary medicine.
  • Suitable vehicles are those organic or inorganic substances which are suitable for parenteral, enteral, or topical application and which do not react with the novel compounds, such as, for example, water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol.
  • solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • Suitable for enteral application are tablets, drages, syrups, elixirs, or suppositories, and for topical use, salves, creams, or powders.
  • auxiliary agents such as lubricants, preservatives, stabilizers, or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers, coloring, flavoring and/or aromatic substances.
  • the substances are preferably administered in a dosage of 0.12,000 mg. per dosage unit.
  • temperatures are set forth in degrees centigrade.
  • EXAMPLE 1 (a) 3.6 g. of 2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-allyl alcohol (obtainable from 2-(3-nitro-4- chlorophenyl)-allyl alcohol and 3-hydroxypiperidine, catalytic reduction to the amino compound, diazotization, and exchange of the diazonium group against chlorine) is hydrogenated in a mixture of methanol and ethyl acetate with hydrogen at room temperature in the presence of 0.6 g. of a Pd-C catalyst (5% by weight Pd).
  • reaction solution is poured into water, extracted with ether, the ether phase washed with water, dried over Na SO the ether distilled oif, and, after purifying the residue by chromatography (silica gel/ benzene), one obtains 2-[3-chloro-4-(3-methoxypiperidino)-phenyl]-1-methoxypropane, B.P. 143-146/ 0.1 mm.
  • EXAMPLE 3 (a) 6.2 g. of the ethyl ester of 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propionic acid (mixture of two racemates, M.P. -165) is refluxed in 300 ml. of dry tetrahydrofuran with 1.0 g. of LiAlH After cooling, any excess LiAlH, is decomposed with moist tetrahydrofuran; 6 ml.
  • EXAMPLE 4 (a) Analogously to Example 3, by reduction with LiAlH the low-melting racemates of 2-[3-chloro-4-(3- hydroxypiperidino)-phenyl]-1-propanol, M.P. 70-72, is produced from the low-meling racemate of 2-[3-chloro-4- (3-hydroxypiperidino)-phenyl]-propionic acid (M.P. 140- 143 and/or from the corresponding esters.
  • EXAMPLE 6 4.7 g. of l-bromo-2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-propane (produced from 4-bromo-3-nitroacetophenone by reaction with 3-hydroxypiperidine, catalytic hydrogenation of the thus-produced 4-(3-hydroxypiperidino)3-nitroacetophenone, diazotization, and Sandmeyer reaction to 3 chloro-4-(3-hydroxypiperidino)-acetophenone [B.P. 190195/0.2 mm.], reaction with methylmagnesium iodide to 2 [3-chloro-4-(3-hydroxypiperidino)-phenyl1-2-propanol (M.P.
  • EXAMPLE 7 10 g. of 2-(4-amino-3-chlorophenyl)-1-propanol (obtainable from 2-(4-amino-3-chlor0phenyl)-propionic acid [M.P. 114-115 by reduction with LiAlH is refluxed with 28 g. of 1,4-dibromobutan-2-ol (B.P. 70-75/0.4 mm.; obtainable from 1,2,4-trihydroxybutane and HBr) for 7 hours in 70 ml. of water is added dropwise.
  • 2-(4-amino-3-chlorophenyl)-1-propanol obtainable from 2-(4-amino-3-chlor0phenyl)-propionic acid [M.P. 114-115 by reduction with LiAlH is refluxed with 28 g. of 1,4-dibromobutan-2-ol (B.P. 70-75/0.4 mm.; obtainable from 1,2,4-trihydroxy
  • EXAMPLE 9 Analogously to Example 3, from 2-[3-chloro-4-(3-oxopiperidino)-phenyl]-1-propanol (obtainable by reacting 2- (3 nitro-4-bromophenyl)-l-propanol with 3-piperidone ethylene ketal, reduction of the thus-produced 2-[3-nitro- 4-(3,3-ethylenedioxypiperidino)-phenyl] -1-propanol to the amino compound, diazotization under simultaneous ketal hydrolysis, and Sandmeyer reaction) the compound 2-[3- chloro 4-(3-hydroxypiperidino)-phenyl]-propanol-(1) is obtained as a mixture of two racemates, B.P. l80/ 0.05 mm.; M.P. 75-82".
  • EXAMPLE 10 8.0 g. of 2-[3-chloro-4-(3-bromopiperidino)-phenyl]- l-propanol (obtainable from 2-(3-nitro-4-bromophenyl)- l-propanol by reaction with 3,4-dehydropiperidine, reduction of the thus-produced 2-[3-nitro-4-(3,4-dehydropiperidino)-phenyl]-1propanol, Sandmeyer reaction, bromination of the thus-obtained 2-[3-chloro-4-(3,4-dehydropiperidino)-phenyl]-l-propanol with N-bromosuccinimide, and subsequent catalytic hydrogenation) is refluxed for 6 hours in a mixture of 80 ml.
  • compositions of the-novel compounds which can be produced according to conventional standards:
  • Example A.Tablets The coating is a conventional mixture of corn starch,
  • sugar, talc, and tragacanth amounts to 150 mg.
  • Example C.Solution for injection A solution of 2 kg. of the hydrochloride of 2-[3-chloro- 4 (3 hydroxypiperidino)-phenyl]-1-propanol in 198 kg. of distilled Water is prepared and filled into 2 ml. ampoules in such a manner that each ampoule contains 20 mg. of said hydrochloride.
  • Example D Syrup A mixture of 2 [3 chloro 4-(3-acetoxypiperidino)-phenyl]- l-propyl acetate Glycerol (twice distilled) 7.5 Cane sugar 56.0 Methyl p-hydroxybenzoate 0.07 n-Propyl p-hydroxybenzoate 0.03 Ethanol 10.0 Flavorings As desired is prepared and mixed with distilled water in such a manner that the volume of the entire preparation is 100 l. A dosage unit (5 ml.) contains 20 mg. of active substance.
  • Example E.-Hard gelatin capsules Each hard gelatin capsule is filled with a fine powder consisting of Mg. 2 [3 chloro 4-(3-hydroxypiperidino)-phenyl]- 1 propanol Lactose 180 Talc 18 Magnesium stearate 2 Instead of the hydrochloride other physiologically compatible acid or base addition salts, respectively, of 2- [3 chloro 4-(3-hydroxypiperidino)-phenyl]-1-propanol or 2 [3 chloro 4 (3-acetoxypiperidino)-phenyl]-1- propyl acetate or other compounds covered by Formula 1, as well as the physiologically compatible acid addition salts, thereof, can be incorporated into similar compositions.
  • R is OH, alkoxy of up to 6 carbon atoms, cycld alkoxy of up to 6 carbon atoms, aryloxy, aralkoxy of 7- 12 carbon atoms, or alkanoyloxy of up to 18 carbon atoms;
  • R is H, alkyl of up to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl, aralkyl of 7-12 carbon atoms, or alkanoyl of up to 18 carbon atoms;
  • aryl in each of the above instances is phenyl, tolyl, xylyl or naphthyl;
  • R is H or CH
  • R is Cl, Br or CH and n is 2 or 3; and the physiologically acceptable acid addition and quaternary ammonium salts thereof.
  • R is alkanoyloxy of up to 18 carbon atoms.
  • R is alkanoyl of up to 18 carbon atoms.
  • R is alkanoyloxy of up to 18 carbon atoms, R is H, R is CH and R is Cl.
  • a compound of claim 1 2-[3-chloro-4-(3-hydroxy- 19.
  • Claim l8 should read as follows 18. A compound of Claim 1, 2- [3chloro4 (3-hydroxy-piperidino)-phenyl]-lpropanol'.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3936467A (en) * 1968-03-27 1976-02-03 Ciba-Geigy Corporation Hydroxyalkylenimino-phenyl-acetic acids
US3993763A (en) * 1969-03-18 1976-11-23 Ciba-Geigy Corporation Tertiary aminoacids as anti-inflammatory agents
US4216326A (en) * 1975-01-20 1980-08-05 Sterling Drug Inc. Intermediates for preparing anti-inflammatory phenyl-lower-alkylamines
US4417052A (en) * 1980-02-15 1983-11-22 Sterling Drug Inc. Phenyl-lower-alkyl piperidines and pyrrolidines
US20050288329A1 (en) * 2004-06-24 2005-12-29 Wenqing Yao 2-Methylprop anamides and their use as pharmaceuticals
US20060004049A1 (en) * 2004-06-24 2006-01-05 Wenqing Yao N-substituted piperidines and their use as pharrmaceuticals
US20060009491A1 (en) * 2004-06-24 2006-01-12 Incyte Corporation Amido compounds and their use as pharmaceuticals
US20060009471A1 (en) * 2004-06-24 2006-01-12 Wenqing Yao Amido compounds and their use as pharmaceuticals
US20060122197A1 (en) * 2004-08-10 2006-06-08 Wenqing Yao Amido compounds and their use as pharmaceuticals
US20070208001A1 (en) * 2006-03-03 2007-09-06 Jincong Zhuo Modulators of 11- beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
US20070213311A1 (en) * 2006-03-02 2007-09-13 Yun-Long Li Modulators of 11-beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
US20070270424A1 (en) * 2006-05-17 2007-11-22 Yun-Long Li Heterocyclic inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1 and methods of using the same
US20070293529A1 (en) * 2006-05-01 2007-12-20 Yun-Long Li Tetrasubstituted ureas as modulators of 11-beta hydroxyl steroid dehydrogenase type 1
US20080108820A1 (en) * 2002-03-22 2008-05-08 Campagna Silvio A Hemiasterlin Derivatives and Uses Thereof
US20080255154A1 (en) * 2004-05-07 2008-10-16 Incyte Corporation Amido Compounds And Their Use As Pharmaceuticals

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH501616A (de) * 1968-04-29 1971-01-15 Ciba Geigy Ag Verfahren zur Herstellung von neuen, substituierten Phenäythylestern
DE2013376A1 (de) * 1970-03-20 1971-10-07 Merck Patent Gmbh Substituierte Phenylessigsauren und Verfahren zu ihrer Herstellung

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3936467A (en) * 1968-03-27 1976-02-03 Ciba-Geigy Corporation Hydroxyalkylenimino-phenyl-acetic acids
US3993763A (en) * 1969-03-18 1976-11-23 Ciba-Geigy Corporation Tertiary aminoacids as anti-inflammatory agents
US4216326A (en) * 1975-01-20 1980-08-05 Sterling Drug Inc. Intermediates for preparing anti-inflammatory phenyl-lower-alkylamines
US4417052A (en) * 1980-02-15 1983-11-22 Sterling Drug Inc. Phenyl-lower-alkyl piperidines and pyrrolidines
US20080108820A1 (en) * 2002-03-22 2008-05-08 Campagna Silvio A Hemiasterlin Derivatives and Uses Thereof
US9957229B2 (en) 2004-05-07 2018-05-01 Incyte Holdings Corporation Amido compounds and their use as pharmaceuticals
US9670154B2 (en) 2004-05-07 2017-06-06 Incyte Holdings Corporation Amido compounds and their use as pharmaceuticals
US9126927B2 (en) 2004-05-07 2015-09-08 Incyte Holdings Corporation Amido compounds and their use as pharmaceuticals
US8058288B2 (en) 2004-05-07 2011-11-15 Incyte Corporation Amido compounds and their use as pharmaceuticals
US20100256114A1 (en) * 2004-05-07 2010-10-07 Incyte Corporation Amido Compounds And Their Use As Pharmaceuticals
US7776874B2 (en) 2004-05-07 2010-08-17 Incyte Corporation Amido compounds and their use as pharmaceuticals
US20080255154A1 (en) * 2004-05-07 2008-10-16 Incyte Corporation Amido Compounds And Their Use As Pharmaceuticals
US20060009491A1 (en) * 2004-06-24 2006-01-12 Incyte Corporation Amido compounds and their use as pharmaceuticals
US8288417B2 (en) 2004-06-24 2012-10-16 Incyte Corporation N-substituted piperidines and their use as pharmaceuticals
US20050288329A1 (en) * 2004-06-24 2005-12-29 Wenqing Yao 2-Methylprop anamides and their use as pharmaceuticals
US20060004049A1 (en) * 2004-06-24 2006-01-05 Wenqing Yao N-substituted piperidines and their use as pharrmaceuticals
US7687665B2 (en) 2004-06-24 2010-03-30 Incyte Corporation 2-methylprop anamides and their use as pharmaceuticals
US20060009471A1 (en) * 2004-06-24 2006-01-12 Wenqing Yao Amido compounds and their use as pharmaceuticals
US8071624B2 (en) 2004-06-24 2011-12-06 Incyte Corporation N-substituted piperidines and their use as pharmaceuticals
US20060122197A1 (en) * 2004-08-10 2006-06-08 Wenqing Yao Amido compounds and their use as pharmaceuticals
US20070213311A1 (en) * 2006-03-02 2007-09-13 Yun-Long Li Modulators of 11-beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
US20070208001A1 (en) * 2006-03-03 2007-09-06 Jincong Zhuo Modulators of 11- beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
WO2007103719A3 (en) * 2006-03-03 2008-01-24 Incyte Corp MODULATORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME
US20070293529A1 (en) * 2006-05-01 2007-12-20 Yun-Long Li Tetrasubstituted ureas as modulators of 11-beta hydroxyl steroid dehydrogenase type 1
US7838544B2 (en) 2006-05-17 2010-11-23 Incyte Corporation Heterocyclic inhibitors of 11-β hydroxyl steroid dehydrogenase type 1 and methods of using the same
US20070270424A1 (en) * 2006-05-17 2007-11-22 Yun-Long Li Heterocyclic inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1 and methods of using the same

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CH588460A5 (enrdf_load_stackoverflow) 1977-06-15
BE781212A (fr) 1972-09-25
IL38972A (en) 1976-01-30
DE2114420A1 (de) 1972-10-05
PL83328B1 (enrdf_load_stackoverflow) 1975-12-31
FR2130659B1 (enrdf_load_stackoverflow) 1975-03-14
CS163797B2 (enrdf_load_stackoverflow) 1975-11-07
CS163796B2 (enrdf_load_stackoverflow) 1975-11-07
CS168694B2 (enrdf_load_stackoverflow) 1976-06-29
FR2130659A1 (enrdf_load_stackoverflow) 1972-11-03
DK137273B (da) 1978-02-13
CH605739A5 (enrdf_load_stackoverflow) 1978-10-13
DD96946A5 (enrdf_load_stackoverflow) 1973-04-12
ZA721653B (en) 1972-12-27
AU4040472A (en) 1973-09-27
GB1359600A (en) 1974-07-10
CS163798B2 (enrdf_load_stackoverflow) 1975-11-07
DK137273C (da) 1978-07-17
AT344169B (de) 1978-07-10
AU465561B2 (en) 1973-09-27
NL7203986A (enrdf_load_stackoverflow) 1972-09-27
CA980353A (en) 1975-12-23
ES401198A1 (es) 1975-10-01
BR7201760D0 (pt) 1974-01-08
IL38972A0 (en) 1972-05-30
SE374918B (enrdf_load_stackoverflow) 1975-03-24

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