US3126393A - X-gamma-dffithylaminopropylamino - Google Patents

X-gamma-dffithylaminopropylamino Download PDF

Info

Publication number
US3126393A
US3126393A US3126393DA US3126393A US 3126393 A US3126393 A US 3126393A US 3126393D A US3126393D A US 3126393DA US 3126393 A US3126393 A US 3126393A
Authority
US
United States
Prior art keywords
parts
mixture
tetramethylpiperidine
ether
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Publication date
Application granted granted Critical
Publication of US3126393A publication Critical patent/US3126393A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • 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
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • 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
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/067—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • This invention relates to new organic compounds and more particularly it relates to new piperidine derivatives which possess valuable therapeutic properties.
  • R1 A R as f R4 R wherein R stands for hydrogen or for an alkyl radical or an alkenyl radical of not more than 6 carbon atoms, optionally substituted, wherein R R R and R which may be the same or different, stand for methyl or ethyl radicals, and wherein the piperidine ring (A) may optionally be further substituted by a lower alkyl radical, a phenyl radical or a di-alkylamino-alkylamino radical, and the non-toxic pharmaceutically-acceptable acid addi tion salts and certain quaternary salts thereof.
  • quaternary salts thereo we include only those salts wherein the ring nitrogen atom is linked to two methyl radicals that is to say those compounds wherein R stands for a methyl radical and the ring nitrogen atom is further methylated.
  • alkyl radical (R) there may be mentioned for example hydroxy, alkoxy and acyloxy substituents as illustrated by the B-hydroxyethyl, fi-ethoxyethyl, ,B-acetoxyethyl and 56:4:5- trimethoxybenzoyloxyethyl radicals.
  • non-toxic pharmaceutically-acceptable acid addition salts there may be mentioned for example the hydrochlorides, sulphates, phosphates, succinates, malea-tes, lactates and tartates and suitable quaternary salts may be for example the methiodides.
  • Particularly valuable compounds of the above stated formula are 1-ethyl-2a2z6:6-tetramethylpiperidine, 1:2:2: 6 6-pentamethylpiperidine, 1- ,B-acetoxy-ethyl-Z 2 2 :6 6-tetramethylpiperidine, l-B-hydroxyethyl-Z 2: 6: 6-te-tramethylpiperidine, 1 1 :2 2 6: 6-hexamethy1-piperidinium iodide, 1-n buty-1-2:2: 6: 6-tetramethyl-piperidine, 1-allyl-2 2 6 6- tetramethylpipenidine, 2: 6-diethyl-2 3 6-tnimethylpiperidine and 2:2: 6 6-tetramethyl-1-fi- 3 :4 :5 '-trimethoxybenzoyloxy)ethylpiperidine and of these, the preferred compound is l-ethyl-2 2: 6 G-tetramethylpiperidine.
  • the said reduction process may be carried out by any means known to the art for example by the Clemmensen method by heating with amalgamated zinc and hydrochloric acid or by the Woltf-Kishner method by heating the corresponding hydrazone derivative with sodium or potassium ethoxide or with sodium or potassium hydroxide in the presence of an inert diluent or solvent for example dior tri-ethylene glycol.
  • R, R R R and R have the meaning stated above and wherein the tetrahydropyridine ring (B) may optionally be further substituted by a lower alkyl radical or by a phenyl radical.
  • the said reduction may be carried out by any means known to the art for example by the use of hydrogen and a catalyst for example Raney nickel or Adams platinum oxide catalyst in the presence of methanol or by the use of sodium and ethanol,
  • the tetrahydropyridine derivatives used as starting materials may be obtained by dehydration of the corresponding 4-piperidols which may themselves be obtained either by reduction of the corresponding 4-piper-idones or by treating the corresponding 4-piperidones with a Grignard reagent or with an acetylenic compound.
  • R R R R and A have the meaning stated above.
  • the said alkylation process may be carried out by use of an alkyl halide or sulphate for example n-butyl bromide, allyl bromide or die-thyl sulphate or an alkyl sulphonate for example methyl-p-toluene sulphonate.
  • an acid-binding agent for example excess of the piperidine base, lithium hydroxide or anhydrous potassium carbonate and there may optionally be present an inert diluent or solvent for example an excess of the piperidine base.
  • the alkylation process may be carried out by the use of aqueous formaldehyde or a mixture of aqueous formaldehyde and formic acid and when R stands for a B-hyd-roxyethyl radical, the alkylation process may be carried out by the use of ethylene chlorohydrin.
  • Suitable acylating agents may be for example acid anhydrides for example acetic anhydride or acid halides for example 3:4:5-trimethoxybenzoyl chloride.
  • the reaction may be carried out, if necessary, in the presence of an inert diluent or solvent for example benzene.
  • the reaction may be carried out in the presence of the corresponding alcohol for example ethanol when the alkali metal alkoxide is sodium ethoxide.
  • the said quaternisation process may be carried out using a methyl halide for example methyl iodide preferably in the presence of an inert diluent or solvent for example acetonitrile.
  • the new piperidine derivatives and the non-toxic pharmaceutically-acceptable acid-addition salts and quaternary salts thereof possess valuable thereapeutic properties and in articular they possess ganglion-blocking and hypotensive properties such as to render them of value in the treatment of hypertension.
  • These compounds compare favorably with the known drug, mecamylamine, used in the treatment of hypertension. They may be used in combination with known drugs for example meprobamate, reserpine or aspirin.
  • the bases and the acid-addition salts thereof are generally long-acting and are particularly suitable for the treatment of hypertensive disease while the quaternary salts are highly active and short-acting and are more suitable for controlled hypotension in surgical procedures.
  • Example 1 A mixture of 4 parts of 2:2:6:6-tetramethylpiperidine, 12 parts of 98% w./v. of aqueous formic acid and 15 parts of 38% w./v. of aqueous formaldehyde is heated gently under reflux for 8 hours. The solution is then cooled, made alkaline with aqueous sodium hydroxide solution and the mixture is extracted with 4 portions (35 parts each) of ether. The ethereal solution is dried, the ether evaporated and the residue is distilled to give 1:2:2:6:6-pentamethylpiperidine, B.P. 183-184 C./771 mm. It forms a picrate which may be crystallised from ethanol to give 1:2:2:6:6-pentamethylpiperdine picrate as a yellow crystalline solid, M.P. 274276 C. with decomposition.
  • Example 2 A solution of 2.25 parts of 1:222:6z6-pentamethyl- A -tetrahydropyridine hydrochloride in 40 parts of methanol is shaken in an atmosphere of hydrogen with 0.5 parts of Adams platinum oxide catalyst until the theoretical amount of hydrogen has been adsorbed. The reaction mixture is filtered and the filtrate is evaporated to about 5 parts. Ether is then added and after standing for a short time there is obtained the hydrochloride of Example 3 A mixture of 14.1 parts of 2:2:6:6-tetramethylpiperdine and 7.7 parts of ethyl sulphate is heated at l00 C. for 15 hours and is then cooled and diluted with 35 parts of ether.
  • the mixture is filtered and the solid residue is washed twice with 20 parts of ether.
  • the combined ethereal filtrates are evaporated and the residual oil is distilled and the fraction B.P. 188-198 C. at 760 mm. is collected. It is redistilled and there is thus obtained 1-ethyl-2:2:6:6-tetramethylpiperidine B.P. 194-198 C. at 760 mm.
  • the base forms a picrate which when crystallised from ethanol has M.P. 245-247 C. with decomposition and a hydriodide which when crystallised from dilute aqueous hydriodic acid has M.P. 269270 C. with decomposition.
  • Example 4 A mixture of 14.1 parts of 2:226:6-tetramethylpiperidine and 605 parts of allyl bromide is heated under reflux for 18 hours. 35 parts of ether are then added to the cooled mass and the mixture is filtered and the solid residue is washed twice with 35 parts of ether. The combined ethereal filtrates are evaporated and the residual oil is distilled and the fraction of B.P. 205-215 C. at 763 mm. is collected. It is redistilled and there is obtained 1 allyl 222:6:6 tetramethylpiperidine, B.P. 9698 C. at 20 mm. pressure.
  • the base forms a picrate which when crystallised from ethanol has M.P. 162-163 C.
  • Example 5 A mixture of 14.1 parts of 2:216:6-tetramethylpiperidine and 6.84 parts of n-butyl bromide is heated under reflux for 96 hours. The mixture is filtered and the filtrate is distilled and the fraction B.P. 108-112" C. at 18 mm. is collected. It is redistilled and there is obtained 1-n-butyl-2z2:6:6-tetramethylpiperidine B.P. 96-98 C. at 12 mm.
  • the base forms a picrate which when crystallised from ethanol has M.P. 181182 C.
  • Example 6 A mixture of 28.2 parts of 2:2:6:6-tetramethylpiperidine and 16.2 parts of ethylene chlorohydrin is heated in an oil bath at 155 C. for 3 hours. The mixture is cooled and an excess of 50% aqueous sodium hydroxide solution is added. The liberated base is extracted with four portions of 35 parts of ether and the ethereal extract is dried over anhydrous potassium carbonate and then evaporated. The residual oil is distilled and unreacted. 212:6:G-tetramethylpiperidine distils at 4060 C. at 12 mm. and can be retreated.
  • the desired product l-phydroxyethyl-2:2:6:6-tetramethylpiperidine, distils as a colourless oil B.P. 142 C. at 12 mm. which solidifies on cooling and has M.P. 96 C. It forms a picrate which when crystallised from ethanol has M.P. 215216 C.
  • Example 7 5 parts of acetic anhydride are added to 5 parts of l-p-hydroxyethyl-Z :2 6 6-tetramethylpiperidine and the mixture is heated gently under reflux for /2 hour. It is then cooled and poured into 20 parts of ice and excess of 40% aqueous sodium hydroxide solution is added. The mixture is extracted three times with 35 parts of ether and the combined ethereal extracts are dried over anhydrous potassium carbonate and evaporated. The residual oil is distilled and there is thus obtained l-fi-acetoxyethyl- 2:2:6:G-tetramethylpiperidine, B.P. 139-141 C.
  • Example 8 4.61 parts of 3:4:S-trimethoxybenzoylchloride are added to a solution of 3.7 parts of l-B-hydroxyethyl- 2:2:6:6-tetramethylpiperidine in 22 parts of benzene and the mixture is heated under reflux for 1 hour. It is then cooled and filtered and the solid residue is washed with 8 parts of benzene and dried. It is then crystallised from ethyl acetate to give 2:2:6:6-tetramethyl-1-[3-(3'z4':5- trimethoxybenzoyloxy) ethylpiperidine hemihydrochloride, as a colourless crystalline solid, M.P. 157 C.
  • Example 9 4 parts of 1-fi-chloroethyl-2:2:6:6-tetramethylpiperidine hydrochloride are added to a solution of sodium ethoxide prepared by dissolving 1 part of sodium in 200 parts of ethanol. The mixture is heated under reflux for 4 hours and is then cooled and filtered. The filtrate is concentrated by evaporation and 50 parts of Water are added to the residue. The mixture is then extracted three times with 35 parts of ether. The combined ethereal extracts are dried over potassium carbonate and evaporated. The residual oil is distilled and there is thus obtained l-B-ethoxyethyl-Z 2 6 6-tetramethylpiperidine, B.P. 13 2- 136 C. at 18 mm.
  • Example 10 5 parts of methyl iodide are added to a solution of 3.1 parts of 1:2:2:6:6-pentamethylpiperidine in 16 parts of acetonitrile and the mixture is heated under reflux for 3 hours. It is then cooled and filtered and there is thus obtained 1:1:2:2:6:6-hexamethylpiperidinium iodide, M.P. 21021l C.
  • Example 11 10 parts of 4-ethyl-4-hydroxy-2z2z 6c6-tetramethylpiperidine hydriodide are heated at 195200 C. for /2 hour and the resulting 4-ethyl-122:5:6-tet-rahydro-2:2:6:6 tetramethylpyridine hydriodide is dissolved in 100 parts of water and excess of aqueous sodium hydroxide solution is added. The pyridine base is extracted with four equal portions of 70 parts of ether.
  • the combined ethereal extracts are saturated with hydrochloric acid gas and the 4 ethyl-1:225 6-tetrahydro-2z2:6:6-tetramethylpyridine hydrochloride so obtained is dissolved in 40 parts of methanol and shaken in an atmosphere of hydrogen with 0.5 part of Adams platinum oxide catalyst.
  • the reaction mixture is filtered and the filtrate is evaporated.
  • the gummy residue is dissolved in 225 parts of ethyl acetate and the solution is filtered and evaporated to about 40 parts when there is obtained 4-ethyl-2:2:6:6-tetramethylpiperidine hydrochloride, M.P. 178 C.
  • the 4 ethyl-4-hydroxy-2z2z6:6-tetramethylpiperidine hydriodide used as starting material may be prepared as follows: A solution of 5 parts of 4-ethynyl-4-hydroxy- 2:2:6:6-tetramethylpiperidine in 40 parts of methanol is shaken in an atmosphere of hydrogen with 0.25 part of Raney nickel catalyst until no more hydrogen is adsorbed (2 molecular proportions). The reaction mixture is then filtered and the filtrate is evaporated to give 4-ethyl-4- hydroxy-2s2z6:6-tetramethylpiperidine as an oil which solidifies on cooling and has M.P. 7072 C. The hydriodide is obtained by crystallising the base from hydriodic acid. It has M.P. 195 C.
  • Example 12 A mixture of 5.5 parts of 4-keto-1:2:2:6:6-pentamethylpipe-ridine, 30 parts of triethylene glycol, 6 parts of hydrazine hydrate and 6 parts of potassium hydroxide is heated in an oil bath under reflux.
  • the condenser is fitted with a take-0E head so that water appearing in the distillate can be removed.
  • the internal temperature is gradually raised to 180 C. during 2 hours during which time water is drawn off from the distillate.
  • the internal temperature is then raised gradually from 180 C. to 200 C. and the product 1:2:2:6:6-pentamethylpiperidine is collected. It is purified by distillation and has B.P. 182- 183" C. at 768 mm. It forms a picrate of M.P. 274276 C. with decomposition.
  • Example 13 A mixture of 10 parts of 2:6-diethyl-4-keto-2z3:6-trimethylpiperidine, 50 parts of triethylene glycol, 10 parts of hydrazine hydrate and 10 parts of potassium hydroxide is heated in an oil bath gently under reflux. The condenser is fitted with a take-oif head so that water formed in the distillate can be removed. The internal temperature is allowed to rise slowly during the course of 1 hour from 120-200 C. The mixture is then cooled and poured into 500 parts of water and is extracted three times with 35 parts of ether. The combined ethereal extracts are dried and the ether evaporated and the oily residue is distilled.
  • Example 14 A mixture of 3 parts of 2:6-diethyl 223:6-trimethylpiperidine, 8.5 parts of formic acid and 10 parts of formalin (36%) is heated at 98-100 C. for 72 hours and is then cooled. An excess of 40% aqueous sodium hydroxide solution is added and the oily base is separated and the aqueous layer is extracted with 7 parts of ether. The combined ethereal extract and oily base is then dried pver potassium hydroxide and the ether distilled. The residual oil is distilled to give 2:6-diethyl-1:2:3:6-tetramethylpiperidine, B.P. 119121 C. at 18 mm.
  • Example 16 A solution of 2 parts of 4-pl1enyl-2z2:6:6-tetramethyl A -tetrahydropyridine hydrochloride in 40 parts of methanol is shaken in an atmosphere of hydrogen with 0.5 part of Adams platinum oxide catalyst until no more hydrogen is adsorbed. The reaction mixture is filtered and the methanol is removed by evaporation under reduced pressure. There is thus obtained 4-pheny1-2:2:'6:6- tetramethylpiperidine hydrochloride as a colourless solid M.P. 225-226" C.
  • Example 17 A solution of 10 parts of triacetoneamine hydrate and 7.5 parts of gamma-diethylaminopropylamine in parts of methanol is shaken with 0.5 part of Adams platinum
  • Example 18 37.2 parts of methyl p-toluenesulphonate are added with stirring to 28.2 parts of 2:2: 6z6-tetramethylpiperidine. parts of lithium hydroxide monohydrate are then added and the mixture is allowed to Warm spontaneously. After /2 hour the mixture is heated at 100 C. for 2 hours and then 100 parts of water and 25 parts of 40% aqueous sodium hydroxide are added. The oily layer is separated and distilled when there is obtained 1:2:2:6:6-pentamethylpiperidine which boils at 182-185 C. at 763 mm. pressure.
  • Example 19 A mixture of 28.2 parts of 2: 2:6:6tetramethylpiperidine and 20 parts of ethyl p-toluenesulphonate is heated on a steam bath for 24 hours. It is then cooled to 25 C. and made alkaline by the addition of 50 parts of 40% aqueous sodium hydroxide solution and extracted with 105 parts of ether divided into three equal portions. The ethereal extract is dried over potassium hydroxide and the ether is then distilled. The residual oil is fractionated and there is thus obtained 1-ethyl-2:2:6:6tetramethylpiperidine, B.P. 193197 C. at 740 mm.
  • a piperidine selected from the group consisting of 4 gamma-diethylaminopropylamino-Z:2: 6: 6-tetramethy1- piperidine and the non-toxic pharmaceutically-acceptable acid addition salts thereof.

Description

United States Patent O 3,126,393 4-GAMMA-DIETHYLAMINOPROPYLAMJNO- 2:2:6:6-TETRAMETHYLPIPERIDINE Edwin Harry Paterson Young, Manchester, England,
assignor to Imperial Chemical Industries Limited, London, England, a corporation of Great Britain N Drawing. Filed Feb. 3, 1958, Ser. No. 712,624 Claims priority, application Great Britain Feb. 13, 1957 1 Claim. (Cl. 260-293) This invention relates to new organic compounds and more particularly it relates to new piperidine derivatives which possess valuable therapeutic properties.
According to the invention we provide new piperidine derivatives of the formula:
R1 A R as f R4 R wherein R stands for hydrogen or for an alkyl radical or an alkenyl radical of not more than 6 carbon atoms, optionally substituted, wherein R R R and R which may be the same or different, stand for methyl or ethyl radicals, and wherein the piperidine ring (A) may optionally be further substituted by a lower alkyl radical, a phenyl radical or a di-alkylamino-alkylamino radical, and the non-toxic pharmaceutically-acceptable acid addi tion salts and certain quaternary salts thereof.
It is to be understood that when the piperidine ring (A) contains no further substi-tuents in positions 3, 4 or 5 then the substituents R, R R R and R together contain more than 4 carbon atoms.
It is further to be understood that by the expression quaternary salts thereo we include only those salts wherein the ring nitrogen atom is linked to two methyl radicals that is to say those compounds wherein R stands for a methyl radical and the ring nitrogen atom is further methylated.
As suitable optional substituents in the alkyl radical (R) there may be mentioned for example hydroxy, alkoxy and acyloxy substituents as illustrated by the B-hydroxyethyl, fi-ethoxyethyl, ,B-acetoxyethyl and 56:4:5- trimethoxybenzoyloxyethyl radicals.
As suitable non-toxic pharmaceutically-acceptable acid addition salts there may be mentioned for example the hydrochlorides, sulphates, phosphates, succinates, malea-tes, lactates and tartates and suitable quaternary salts may be for example the methiodides.
Particularly valuable compounds of the above stated formula are 1-ethyl-2a2z6:6-tetramethylpiperidine, 1:2:2: 6 6-pentamethylpiperidine, 1- ,B-acetoxy-ethyl-Z 2 2 :6 6-tetramethylpiperidine, l-B-hydroxyethyl-Z 2: 6: 6-te-tramethylpiperidine, 1 1 :2 2 6: 6-hexamethy1-piperidinium iodide, 1-n buty-1-2:2: 6: 6-tetramethyl-piperidine, 1-allyl-2 2 6 6- tetramethylpipenidine, 2: 6-diethyl-2 3 6-tnimethylpiperidine and 2:2: 6 6-tetramethyl-1-fi- 3 :4 :5 '-trimethoxybenzoyloxy)ethylpiperidine and of these, the preferred compound is l-ethyl-2 2: 6 G-tetramethylpiperidine.
According to a further feature of the invention we provide a process for the manufacture of certain of the new piperidine derivatives which comprises reduction of the corresponding compounds of the formula:
R1 A R3 3,l2,3% Patented Mar. 24, 1%64 ICC wherein R, R R R R and A have the meaning stated above.
The said reduction process may be carried out by any means known to the art for example by the Clemmensen method by heating with amalgamated zinc and hydrochloric acid or by the Woltf-Kishner method by heating the corresponding hydrazone derivative with sodium or potassium ethoxide or with sodium or potassium hydroxide in the presence of an inert diluent or solvent for example dior tri-ethylene glycol.
According to yet a further feature of the invention we provide a process for the manufacture of the new piperidine derivatives which comprises reduction of the corresponding tetrahydropyr-idine derivatives of the formula:
wherein R, R R R and R have the meaning stated above and wherein the tetrahydropyridine ring (B) may optionally be further substituted by a lower alkyl radical or by a phenyl radical.
The said reduction may be carried out by any means known to the art for example by the use of hydrogen and a catalyst for example Raney nickel or Adams platinum oxide catalyst in the presence of methanol or by the use of sodium and ethanol,
The tetrahydropyridine derivatives used as starting materials may be obtained by dehydration of the corresponding 4-piperidols which may themselves be obtained either by reduction of the corresponding 4-piper-idones or by treating the corresponding 4-piperidones with a Grignard reagent or with an acetylenic compound.
According to still a further feature of the invention we provide a process for the manufacture of those of the new piperidine derivatives wherein R is a radical other than hydrogen which comprises alkylation of a compound of the formula:
R A R3 wherein R R R R and A have the meaning stated above.
The said alkylation process may be carried out by use of an alkyl halide or sulphate for example n-butyl bromide, allyl bromide or die-thyl sulphate or an alkyl sulphonate for example methyl-p-toluene sulphonate. There may optionally be present an acid-binding agent for example excess of the piperidine base, lithium hydroxide or anhydrous potassium carbonate and there may optionally be present an inert diluent or solvent for example an excess of the piperidine base. Furthermore, when R stands for a methyl radical, the alkylation process may be carried out by the use of aqueous formaldehyde or a mixture of aqueous formaldehyde and formic acid and when R stands for a B-hyd-roxyethyl radical, the alkylation process may be carried out by the use of ethylene chlorohydrin.
According to a further feature of the invention we provide a process for the manufacture of those of the new piperidine derivatives wherein R stands for an alkyl radical containing a terminal acyloxy radical which comprises acylating the corresponding compounds wherein R stands for an alkyl radical containing a terminal hydroxy group.
Suitable acylating agents may be for example acid anhydrides for example acetic anhydride or acid halides for example 3:4:5-trimethoxybenzoyl chloride. The reaction may be carried out, if necessary, in the presence of an inert diluent or solvent for example benzene.
According to a further feature of the invention We provide a process for the manufacture of those of the new piperidine derivatives wherein R is an alkyl radical containing a terminal alkoxy substituent which comprises interaction of the corresponding compound wherein R is an alkyl radical containing a terminal halogen substituent and an alkali metal alkoxide for example sodium ethoxide.
The reaction may be carried out in the presence of the corresponding alcohol for example ethanol when the alkali metal alkoxide is sodium ethoxide.
According to a further feature of the invention we provide a process for the manufacture of those of the new piperidine derivatives which are quaternary salts which comprises methylating the corresponding tertiary bases wherein R stands for a methyl radical by known means.
The said quaternisation process may be carried out using a methyl halide for example methyl iodide preferably in the presence of an inert diluent or solvent for example acetonitrile.
According to a further feature of the invention we provide a process for the manufacture of those of the new piperidine derivatives wherein the piperidine ring (A) is further substituted in the 4-position by a dialkylaminoalkylamino radical which comprises reductive alkylation of the corresponding 4-piperidone with a dialkylaminoalkylamine in the presence of hydrogen and a platinum catalyst for example Adams platinum catalyst.
As stated above the new piperidine derivatives and the non-toxic pharmaceutically-acceptable acid-addition salts and quaternary salts thereof possess valuable thereapeutic properties and in articular they possess ganglion-blocking and hypotensive properties such as to render them of value in the treatment of hypertension. These compounds compare favorably with the known drug, mecamylamine, used in the treatment of hypertension. They may be used in combination with known drugs for example meprobamate, reserpine or aspirin. The bases and the acid-addition salts thereof are generally long-acting and are particularly suitable for the treatment of hypertensive disease while the quaternary salts are highly active and short-acting and are more suitable for controlled hypotension in surgical procedures.
The invention is illustrated but not limited by the following examples in which the parts are by weight:
Example 1 A mixture of 4 parts of 2:2:6:6-tetramethylpiperidine, 12 parts of 98% w./v. of aqueous formic acid and 15 parts of 38% w./v. of aqueous formaldehyde is heated gently under reflux for 8 hours. The solution is then cooled, made alkaline with aqueous sodium hydroxide solution and the mixture is extracted with 4 portions (35 parts each) of ether. The ethereal solution is dried, the ether evaporated and the residue is distilled to give 1:2:2:6:6-pentamethylpiperidine, B.P. 183-184 C./771 mm. It forms a picrate which may be crystallised from ethanol to give 1:2:2:6:6-pentamethylpiperdine picrate as a yellow crystalline solid, M.P. 274276 C. with decomposition.
Example 2 A solution of 2.25 parts of 1:222:6z6-pentamethyl- A -tetrahydropyridine hydrochloride in 40 parts of methanol is shaken in an atmosphere of hydrogen with 0.5 parts of Adams platinum oxide catalyst until the theoretical amount of hydrogen has been adsorbed. The reaction mixture is filtered and the filtrate is evaporated to about 5 parts. Ether is then added and after standing for a short time there is obtained the hydrochloride of Example 3 A mixture of 14.1 parts of 2:2:6:6-tetramethylpiperdine and 7.7 parts of ethyl sulphate is heated at l00 C. for 15 hours and is then cooled and diluted with 35 parts of ether. The mixture is filtered and the solid residue is washed twice with 20 parts of ether. The combined ethereal filtrates are evaporated and the residual oil is distilled and the fraction B.P. 188-198 C. at 760 mm. is collected. It is redistilled and there is thus obtained 1-ethyl-2:2:6:6-tetramethylpiperidine B.P. 194-198 C. at 760 mm. The base forms a picrate which when crystallised from ethanol has M.P. 245-247 C. with decomposition and a hydriodide which when crystallised from dilute aqueous hydriodic acid has M.P. 269270 C. with decomposition.
Example 4 A mixture of 14.1 parts of 2:226:6-tetramethylpiperidine and 605 parts of allyl bromide is heated under reflux for 18 hours. 35 parts of ether are then added to the cooled mass and the mixture is filtered and the solid residue is washed twice with 35 parts of ether. The combined ethereal filtrates are evaporated and the residual oil is distilled and the fraction of B.P. 205-215 C. at 763 mm. is collected. It is redistilled and there is obtained 1 allyl 222:6:6 tetramethylpiperidine, B.P. 9698 C. at 20 mm. pressure.
The base forms a picrate which when crystallised from ethanol has M.P. 162-163 C.
Example 5 A mixture of 14.1 parts of 2:216:6-tetramethylpiperidine and 6.84 parts of n-butyl bromide is heated under reflux for 96 hours. The mixture is filtered and the filtrate is distilled and the fraction B.P. 108-112" C. at 18 mm. is collected. It is redistilled and there is obtained 1-n-butyl-2z2:6:6-tetramethylpiperidine B.P. 96-98 C. at 12 mm.
The base forms a picrate which when crystallised from ethanol has M.P. 181182 C.
Example 6 A mixture of 28.2 parts of 2:2:6:6-tetramethylpiperidine and 16.2 parts of ethylene chlorohydrin is heated in an oil bath at 155 C. for 3 hours. The mixture is cooled and an excess of 50% aqueous sodium hydroxide solution is added. The liberated base is extracted with four portions of 35 parts of ether and the ethereal extract is dried over anhydrous potassium carbonate and then evaporated. The residual oil is distilled and unreacted. 212:6:G-tetramethylpiperidine distils at 4060 C. at 12 mm. and can be retreated. The desired product, l-phydroxyethyl-2:2:6:6-tetramethylpiperidine, distils as a colourless oil B.P. 142 C. at 12 mm. which solidifies on cooling and has M.P. 96 C. It forms a picrate which when crystallised from ethanol has M.P. 215216 C.
Example 7 5 parts of acetic anhydride are added to 5 parts of l-p-hydroxyethyl-Z :2 6 6-tetramethylpiperidine and the mixture is heated gently under reflux for /2 hour. It is then cooled and poured into 20 parts of ice and excess of 40% aqueous sodium hydroxide solution is added. The mixture is extracted three times with 35 parts of ether and the combined ethereal extracts are dried over anhydrous potassium carbonate and evaporated. The residual oil is distilled and there is thus obtained l-fi-acetoxyethyl- 2:2:6:G-tetramethylpiperidine, B.P. 139-141 C. at 12 Example 8 4.61 parts of 3:4:S-trimethoxybenzoylchloride are added to a solution of 3.7 parts of l-B-hydroxyethyl- 2:2:6:6-tetramethylpiperidine in 22 parts of benzene and the mixture is heated under reflux for 1 hour. It is then cooled and filtered and the solid residue is washed with 8 parts of benzene and dried. It is then crystallised from ethyl acetate to give 2:2:6:6-tetramethyl-1-[3-(3'z4':5- trimethoxybenzoyloxy) ethylpiperidine hemihydrochloride, as a colourless crystalline solid, M.P. 157 C.
Example 9 4 parts of 1-fi-chloroethyl-2:2:6:6-tetramethylpiperidine hydrochloride are added to a solution of sodium ethoxide prepared by dissolving 1 part of sodium in 200 parts of ethanol. The mixture is heated under reflux for 4 hours and is then cooled and filtered. The filtrate is concentrated by evaporation and 50 parts of Water are added to the residue. The mixture is then extracted three times with 35 parts of ether. The combined ethereal extracts are dried over potassium carbonate and evaporated. The residual oil is distilled and there is thus obtained l-B-ethoxyethyl-Z 2 6 6-tetramethylpiperidine, B.P. 13 2- 136 C. at 18 mm.
Example 10 5 parts of methyl iodide are added to a solution of 3.1 parts of 1:2:2:6:6-pentamethylpiperidine in 16 parts of acetonitrile and the mixture is heated under reflux for 3 hours. It is then cooled and filtered and there is thus obtained 1:1:2:2:6:6-hexamethylpiperidinium iodide, M.P. 21021l C.
Example 11 10 parts of 4-ethyl-4-hydroxy-2z2z 6c6-tetramethylpiperidine hydriodide are heated at 195200 C. for /2 hour and the resulting 4-ethyl-122:5:6-tet-rahydro-2:2:6:6 tetramethylpyridine hydriodide is dissolved in 100 parts of water and excess of aqueous sodium hydroxide solution is added. The pyridine base is extracted with four equal portions of 70 parts of ether. The combined ethereal extracts are saturated with hydrochloric acid gas and the 4 ethyl-1:225 6-tetrahydro-2z2:6:6-tetramethylpyridine hydrochloride so obtained is dissolved in 40 parts of methanol and shaken in an atmosphere of hydrogen with 0.5 part of Adams platinum oxide catalyst. When there is no further adsorption of hydrogen the reaction mixture is filtered and the filtrate is evaporated. The gummy residue is dissolved in 225 parts of ethyl acetate and the solution is filtered and evaporated to about 40 parts when there is obtained 4-ethyl-2:2:6:6-tetramethylpiperidine hydrochloride, M.P. 178 C.
The 4 ethyl-4-hydroxy-2z2z6:6-tetramethylpiperidine hydriodide used as starting material may be prepared as follows: A solution of 5 parts of 4-ethynyl-4-hydroxy- 2:2:6:6-tetramethylpiperidine in 40 parts of methanol is shaken in an atmosphere of hydrogen with 0.25 part of Raney nickel catalyst until no more hydrogen is adsorbed (2 molecular proportions). The reaction mixture is then filtered and the filtrate is evaporated to give 4-ethyl-4- hydroxy-2s2z6:6-tetramethylpiperidine as an oil which solidifies on cooling and has M.P. 7072 C. The hydriodide is obtained by crystallising the base from hydriodic acid. It has M.P. 195 C.
Example 12 A mixture of 5.5 parts of 4-keto-1:2:2:6:6-pentamethylpipe-ridine, 30 parts of triethylene glycol, 6 parts of hydrazine hydrate and 6 parts of potassium hydroxide is heated in an oil bath under reflux. The condenser is fitted with a take-0E head so that water appearing in the distillate can be removed. The internal temperature is gradually raised to 180 C. during 2 hours during which time water is drawn off from the distillate. The internal temperature is then raised gradually from 180 C. to 200 C. and the product 1:2:2:6:6-pentamethylpiperidine is collected. It is purified by distillation and has B.P. 182- 183" C. at 768 mm. It forms a picrate of M.P. 274276 C. with decomposition.
Example 13 A mixture of 10 parts of 2:6-diethyl-4-keto-2z3:6-trimethylpiperidine, 50 parts of triethylene glycol, 10 parts of hydrazine hydrate and 10 parts of potassium hydroxide is heated in an oil bath gently under reflux. The condenser is fitted with a take-oif head so that water formed in the distillate can be removed. The internal temperature is allowed to rise slowly during the course of 1 hour from 120-200 C. The mixture is then cooled and poured into 500 parts of water and is extracted three times with 35 parts of ether. The combined ethereal extracts are dried and the ether evaporated and the oily residue is distilled. There is thus obtained 2:6-diethyl- 2:3:6-trimethylpiperidine, B.P. 108-110" C. at 23 mm. It forms an acid oxalate which has M.P. 199 C. with decomposition after crystallisation from a mixture of ethanol and ethyl acetate.
Example 14 A mixture of 3 parts of 2:6-diethyl 223:6-trimethylpiperidine, 8.5 parts of formic acid and 10 parts of formalin (36%) is heated at 98-100 C. for 72 hours and is then cooled. An excess of 40% aqueous sodium hydroxide solution is added and the oily base is separated and the aqueous layer is extracted with 7 parts of ether. The combined ethereal extract and oily base is then dried pver potassium hydroxide and the ether distilled. The residual oil is distilled to give 2:6-diethyl-1:2:3:6-tetramethylpiperidine, B.P. 119121 C. at 18 mm.
Example 15 60 parts of zinc are allowed to stand for 1 hour in 120 parts of a 5% aqueous solution of mercuric chloride. The solution is then decanted and the amalgamated zinc is washed with water. 60 parts of a mixture of equal parts of water and concentrated aqueous hydrochloric acid (density=l.18) and 10 parts of 4-keto-1:2:Q:6:6- pentamethylpiperidine are added to the zinc and the mix ture is heated under reflux for 24 hours. During the first 5 hours, 5.9 parts of concentrated aqueous hydrochloric acid are added each hour to the reaction mixture. The mixture is then cooled and filtered. The solid residue is washed with a little water. The combined filtrates are made alkaline with excess of aqueous sodium hydroxide solution and the mixture is extracted twice with 70 parts of ether. The extract is dried and the ether is evaporated and the residue distilled. The fraction B.P. 172-186 C. is collected and redistilled. There is thus obtained 1:2:2:6:6-pentamethyl piperidine B.P. 183184 C. at 771 mm. which forms a picrate identical with the product described in Example 1.
Example 16 A solution of 2 parts of 4-pl1enyl-2z2:6:6-tetramethyl A -tetrahydropyridine hydrochloride in 40 parts of methanol is shaken in an atmosphere of hydrogen with 0.5 part of Adams platinum oxide catalyst until no more hydrogen is adsorbed. The reaction mixture is filtered and the methanol is removed by evaporation under reduced pressure. There is thus obtained 4-pheny1-2:2:'6:6- tetramethylpiperidine hydrochloride as a colourless solid M.P. 225-226" C.
Example 17 A solution of 10 parts of triacetoneamine hydrate and 7.5 parts of gamma-diethylaminopropylamine in parts of methanol is shaken with 0.5 part of Adams platinum Example 18 37.2 parts of methyl p-toluenesulphonate are added with stirring to 28.2 parts of 2:2: 6z6-tetramethylpiperidine. parts of lithium hydroxide monohydrate are then added and the mixture is allowed to Warm spontaneously. After /2 hour the mixture is heated at 100 C. for 2 hours and then 100 parts of water and 25 parts of 40% aqueous sodium hydroxide are added. The oily layer is separated and distilled when there is obtained 1:2:2:6:6-pentamethylpiperidine which boils at 182-185 C. at 763 mm. pressure.
Example 19 A mixture of 28.2 parts of 2: 2:6:6tetramethylpiperidine and 20 parts of ethyl p-toluenesulphonate is heated on a steam bath for 24 hours. It is then cooled to 25 C. and made alkaline by the addition of 50 parts of 40% aqueous sodium hydroxide solution and extracted with 105 parts of ether divided into three equal portions. The ethereal extract is dried over potassium hydroxide and the ether is then distilled. The residual oil is fractionated and there is thus obtained 1-ethyl-2:2:6:6tetramethylpiperidine, B.P. 193197 C. at 740 mm.
What I claim is:
A piperidine selected from the group consisting of 4 gamma-diethylaminopropylamino-Z:2: 6: 6-tetramethy1- piperidine and the non-toxic pharmaceutically-acceptable acid addition salts thereof.
References Cited in the file of this patent UNITED STATES PATENTS 2,596,450 Wachter May 13, 1952 2,636,881 Schultz Apr. 28, 1953 2,739,968 Sperber et al. Mar. 27, 1956 2,773,870 Elpern Dec. 11, 1956 2,907,764 Voegtli Oct. 6, 1959 FOREIGN PATENTS 103,541 Great Britain Feb. 1, 1917 OTHER REFERENCES Fischer: Deutsche Chemische Gesellschaft (Berichte), vol. 16, pages 1604-1606 (1883).
Beilstein: Beilsteins Handbuch der Chemie, vol. 20 (original 1935), page 125.
Beilstein: Beilstein Handbuch der Organischen Chemie, vol. XX (original 1935), p. 129.
Anker et al.: Journal of the Chemical Society (1945), pages 917-920.
Matter: Helvetica Chimica Acta, vol. 31, pages 619 and 620 (1948).
Leonard: J.A.C.S., vol. 71, pages 2808-43 (1949) (p. 2810 relied on).
Cusic et al.: Journal of Organic Chemistry, vol. 16, page 1929 (1951).
Beaver et al.: Journal of the Chemical Society (1952), page 867.
Beilstein: Vol. XX (2nd supp.) (1953), pages 64-65.
Hancox: Australian J. Chem, vol. 6, pages 143-51 (1953), abstracted from Chem. Abst, vol. 48, col. 2709 (1954).
Cromwell et al.: Journal of the American Chemical Society, vol. 77, page 1570 (1955).
Binovic: Bulletin de la Societe Chimique de France (1957), page 170.
Organischen
US3126393D 1957-02-13 X-gamma-dffithylaminopropylamino Expired - Lifetime US3126393A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB4905/57A GB834290A (en) 1957-02-13 1957-02-13 Substituted piperidines

Publications (1)

Publication Number Publication Date
US3126393A true US3126393A (en) 1964-03-24

Family

ID=9786082

Family Applications (1)

Application Number Title Priority Date Filing Date
US3126393D Expired - Lifetime US3126393A (en) 1957-02-13 X-gamma-dffithylaminopropylamino

Country Status (4)

Country Link
US (1) US3126393A (en)
BE (1) BE564780A (en)
GB (1) GB834290A (en)
NL (2) NL101733C (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3513170A (en) * 1966-07-23 1970-05-19 Sankyo Co Preparation of 2,2,6,6-tetramethyl-4-oxopiperidine
US3898303A (en) * 1972-05-31 1975-08-05 Sankyo Co Piperidine-spiro-hydantoin derivatives and their use as stabilizers
US3941744A (en) * 1971-06-05 1976-03-02 Sankyo Company Limited Piperidine derivatives and their use as stabilizers
US3975357A (en) * 1973-04-19 1976-08-17 Sankyo Company Limited Stabilized synthetic polymer compositions
US4525506A (en) * 1982-03-31 1985-06-25 Adeka Argus Chemical Co., Ltd. Polyhydric alcohol ethers of 2,2,6,6-tetramethyl-4-piperidone ketals and synthetic resin compositions

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3072668A (en) * 1961-09-25 1963-01-08 Warner Lambert Pharmaceutical 1, 4-bis(tetramethyl-4-hydroxy-4-piperidyl) butadiyne
US4001190A (en) * 1973-09-17 1977-01-04 E. I. Du Pont De Nemours And Company Acid-dyeable fibers of polyester modified with tetramethylpiperidine polyether glycols
GB1496844A (en) 1975-05-28 1978-01-05 Ciba Geigy Ag Stabilization of polymers
DE3321332A1 (en) * 1983-06-13 1984-12-13 Chemische Werke Hüls AG, 4370 Marl METHOD FOR PRODUCING POLYALKYLPIPERIDYLAMINES

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB103541A (en) * 1916-02-05 1917-02-01 Hilda Mary Judd Improvement in the Manufacture of alpha alpha Dimethyl-gamma-hydroxy-piperidines substituted in the alpha1 position, including their N-methyl Derivatives.
US2596450A (en) * 1946-10-28 1952-05-13 Shell Dev Corrosion-inhibiting coating composition containing organic amine nitrites
US2636881A (en) * 1951-01-06 1953-04-28 Sharp & Dohme Inc 3-substituted, 3-aryl, 2-pipecolines and salts thereof
US2739968A (en) * 1950-12-05 1956-03-27 Schering Corp Substituted piperidines
US2773870A (en) * 1953-06-04 1956-12-11 Sterling Drag Inc 1-(lower alkyl)-4-phenyl-4-(tertiaryaminoalkoxymethyl- and tertiary-aminoalkoxy) piperidines and their preparation
US2907764A (en) * 1956-07-30 1959-10-06 Searle & Co Heterocyclic esters of 3, 4, 5-trimethoxybenzoic acid

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB103541A (en) * 1916-02-05 1917-02-01 Hilda Mary Judd Improvement in the Manufacture of alpha alpha Dimethyl-gamma-hydroxy-piperidines substituted in the alpha1 position, including their N-methyl Derivatives.
US2596450A (en) * 1946-10-28 1952-05-13 Shell Dev Corrosion-inhibiting coating composition containing organic amine nitrites
US2739968A (en) * 1950-12-05 1956-03-27 Schering Corp Substituted piperidines
US2636881A (en) * 1951-01-06 1953-04-28 Sharp & Dohme Inc 3-substituted, 3-aryl, 2-pipecolines and salts thereof
US2773870A (en) * 1953-06-04 1956-12-11 Sterling Drag Inc 1-(lower alkyl)-4-phenyl-4-(tertiaryaminoalkoxymethyl- and tertiary-aminoalkoxy) piperidines and their preparation
US2907764A (en) * 1956-07-30 1959-10-06 Searle & Co Heterocyclic esters of 3, 4, 5-trimethoxybenzoic acid

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3513170A (en) * 1966-07-23 1970-05-19 Sankyo Co Preparation of 2,2,6,6-tetramethyl-4-oxopiperidine
US3941744A (en) * 1971-06-05 1976-03-02 Sankyo Company Limited Piperidine derivatives and their use as stabilizers
US3898303A (en) * 1972-05-31 1975-08-05 Sankyo Co Piperidine-spiro-hydantoin derivatives and their use as stabilizers
US3975357A (en) * 1973-04-19 1976-08-17 Sankyo Company Limited Stabilized synthetic polymer compositions
US4525506A (en) * 1982-03-31 1985-06-25 Adeka Argus Chemical Co., Ltd. Polyhydric alcohol ethers of 2,2,6,6-tetramethyl-4-piperidone ketals and synthetic resin compositions

Also Published As

Publication number Publication date
NL101733C (en)
NL98891C (en)
GB834290A (en) 1960-05-04
BE564780A (en)

Similar Documents

Publication Publication Date Title
EP0040639B1 (en) Isoxazole derivatives
US3183235A (en) 1-[3-, 2-, and 1-indolyl-lower-alkanoyl] piperidines
US3458521A (en) 4-phenylpiperidine derivatives
US3963729A (en) Pharmacologically active pyridine derivatives
US3126393A (en) X-gamma-dffithylaminopropylamino
CS226405B2 (en) Method of preparing piperidinepropoxyquinoline and piperidinepropoxycoumarin
US3428646A (en) 4-imidazolidones and processes for preparing same
US3476762A (en) 4' - dimethylamino - 4 - (4 - hydroxy-4-phenyl piperidino)butyrophenones and 4 - (4-phenyl-4-hydroxy - piperidino)-1,1-ethylenedioxy - 1 - (4 - dimethylaminophenyl)butanes
US2872453A (en) Indole derivatives
US3686187A (en) 4-anilino-1-(4-p-fluorophenyl-1-butyl) piperidine compounds
US3907812A (en) Butyrophenone derivatives
US2387879A (en) Piperidinol esters as antispasmodic agents
US3491097A (en) 3-(piperazinoalkyl)-pyrazoles
US3706755A (en) Certain 4(3-(4-(phenyl)-3,6-dihydro-1(2h)pyridyl)-2 - hydroxy-propoxy)-benzophenones
US3963727A (en) 1,2 Disubstituted benzimidazole derivatives
US2830057A (en) Certificate of correction
US3523950A (en) Certain 4 - phenyl - 1,2,3,6 - tetrahydropyridyl-n-lower alkylene-ureas and derivatives
US3211792A (en) 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof
US4076821A (en) 4,4-Diphenylcycloalkylpiperidines and psychotropic compositions thereof
US3354161A (en) 8alpha-(4-phenyl-1-piperazyl)-4alpha, 5, 6, 7, 8alpha-hexahydro-4h-1-benzopyrans and process
DE1289845B (en) 4- (4'-Hydroxy-4'-phenylpiperidino) -butyrophenones, their acid addition salts and processes for their preparation
LEE et al. Piperidine derivatives. Part 1. Lobelan and related compounds
US2485662A (en) Alpha-(aminoalkyl)-stilbenes
US3391143A (en) 9-piperidyl and 9-piperidylidene derivatives of acridan
US3816434A (en) 4-(3-(4-phenyl-piperidino)-2-hydroxy-propoxy)-benzophenones