US3240784A - Esters of quaternary z-hydroxy methyl piperidinium compounds - Google Patents

Esters of quaternary z-hydroxy methyl piperidinium compounds Download PDF

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US3240784A
US3240784A US3240784DA US3240784A US 3240784 A US3240784 A US 3240784A US 3240784D A US3240784D A US 3240784DA US 3240784 A US3240784 A US 3240784A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • 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
    • C07D211/18—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—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 substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Another object of the present invention is to provide a simple and elfective process of producing such new carboxylic acid esters of Z-hydroxy methyl piperidinium compounds.
  • a further object of the present invention is to provide highly effective and well tolerated spasmolytic compositions containing, as active agent, such new carboxylic acid esters of 2-hydroxy methyl piperidinium compounds.
  • Still another object of the present invention is to provide a simple and eitective process of relaxing spastic conditions.
  • the new and valuable spasmolytic compounds according to the present invention are carboxylic acid esters of 2-hydroxy methyl piperidinium compounds of Formula I wherein R represents hydrogen, alkyl, aralkyl, cycloalkyl, aryl,
  • R represents hydrogen, alkyl, cycloalkyl, aralkyl, or aryl radicals which may be substituted;
  • R represents an aryl or a cycloalkyl radical which may be substituted
  • R represents hydrogen, a hydroxyl group which may be esterified, or halogen
  • R represents an alkyl radical which may be substituted
  • An indicates an anion
  • the new compounds of Formula I are very effective spasmolytic agents of a surprisingly/low toxicity.
  • the LD i.e. the dose after administration of which 50% of the test animals die, is, for instance, for the metho- Patented Mar. 15, 1966 sulfate of (l-methyl piperidyl-2)-methyl benzilate of Formula II N 0 CH3 SO4CH3 CH3 (II) which compound will be designated hereinafter as compound A on oral administration about 1.900 mg./kg. of mouse body weight or respectively, about 3.700 ing/kg. of rat body weight, and on subcutaneous administration 350 mg./kg. of mouse body weight or respectively, more than 2.000 mg./kg. of rat body Weight.
  • the amount of Compound A needed for relaxation of the spastic condition of the isolated surviving rat ileum caused by barium chloride is only one fiftieth of the required amount of papaverine.
  • the spastic condition of the isolated surviving rat ileum caused by acetylcholine is relaxed by Compound A in a concentration of 0.002 mg./ 1.
  • the same results are obtained, for instance, by testing the benzilates of (l-n-butyl piperidyl-Z) -methanol methoiodide or (l-n-octyl piperidyl-2)-methanol methobromide.
  • the new compounds of Formula I are prepared for instance, by the following methods:
  • X represents halogen or a sulfuric acid ester group.
  • an inert organic solvent preferably in the presence of a compound capable of binding the acid formed in the reaction, for instance, in the presence of a tertiary amine, an alkali metal carbonate, an alkali metal bicarbonate, or the like.
  • the anion present in the compound of Formula I resulting from proceeding according to one of the processes described herein above can be replaced by another suitable anion.
  • a halide of the resulting quaternary ammonium compound may be reacted with a. suitable silver salt.
  • compounds of Formula I can be produced the preparation of which is difficult when following the processes described above.
  • the new compounds of Formula I contain at least one carbon atom which is asymmetrically substituted. Therefore, they can be obtained as racemic mixtures or in their optically active forms.
  • optically active starting materials may be used in the processes described hereinabove.
  • the new optically active compounds may also be prepared first in their racemic form which is subsequently resolved to their optically active isomers.
  • Example 1 5 g. of (l-methyl piperidyl-2)-methyl benzilate are suspended in 10 ml. of acetonitrile. A solution of 6.4 g. of methyliodide in 20 ml. of acetonitrile is added thereto. The reaction mixture is allowed to stand at 3040 C. for 48 hours whereafter the solvent is distilled off in a vacuum. The residue is recrystallized from a mixture of acetone and petroleum ether, whereby the methiodide of the starting material is obtained in a yield of 70% of the theoretical yield. Melting point: l30l32 C.
  • Example 2 A mixture of 5 g. of (l-methyl piperidyl-2)-methyl 'benzilate, 7 g. of 'ethyliodide, and 30 ml. of dry acetone is refluxed for 6 hours. The residue obtained on distilling off the solvent is recrystallized from a mixture of ethanol and petroleum ether. The resulting ethiodide of the starting material is obtained in a yield of 60% of the theoretical yield. It melts at 151154 C.
  • Example 3 A mixture of 7.6 g. of dimethylsulfate and 15 ml. of acetone is added to a solution of 10.2 g. of (l-methyl piperidyl-2)-methyl benzilate in 50 ml. of dry acetone. The reaction mixture is allowed to stand at 3040 C. for 2 days. The precipitated crystals are filtered ofl? and recrystallized from a mixture of acetone and ethanol while heating and adding petroleum ether to the warm solution. The resulting methosulfate is the compound A mentioned hereinabove. It melts at 134-135 C. Yield: 92% of the theoretical yield.
  • Example 4 A solution of 5.7 g. of methyliodide in 10 ml. of acetone is added to a solution of 7.6 g. of (l-n-butyl piperidyl-2)-methyl benzilate in ml. of dry acetone. The reaction mixture is allowed to stand at 3040 C. for 24 hours. Petroleum ether is added thereto until the mixture becomes turbid. The precipitate formed gradually after standing for 1 day to 2 days is filtered off by suction and is recrystallized twice from a mixture of acetone and ethanol While heating and adding petroleum ether to the warm solution. The resulting methiodide of the starting material melts at l74175 C. The yield is about 40% of the theoretical yield.
  • Example 5 A solution of 4.8 g. of methylbromide in 25 ml. of absolute ethanol is added to a solution of 11 g. of (l-noctyl piperidyl-2)-methyl benzilate in 40 ml. of dry acctone. After standing for 2 days at 30-40 C., the solvents are removed by distillation in a vacuum. The residue is recrystallized from a mixture of acetone and ethanol while heating and adding petroleum ether to the warm solution whereby the methobromide of the starting material which melts at l83l84 C. is obtained in a yield of 58% of the theoretical yield.
  • Example 6 A solution of 5.7 g. of methyl iodide in 10 ml. of acetone is added to a solution of 8.6 g. of (l-B-phenyl ethyl piperidyl-2)-methyl 'benzilate in 25 ml. of dry acetone. After standing at 30-40" C. for 2 days, the reaction mixture is freed of the solvent by distillation in a vacuum. The residue is recrystallized from a mixture of acetone and ether whereby the methiodide of the starting material is obtained in a yield of of the theoretical yield. Melting point: 173 C.
  • Example 7 6 g. of the (l-methyl pi peridyl-2)-methyl ester of diphenyl acetic acid are dissolved in 20 ml. of absolute methanol. 15 g. of a 25% solution of methyl bromide in methanol are added thereto. The reaction mixture is allowed to stand at room temperature for one week. After concentrating the reaction mixture by distillation in a Vacuum, the residue is triturated with absolute ether. The resulting precipitate is filtered off by suction and is recrystallized twice from a mixture of absolute ethanol and absolute ether. The methobromicle of the starting material is obtained in a yield of 39% of the theoretical yield. Melting point: 176-178 C.
  • Example 8 A mixture of 4.9 g. of ethyl bromide and ml. of acetone is added to a solution of 5 g. of (l-methyl piperidyl-2)-methyl benzilate in 25 ml. of dry acetone. The reaction mixture is allowed to stand at room temperature for 6 days. After concentrating the reaction mixture by distillation in a vacuum, the residue is recrystallized first from a mixture of acetone and petroleum ether and then from a mixture of absolute ethanol and petroleum ether. The ethobromide of the starting material is thereby obtained in a yield of 46% of the theoretical yield. Melting point: l85-l87 C.
  • Example 9 A mixture of 10.2 g. of (l-methyl-piperidyl-2)-methyl benzilate, dissolved 50 ml. of acetone, and 25 ml. of a 25% solution of methylbromide in methanol is allowed to stand at room temperature for three days. Petroleum ether is added thereto until the solution becomes turbid. The precipitate formed after standing overnight in an ice box, is filtered ofI, dried by exposure to the air, and recrystallized from a mixture of absolute ethanol and petroleum ether. After drying by exposure to the air, the hydrate of the methobromide. of the starting material is obtained in a yield of 66% of the theoretical yield. Melting point: 108-109 C.
  • Example 10 3 g. of freshly prepared silver chloride are added to a solution of 4.8 g. of (l-methyl piperidyl-2)-methyl benzilate methiodide in 20 ml. of methanol. The mixture is shaken for 10 minutes and then allowed to stand in the dark for 24 hours. After filtering otf the precipitate by suction, the filtrate is freed of solvent by distillation in a vacuum. The residue is recrystallized from a mixture of acetone and ethanol while heating and adding petroleum ether to the Warm solution whereby (l-methyl piperidyl- 2)-methyl benzilate methochloride, melting at 1l5-l18 C. is obtained in a yield of 64% of the theoretical yield.
  • Example 11 Methyl bromide is passed at room temperature into a solution of 5 g. of the ester of a-cyclohexyl phenyl glycolic acid and (l-methyl piperidyl-2)-methanol in 50 ml. of acetone until 12 g. of methylbromide have been absorbed. Colorless crystals start to precipitate during introduction of the methylbromide. The reaction mixture is cooled in an ice bath and the precipitated crystals are filtered off by suction. Thereby, the methobromide of the starting material is obtained in a yield of 63% of the theoretical yield. After recrystallization from a mixture of acetone, ethanol, and petroleum ether, its melting point is 197- 199 C.
  • Example 12 A mixture of 5.4 g. of 1-methyl-2-hydroxy methyl-piperidine methiodide, 4.6 g. of diphenyl acetylchloride, 2 g. of triethylamine, and 100 ml. of dry dioxane is refluxed for three hours while stirring. After standing overnight, the solvent is decanted off and the residue is recrystallized from a mixture of ethanol and petroleum ether. Thereby, the (l-methyl piperidyl-2)-methyl diphenylacetate methiodide is obtained in a yield of 54% of the theoretical yield. Melting point: l65-1-68 C.
  • Example 13 4.9 g. of l-methyl-Z-chloro methyl piperidine methobromide and 5.3 g. of potassium benzilate are added to ml. of absolute ethanol. The mixture is refluxed for two hours while stirring and is then filtered while still hot. The filtrate is evaporated to dryness in a vacuum and the resulting residue is recrystallized from a mixture of acetone, ethanol, and petroleum ether whereby (l-methyl piperidyl-2)-methyl benzilate methobromide melting at -162 C. is obtained in a yield of 35% of the theoretical yield.
  • esters of the l-substituted-Z-hydroxy methyl piperidines used in Examples 1 to 9, and 11 there may be employed the esters of other l-substituted-Z-hydroxy methyl piperidines, for instance, the esters of other 1-alkyl-, l-phenyl lower alkyl, l-phenyl-Z-hydroxy methyl piperidines such as (l-benzyl piperidyl-2)-methyl benzilate, (l-ethyl piperidyl-2) methyl diphenyl acetate, (1- n-propyl-piperidyl-2) methyl mandelate, or the ester of a-chloro diphenyl acetic acid with l-methyl-Z-hydroxy methyl piperidine.
  • the esters of other l-substituted-Z-hydroxy methyl piperidines for instance, the esters of other 1-alkyl-, l-phenyl lower alkyl, l-phenyl-Z-hydroxy
  • methyl and ethyl iodide methyl and ethyl bromide, and dimethyl sulfate as used in the preceding examples
  • other quaternizing agents such as benzylbromide, diethyl sulfate, other alkyl or aralkyl halogenides, such as iso-propyl iodide, n-butyl iodide.
  • Especially valuable spasmolytic compounds of low toxicity and high spasmolytic activity are the benzilic acid esters of 1-alkyl-2-hydroxy methyl piperidine methohalides or methosulfates.
  • the new esters of quaternary Z-hydroxy methyl piperidinium compounds are administered orally, parenterally, or rectally.
  • the preferred mode of administration is oral administration in the form of liquid or solid preparations, such as tablets, pills, dragees, powders, capsules, solutions, emulsions, suspensions, dispersions, or in any other suitable form.
  • fine uniform dispersion of the active compounds together with a usual carrier throughout said powder is of importance.
  • a fine dispersion can be achieved by intimately mixing and milling the active compound, for instance, in a ball mill with a solid pulverulent extending agent to the desired degree of fineness or by impregnating the already milled, finely powdered, solid carrier with the active compound in water or with a solution thereof in a suitable organic solvent and then removing the water or solvent.
  • a fine dispersion of the active compound in water, sirup and the like can also be brought about by emulsifying said compound with the aid of a dispersing or emulsifying agent.
  • the commonly used carriers and diluting agents, binders, and the like tableting adjuvants are employed, such as sugar, lactose, starch, pectin, bolus alba, stearic acid, magnesium stearate, and as binders gelatin, gum arabic, methyl cellulose, carboxy ethyl cellulose, yeast extract, agar, tragacanth, and others. It is, of course, understood that any of the tableting materials conventionally used in pharmaceutical practice can be employed provided there is no incompatibility with the active compound.
  • Injectable preparations and suppositories for rectal administration may also be prepared.
  • All (llHz R1 8 X is an acyl group selected from the group consisting of the benziloyl, diphenyl acetyl, u-cyclohexyl phenyl glycoloyl, mandeloyl, and a-chloro diphenylacetyl p;
  • R is a member selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, and phenyl lower alkyl;
  • R is lower alkyl
  • An is a member selected from the group consisting of halogen and the alkyl sulfate group SO R wherein R is lower alkyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Description

United States Patent 3 240 784 ESTERS OF UATERNARi! Z-HYDROXY METHYL PIPERIDINIUM COMPOUNDS Kurt Flick, Stolberg, Rhineland, and Heinrich Mueckter,
Aachen, Rhineland, Germany, assignors, by mesne assignments, to the firm Protochemie AG, Glarus, Glarus, Switzerland, a corporation of Switzerland N0 Drawing. Filed Apr. 30, 1962, Ser. No. 191,322 Claims priority, applicatipnfgermany, Apr. 29, 1961,
6 Claims. 011260-2934 and valuable carboxylic acid esters of Z-hydroxy methyl piperidinium compounds which have a high spasmolytic acitivity and a surprisingly low toxicity.
Another object of the present invention is to provide a simple and elfective process of producing such new carboxylic acid esters of Z-hydroxy methyl piperidinium compounds.
A further object of the present invention is to provide highly effective and well tolerated spasmolytic compositions containing, as active agent, such new carboxylic acid esters of 2-hydroxy methyl piperidinium compounds.
Still another object of the present invention is to provide a simple and eitective process of relaxing spastic conditions.
Other objects of the present invention and advantageous feastures thereof will become apparent as the description proceeds.
In principle the new and valuable spasmolytic compounds according to the present invention are carboxylic acid esters of 2-hydroxy methyl piperidinium compounds of Formula I wherein R represents hydrogen, alkyl, aralkyl, cycloalkyl, aryl,
or heterocyclic radicals which may be substituted;
R represents hydrogen, alkyl, cycloalkyl, aralkyl, or aryl radicals which may be substituted;
R represents an aryl or a cycloalkyl radical which may be substituted;
R represents hydrogen, a hydroxyl group which may be esterified, or halogen;
R represents an alkyl radical which may be substituted;
and
An indicates an anion.
The new compounds of Formula I are very effective spasmolytic agents of a surprisingly/low toxicity. The LD i.e. the dose after administration of which 50% of the test animals die, is, for instance, for the metho- Patented Mar. 15, 1966 sulfate of (l-methyl piperidyl-2)-methyl benzilate of Formula II N 0 CH3 SO4CH3 CH3 (II) which compound will be designated hereinafter as compound A on oral administration about 1.900 mg./kg. of mouse body weight or respectively, about 3.700 ing/kg. of rat body weight, and on subcutaneous administration 350 mg./kg. of mouse body weight or respectively, more than 2.000 mg./kg. of rat body Weight. The amount of Compound A needed for relaxation of the spastic condition of the isolated surviving rat ileum caused by barium chloride is only one fiftieth of the required amount of papaverine. The spastic condition of the isolated surviving rat ileum caused by acetylcholine is relaxed by Compound A in a concentration of 0.002 mg./ 1. Approximately, the same results are obtained, for instance, by testing the benzilates of (l-n-butyl piperidyl-Z) -methanol methoiodide or (l-n-octyl piperidyl-2)-methanol methobromide.
These results could be confirmed for Compound A in clinical investigations on humans. Side-elfects were not observed when the compound was given orally, rectally, subcutaneously, or intramuscularly, respectively. In adults good spasmolytic efiects were observed after oral or rectal administration of 20 mg. of Compound A or after intramuscular administration of 1 mg. of Compound A. Cases of spastic bronchitis, of gastritis and/ or gastric ulcer, spastic colitis, spasms of the gall-bladder and bileducts, renal colics, and others were treated with these new agents.
The new compounds of Formula I are prepared for instance, by the following methods:
(A) A compound of Formula III wherein R R R and R have the same meaning as indicated in Formula I, is reacted, preferably in the presence of a solvent, with a compound of Formula IV 5 1 (IV) wherein R has the same meaning as indicated in Formula I, and
X represents halogen or a sulfuric acid ester group.
(B) A compound of Formula V wherein R R R and R have the same meaning as indicated in Formula I, is reacted, if required, while heat- R CH X wherein R has the same meaning as indicated in For- 5 mula I, and X has the same meaning as indicated in Formula IV.
(C) A compound of Formula VII N CH: Hal B, An
(I111; R (VII) wherein R R and An have the same meaning as indi cated in Formula I, and Hal represents halogen, is reacted with an acid of Formula VIII I'M HOOC-(F-Rs R4 (VIII) wherein R R and R have the same meaning as indicated in Formula I, in the presence of a compound capable of binding hydrogen halide or with a salt of such an acid of Formula VIII, if desired, in presence of a solvent and preferably while heating.
(D) A compound of Formula IX N -CHzOH 12 An CH2 R1 (IX) wherein R R and An have the same meaning as indicated in Formula I, is reacted with a compound of Formula X 2 -tr 0 R4 (X) wherein R R and R have the same meaning as indicated in Formula I, and Y represents halogen or an esterified hydroxyl group,
0 either in the absence or m the presence of an inert organic solvent, preferably in the presence of a compound capable of binding the acid formed in the reaction, for instance, in the presence of a tertiary amine, an alkali metal carbonate, an alkali metal bicarbonate, or the like.
The anion present in the compound of Formula I resulting from proceeding according to one of the processes described herein above can be replaced by another suitable anion. For this purpose, for instance, a halide of the resulting quaternary ammonium compound may be reacted with a. suitable silver salt. In this manner compounds of Formula I can be produced the preparation of which is difficult when following the processes described above.
The new compounds of Formula I contain at least one carbon atom which is asymmetrically substituted. Therefore, they can be obtained as racemic mixtures or in their optically active forms. In order to prepare said compounds in their optically active forms, optically active starting materials may be used in the processes described hereinabove. However, the new optically active compounds may also be prepared first in their racemic form which is subsequently resolved to their optically active isomers.
The following examples serve to illustrate the present invention without, however, limiting the same to the contents of said examples.
Example 1 5 g. of (l-methyl piperidyl-2)-methyl benzilate are suspended in 10 ml. of acetonitrile. A solution of 6.4 g. of methyliodide in 20 ml. of acetonitrile is added thereto. The reaction mixture is allowed to stand at 3040 C. for 48 hours whereafter the solvent is distilled off in a vacuum. The residue is recrystallized from a mixture of acetone and petroleum ether, whereby the methiodide of the starting material is obtained in a yield of 70% of the theoretical yield. Melting point: l30l32 C.
Example 2 A mixture of 5 g. of (l-methyl piperidyl-2)-methyl 'benzilate, 7 g. of 'ethyliodide, and 30 ml. of dry acetone is refluxed for 6 hours. The residue obtained on distilling off the solvent is recrystallized from a mixture of ethanol and petroleum ether. The resulting ethiodide of the starting material is obtained in a yield of 60% of the theoretical yield. It melts at 151154 C.
Example 3 A mixture of 7.6 g. of dimethylsulfate and 15 ml. of acetone is added to a solution of 10.2 g. of (l-methyl piperidyl-2)-methyl benzilate in 50 ml. of dry acetone. The reaction mixture is allowed to stand at 3040 C. for 2 days. The precipitated crystals are filtered ofl? and recrystallized from a mixture of acetone and ethanol while heating and adding petroleum ether to the warm solution. The resulting methosulfate is the compound A mentioned hereinabove. It melts at 134-135 C. Yield: 92% of the theoretical yield.
Example 4 A solution of 5.7 g. of methyliodide in 10 ml. of acetone is added to a solution of 7.6 g. of (l-n-butyl piperidyl-2)-methyl benzilate in ml. of dry acetone. The reaction mixture is allowed to stand at 3040 C. for 24 hours. Petroleum ether is added thereto until the mixture becomes turbid. The precipitate formed gradually after standing for 1 day to 2 days is filtered off by suction and is recrystallized twice from a mixture of acetone and ethanol While heating and adding petroleum ether to the warm solution. The resulting methiodide of the starting material melts at l74175 C. The yield is about 40% of the theoretical yield.
Example 5 A solution of 4.8 g. of methylbromide in 25 ml. of absolute ethanol is added to a solution of 11 g. of (l-noctyl piperidyl-2)-methyl benzilate in 40 ml. of dry acctone. After standing for 2 days at 30-40 C., the solvents are removed by distillation in a vacuum. The residue is recrystallized from a mixture of acetone and ethanol while heating and adding petroleum ether to the warm solution whereby the methobromide of the starting material which melts at l83l84 C. is obtained in a yield of 58% of the theoretical yield.
Example 6 A solution of 5.7 g. of methyl iodide in 10 ml. of acetone is added to a solution of 8.6 g. of (l-B-phenyl ethyl piperidyl-2)-methyl 'benzilate in 25 ml. of dry acetone. After standing at 30-40" C. for 2 days, the reaction mixture is freed of the solvent by distillation in a vacuum. The residue is recrystallized from a mixture of acetone and ether whereby the methiodide of the starting material is obtained in a yield of of the theoretical yield. Melting point: 173 C.
Example 7 6 g. of the (l-methyl pi peridyl-2)-methyl ester of diphenyl acetic acid are dissolved in 20 ml. of absolute methanol. 15 g. of a 25% solution of methyl bromide in methanol are added thereto. The reaction mixture is allowed to stand at room temperature for one week. After concentrating the reaction mixture by distillation in a Vacuum, the residue is triturated with absolute ether. The resulting precipitate is filtered off by suction and is recrystallized twice from a mixture of absolute ethanol and absolute ether. The methobromicle of the starting material is obtained in a yield of 39% of the theoretical yield. Melting point: 176-178 C.
Example 8 A mixture of 4.9 g. of ethyl bromide and ml. of acetone is added to a solution of 5 g. of (l-methyl piperidyl-2)-methyl benzilate in 25 ml. of dry acetone. The reaction mixture is allowed to stand at room temperature for 6 days. After concentrating the reaction mixture by distillation in a vacuum, the residue is recrystallized first from a mixture of acetone and petroleum ether and then from a mixture of absolute ethanol and petroleum ether. The ethobromide of the starting material is thereby obtained in a yield of 46% of the theoretical yield. Melting point: l85-l87 C.
Example 9 A mixture of 10.2 g. of (l-methyl-piperidyl-2)-methyl benzilate, dissolved 50 ml. of acetone, and 25 ml. of a 25% solution of methylbromide in methanol is allowed to stand at room temperature for three days. Petroleum ether is added thereto until the solution becomes turbid. The precipitate formed after standing overnight in an ice box, is filtered ofI, dried by exposure to the air, and recrystallized from a mixture of absolute ethanol and petroleum ether. After drying by exposure to the air, the hydrate of the methobromide. of the starting material is obtained in a yield of 66% of the theoretical yield. Melting point: 108-109 C.
Example 10 3 g. of freshly prepared silver chloride are added to a solution of 4.8 g. of (l-methyl piperidyl-2)-methyl benzilate methiodide in 20 ml. of methanol. The mixture is shaken for 10 minutes and then allowed to stand in the dark for 24 hours. After filtering otf the precipitate by suction, the filtrate is freed of solvent by distillation in a vacuum. The residue is recrystallized from a mixture of acetone and ethanol while heating and adding petroleum ether to the Warm solution whereby (l-methyl piperidyl- 2)-methyl benzilate methochloride, melting at 1l5-l18 C. is obtained in a yield of 64% of the theoretical yield.
Example 11 Methyl bromide is passed at room temperature into a solution of 5 g. of the ester of a-cyclohexyl phenyl glycolic acid and (l-methyl piperidyl-2)-methanol in 50 ml. of acetone until 12 g. of methylbromide have been absorbed. Colorless crystals start to precipitate during introduction of the methylbromide. The reaction mixture is cooled in an ice bath and the precipitated crystals are filtered off by suction. Thereby, the methobromide of the starting material is obtained in a yield of 63% of the theoretical yield. After recrystallization from a mixture of acetone, ethanol, and petroleum ether, its melting point is 197- 199 C.
Example 12 A mixture of 5.4 g. of 1-methyl-2-hydroxy methyl-piperidine methiodide, 4.6 g. of diphenyl acetylchloride, 2 g. of triethylamine, and 100 ml. of dry dioxane is refluxed for three hours while stirring. After standing overnight, the solvent is decanted off and the residue is recrystallized from a mixture of ethanol and petroleum ether. Thereby, the (l-methyl piperidyl-2)-methyl diphenylacetate methiodide is obtained in a yield of 54% of the theoretical yield. Melting point: l65-1-68 C.
Example 13 4.9 g. of l-methyl-Z-chloro methyl piperidine methobromide and 5.3 g. of potassium benzilate are added to ml. of absolute ethanol. The mixture is refluxed for two hours while stirring and is then filtered while still hot. The filtrate is evaporated to dryness in a vacuum and the resulting residue is recrystallized from a mixture of acetone, ethanol, and petroleum ether whereby (l-methyl piperidyl-2)-methyl benzilate methobromide melting at -162 C. is obtained in a yield of 35% of the theoretical yield.
In place of the benzilic acid esters used in Examples 1 to 6, 8 and 9, the diphenyl acetic acid ester used in Example 7, and the a-cyclohexyl phenyl glycolic acid ester used in Example 11, there may be employed other acid esters of l-alkyl-Z-hydroxy methyl piperidines l-phenyl lower alkyl-2-hydroxy methyl piperidines such as the corresponding esters with a-chloro diphenyl acetic acid or mandelic acid.
In place of the esters of the l-substituted-Z-hydroxy methyl piperidines used in Examples 1 to 9, and 11, there may be employed the esters of other l-substituted-Z-hydroxy methyl piperidines, for instance, the esters of other 1-alkyl-, l-phenyl lower alkyl, l-phenyl-Z-hydroxy methyl piperidines such as (l-benzyl piperidyl-2)-methyl benzilate, (l-ethyl piperidyl-2) methyl diphenyl acetate, (1- n-propyl-piperidyl-2) methyl mandelate, or the ester of a-chloro diphenyl acetic acid with l-methyl-Z-hydroxy methyl piperidine.
In place of diphenyl acetylchloride used as reactive acid derivative in Example 12 for esterifying l-methyl-Z-hydroxy methyl piperidine methiodide, there may be employed other carboxylic acids as they are mentioned hereinabove, or reactive derivatives of such acids, for instance, their bromides, their anhydrides, their mixed anhydrides, for instance, with alkyl carbonates, aryl carbonates or aralkyl carbonates.
In place of the l-methyl-Z-hydroxy methyl piperidine methiodide used for reaction with the acid chloride as described in Example 12, there may be employed other quaternary l-substituted-Z-hydroxy methyl piperidinium compounds such as the methosulfate of l-methyl-Z-hydroxy methyl piperidine, the methochloride of l-methyl-2-hydroxy methyl piperidine, the methosulfate of l-ethyl-Z-hydroxy methyl piperidine, the ethosulfate of l-methyl-Z- hydroxy methyl piperidine.
Likewise, in place of l-methyl-Z-chloro methyl piperidine methobromide used for reaction with potassium benzilate as described in Example 13, there may be employed other quaternary l-substituted-Z-halogeno methyl piperidinium compounds such as l-methyl-Z-bromo methyl piperidine methochloride, 1-ethyl-2-bromo methyl piperidine ethobromide, 1-n-butyl-2-chloro methyl methochloride, 1- benzyl-Z-chloro methyl methobromide, 1-methyl-2-bromo methyl methobromide.
In all these reactions and with all these different starting materials the procedure is followed as it is described in the preceding examples.
In place of methyl and ethyl iodide, methyl and ethyl bromide, and dimethyl sulfate as used in the preceding examples, there may be employed other quaternizing agents such as benzylbromide, diethyl sulfate, other alkyl or aralkyl halogenides, such as iso-propyl iodide, n-butyl iodide.
Especially valuable spasmolytic compounds of low toxicity and high spasmolytic activity are the benzilic acid esters of 1-alkyl-2-hydroxy methyl piperidine methohalides or methosulfates.
The new esters of quaternary Z-hydroxy methyl piperidinium compounds are administered orally, parenterally, or rectally. The preferred mode of administration is oral administration in the form of liquid or solid preparations, such as tablets, pills, dragees, powders, capsules, solutions, emulsions, suspensions, dispersions, or in any other suitable form.
In the case of powders, fine uniform dispersion of the active compounds together with a usual carrier throughout said powder is of importance. Such a fine dispersion can be achieved by intimately mixing and milling the active compound, for instance, in a ball mill with a solid pulverulent extending agent to the desired degree of fineness or by impregnating the already milled, finely powdered, solid carrier with the active compound in water or with a solution thereof in a suitable organic solvent and then removing the water or solvent.
A fine dispersion of the active compound in water, sirup and the like can also be brought about by emulsifying said compound with the aid of a dispersing or emulsifying agent.
When preparing tablets, pills, powders, and the like solid preparations, the commonly used carriers and diluting agents, binders, and the like tableting adjuvants are employed, such as sugar, lactose, starch, pectin, bolus alba, stearic acid, magnesium stearate, and as binders gelatin, gum arabic, methyl cellulose, carboxy ethyl cellulose, yeast extract, agar, tragacanth, and others. It is, of course, understood that any of the tableting materials conventionally used in pharmaceutical practice can be employed provided there is no incompatibility with the active compound.
Injectable preparations and suppositories for rectal administration may also be prepared.
Of course, many changes and variations in the starting materials and reactants, in the solvents used, in the reaction conditions, temperature, pH-value of the reaction mixture, duration, in the methods of working up, isolating, and purifying the reaction products, and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.
We claim:
1. The carboxylic acid ester of a quaternary Z-hydroxy methyl piperidinium compound of the formula 5 All (llHz R1 8 X is an acyl group selected from the group consisting of the benziloyl, diphenyl acetyl, u-cyclohexyl phenyl glycoloyl, mandeloyl, and a-chloro diphenylacetyl p;
5 R is a member selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, and phenyl lower alkyl;
R is lower alkyl; and
An is a member selected from the group consisting of halogen and the alkyl sulfate group SO R wherein R is lower alkyl.
2. The benzilic acid ester of l-methyl-Z-hydroxy methyl piperidinium methosulfate of the formula References Cited by the Examiner UNITED STATES PATENTS 2,918,408 12/1959 Biel 260294.3 X 2,955,144 10/1960 Biel 260-294.3 2,995,492 8/1961 Biel 260-2943 40 OTHER REFERENCES Biel et al.: Jour. Am. Chem. Soc., vol. 77, pages 2250- 225 6 (1955 Ryan et al.: Jour. Org. Chem., vol. 26, pages 15474550 (May 1961 NICHOLAS S. RIZZO, Primary Examiner.

Claims (2)

1. THE CARBOXYLIC ACID ESTER OF A QUATERNARY 2-HYDROXY METHYL PIPERIDIMUM COMPOUND OF THE FORMULA
2. THE BENZIULIC ACID ESTER OF 1-METHYL-2-HYDROXY METHYL PIPERIDINIUM METHOSULFATE OF THE FORMULA
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060287362A1 (en) * 2003-06-24 2006-12-21 Collingwood Stephen P Organic compounds
US20120046467A1 (en) * 2009-04-30 2012-02-23 Teijin Pharma Limited Quaternary ammonium salt compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2918408A (en) * 1957-04-08 1959-12-22 Lakeside Lab Inc Anti-spasmodic compositions specific for treating spasm of the colon
US2955144A (en) * 1958-06-18 1960-10-04 American Cyanamid Co Process for refining naphthalene
US2995492A (en) * 1957-12-23 1961-08-08 Lakeside Lab Inc Piperidine derivatives with psychotogenic activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2918408A (en) * 1957-04-08 1959-12-22 Lakeside Lab Inc Anti-spasmodic compositions specific for treating spasm of the colon
US2995492A (en) * 1957-12-23 1961-08-08 Lakeside Lab Inc Piperidine derivatives with psychotogenic activity
US2955144A (en) * 1958-06-18 1960-10-04 American Cyanamid Co Process for refining naphthalene

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060287362A1 (en) * 2003-06-24 2006-12-21 Collingwood Stephen P Organic compounds
JP2008529965A (en) * 2003-06-24 2008-08-07 ノバルティス アクチエンゲゼルシャフト Piperidinium and pyrrolidinium derivatives as ligands for muscarinic M3 receptors
US7947730B2 (en) 2003-06-24 2011-05-24 Novartis Ag Piperidinium and pyrrolidinium derivatives as ligands for the muscarinic M3 receptor
US20120046467A1 (en) * 2009-04-30 2012-02-23 Teijin Pharma Limited Quaternary ammonium salt compounds
US9072734B2 (en) * 2009-04-30 2015-07-07 Teijin Pharma Limited Quaternary ammonium salt compounds

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