US3751470A - N,n-dialkyl-2-(2-(2-cycloalkylvinyl)phenoxy)alkylamines - Google Patents

N,n-dialkyl-2-(2-(2-cycloalkylvinyl)phenoxy)alkylamines Download PDF

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US3751470A
US3751470A US00122253A US3751470DA US3751470A US 3751470 A US3751470 A US 3751470A US 00122253 A US00122253 A US 00122253A US 3751470D A US3751470D A US 3751470DA US 3751470 A US3751470 A US 3751470A
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formula
product
solution
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P Cross
J Stichbury
E Thorpe
N Scollick
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Pfizer Corp Belgium
Pfizer Inc
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Pfizer Corp Belgium
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    • 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
    • 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
    • C07D211/20—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 singly bound oxygen or sulphur atoms
    • C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • This invention relates to compounds having anti-histamine activity, and is particularly concerned with a novel class of ortho-substituted phenoxyalkylamines which are capable of selectively inhibiting gastric acid secretion without causing bronchial constriction or other side effects. These compounds are therefore useful in the treatment of peptic ulcers and other conditions caused or exacerbated by gastric hyperacidity.
  • R is alkyl or cycloalkyl of from 5 to 8 carbon atoms
  • Y is aminoalkyl of the formula in which R and R taken separately are each lower alkyl and R and R taken together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, azepino or diazepino group and Alk represents a divalent alkyl group containing from 2 to 4 carbon atoms, the free valences being located on different carbon atoms; or Y is an aminocyclic group of the formula in which n is 0 to 3 and Z is a divalent group which completes a pyrrolidine, piperidine, morpholine, thiomorphollne, piperazine, azepine, or diazepine ring, the nitrogen atom in said ring being separated from the oxygen atom to which the amino-
  • composition in dosage unit form useful for alleviating excess gastric acid secretion in a host comprising a pharmaceutical carrier and from about 2.5 mg. to about 250 mg. (expressed as the 3,751,470 Patented Aug. 7, 1973 weight of the free base) of a compound having the formula:
  • R is alkyl or cycloalkyl of from 5 to 8 carbon atoms
  • Y is aminoalkyl of the formula in which R and R taken separately are each lower alkyl and R and R taken together with nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, azepino or diazepino group
  • Alk represents a divalent alkyl group containing from 2.
  • Y is an amino-cyclic group of the formula in which n is 0 to 3 and Z is a diavlent group which completes a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine or diazepine ring, the nitrogen atom in said ring being separated from the oxygen atom to which the amino-cyclic group is attached, by a chain of from 2 to 4 carbon atoms; and R is hydrogen, halogen, lower alkyl or lower alkoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • K may be a straight or branched chain group, or may be or contain a cyclic group.
  • it may be a straight or branched chain pentyl, hexyl, heptyl or octyl group, or a cyclo hexyl, cyclohexyl-methyl or cyclo-heptyl group.
  • it is an n-pentyl, n-hexyl or cyclohexyl group.
  • R and R may each be, for example, a methyl, ethyl, propyl or butyl group, or together with the nitrogen atom may form, for example, a pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, azepino or diazepino group.
  • R and R form with the nitrogen atom a saturated heterocyclic group which contains a further nitrogen atom, then such further nitrogen preferably carries a. lower alkyl or benzyl group as substituent.
  • A1k may be, for example, an ethylene, propylene, ethyl-substituted ethylene, dimethyl-substituted ethylene, trimethylene or tetrarnethylene group.
  • Y is a -C H
  • Z may be, for example, a pyrrolidine, piperidine, morpholine, thiomorpholine, piperaziue, azepine or diazepine ring, provided that any nitrogen atom in the ring is separated by at least two carbon atoms from the oxygen to which the group is attached.
  • Any nitrogen atom in Z is preferably Substituted with a lower alkyl or benzyl group which any carbon atom in Z may be substituted with a lower alkyl group.
  • Pharmaceutically-acceptable acid-addition salts of the compounds of the invention can be prepared from acids which form non-toxic addition salts containing pharmaceutically-acceptablable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconte, saccharate, and p-toluene sulfonate salts.
  • pharmaceutically-acceptablable anions such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconte, saccharate, and p-toluene sulfonate salts.
  • Particularly preferred salts of compounds of this invention which are convenient in that they are soluble in the common solvents, are the addition salts formed with polycarboxylic acids, e.g. citric, tartaric, maleic, fumaric and oxalic acids.
  • polycarboxylic acids e.g. citric, tartaric, maleic, fumaric and oxalic acids.
  • the compounds of the invention may be prepared in a number of ways:
  • hal-Alk-N R R or hal-CnHm- where "hal represents a halogen atom, to yield the required product direct; or (b) reaction with a compound of the formula: hal-AlkQ, where Q is halogen or an aryl sulfonyloxy group, to form a compound of the formula:
  • the inert solvent may, for example, be toluene or dimethyl formamide.
  • the formation of the phenate may be carried out by adding sodium hydride cautiously to the solution of the phenol and then heating.
  • the alkali metal phenate may be produced in an inert solvent, e.g. methyl iso-butyl ketone, in the presence of an alkali metal base, e.g. potassium carbonate. Reaction with the halide (e.g. the chloride) may be carried out at reflux temperature.
  • the reaction of the phenol with the compound HalAlk-Q or with the haloalkanol may be carried out under reflux in an inert solvent, e.g. methanol or ethanol, in the presence of a base, e.g. potassium hydroxide or sodium ethoxide.
  • the subsequent reaction with the secondary amine may be carried out in any suitable inert solvent, e.g. ethanol, under reflux conditions, or in a sealed bomb at an elevated temperature.
  • R CH( OH) CHz-R (IV-A) and the carbinol compound is either dehydrated, or halogenated and then dehydrohalogenated, to yield the desired product.
  • (IV-B) may be formed by the Grignard reaction of an aldehyde of the formula R CH CHO or R CHO with magnesium and a compound of the formula:
  • the Grignard reagent is prepared in the usual way from the magnesium and the appropriate halide in a suitable solvent, e.g. diethyl ether, and the appropriate aldehyde is then added slowly in the same solvent to the cooled solution of the Grignard reagent. The mixture is then heated to complete the reaction and the magnesium complex decomposed with acid at about 0 C.
  • a suitable solvent e.g. diethyl ether
  • the dehydration reaction may be carried out be heating the carbinol of either of the Formulae IV-A and IV-B in the presence of strong acid, e.g. p-toluene sulfonic acid.
  • strong acid e.g. p-toluene sulfonic acid.
  • the halogenation reaction may, for example, be effected with thionyl chloride such that the carbinol of the Formula IlV-A is converted to a chloro-compound of the formu a: 1
  • the subsequent dehydrohalogenation stage may then be effected merely by heating the corresponding halide in the presence of acid if necessary.
  • R is a hydrogen atom or an alkyl or alkoxy group
  • R CH is a salicylaldehyde derivative of the Formula III by reaction with lithium and halide of the formula R CH -Hal, to form the carbinol of the Formula IV-A, and, as in method (2), the carbinol compound is either dehydrated, or halogenated and then dehydrohalogenated, to yield the desired product.
  • a mixture of the salicylaldehyde derivative and the halide is added to a stirred suspension of lithium in a dry inert solvent, e.g. tetrahydrofuran with cooling such that the temperature of the mixture does not rise above about 40 C.
  • a dry inert solvent e.g. tetrahydrofuran
  • the mixture is stirred at room temperature for several hours or the addition, and then is hydrolyzed by cautious addition of water and extracted with a suitable solvent, e.g. diethyl ether.
  • the crude product, an oil is obtained on evaporating the organic solution, and is submitted to a reduced-pressure distillation, whereupon the pure carbinol product is isolated.
  • the compounds of the invention may also be prepared from an ortho-acyl phenol of the formula:
  • R H(OH) CHr-R O Y (IV-A) by reaction with a suitable reducing agent, e.g. sodium borohydride, in an inert solvent, e.g. ethanol, under reflux, and the carbinol is subsequently converted to the vinylene Compound I either by conversion to the halocompound followed by dehydrohalogenation or directly by dehydration, according to the procedure in method (2).
  • a suitable reducing agent e.g. sodium borohydride
  • an inert solvent e.g. ethanol
  • acyl phenols of the Formula VII can be readily prepared from the corresponding phenyl carboxylate by the Fries rearrangement reaction, with aluminum chloride or similar Lewis acid catalysts:
  • R B C OCH -R O-C O CH -R OH
  • R is hydrogen
  • the reaction gives a mixture of ortho and para isomers which must be separated to give the required ortho-acyl phenol.
  • Such separations may be eflected in various ways, e.g. by steam distillation, fractional distillation or fractional crystallization.
  • the acyl phenols may be prepared by the Friedel- Crafts reaction between a 4-R -phenol and a carboxylic acid of the formula R 43H COOH in a suitable inert solvent, e.g. o-dichlorobenzene in the presence of a Lewis acid catalyst, e. g. aluminum chloride.
  • the product may be obtained as free base by precipitation or by removal of solvent under reduced pressure, and purified by addition of water (made just basic if necessary to avoid precipitation), extraction into ether, drying, filtration and evaporation under reduced pressure.
  • Acid addition salts may be obtained in the usual manner by addition of the appropriate acid in a suitable solvent, e.g. diethyl ether, to the liquid base, or a solution thereof if solid, and collection of the precipitate. Purification is carried out in the usual manner by recrystallization from a suitable solvent.
  • the compounds of the invention all exist as cis and trans forms relative to the ethylenic double bond and the invention includes the separated cis and trans forms as well as mixtures of the isomers. In all of the described processes, the product is ordinarily obtained as the more stable trans form.
  • the compounds of the invention have been found to have an inhibiting effect on histamine-induced gastric acid secretion which has been measured in experimental animals.
  • anaesthetized rats are sensitized by intravenous injection of carbachol (carbamoyl choline chloride) and are then injected intravenously with a standard dose of histamine and the pH of the gastric contents is measured over a short period, until it stabilizes.
  • the test compound is then administered, also intravenously, and the pH of the gastric contents is measured over a further period, until the inhibiting effect of the compound is no longer apparent.
  • R is an n-pentyl, nhexyl or cyclohexyl group
  • R is a hydrogen or chlorine atom
  • Y is a group of the formula (as hereinbefore defined) which contains 1) a single, tertiary nitrogen atom separated from the oxygen atom by a chain of two carbon atoms only, (2) a total of from 6 to 9 carbon atoms and (3) a methylene group attached to the oxygen atom.
  • the compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they may be administered orally in the form of tablets containing such excipients as starch and lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing liavoring or coloring agents.
  • They may be injected parenterally, for example, intramuscularly or subcutaneously,
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose t9 make the solution isotonic.
  • t3 dosage levels a broad dosage range of 2.5 to 250 mg./day for adults is appropriate, a particularly preferred range being from 10 mg. to 100 rug/day.
  • the physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with age, the weight and response of the particular patient.
  • the above dosages are exemplary of the average host. There can, of course, be individual cases where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the fraction of B.P. 180-186 C./0.3 mm. (29.8 g.) was shown to consist of 95% pure N,N-diethyl 2 [2-(2-cyclohexyl-1-hydroxyethyl)phenoxy]ethylamine as free base.
  • a small quantity (3.19 g.) of the free base was dissolved in ether (75 ml.) and treated with ethanolic HCl (1 ml., 1.0 N) to convert it to the hydrochloride (3.3 g.), M.P. 169-170 C.
  • Example II to IV The following compounds were prepared by the method described in Example I, starting from the appropriately substituted salicylaldehyde derivative and cyclohexylmethylmagnesium bromide, and characterized as the hydrochloride.
  • the product was converted by conventional means to the citrate salt, which was recrystallized from ethanol/diethyl ether to yield a pure sample (3.0 g.) of 1-[2-(2-n-hexylvinyl)phenoxy] 2 pyrrolidinoethane citrate, M.P. 103105 C.
  • Example V By the method of Example V, starting from lithium, 2-(2-pyrrolidinoethoxy)benzaldehyde of l-bromohexane, 1-[2 (2-n-pentylvinyl)phenoxy] 2 pyrrolidinoethane citrate, M.P. 102103.5, was similarly prepared.
  • Example VII (A) To a stirred suspension of anhydrous aluminum chloride (300 g., 2.25 M) in o-dichlorobenzene (500* ml.) at'110 C. was slowly added a solution of cyclohexylacetic acid (.142 g., 1.0 M) and p-chlorophenol (128 g. 1.0 M) in o-dichlorobenzene (250 ml.). When the addition had been completed, the temperature of the mixture was raised to C. and maintained at this point for 12 hours.
  • the hydrochloride salt of a small sample of the product was formed by admixture of the free base with hydrogen chloride in an ethyl acetate-industrial methylated spirit solution and collection of the resultant precipitate by filtration.
  • the product was l-[4-ch1oro-2-( l-hydroxy-Z- cyclohexylethyl phenoxy] -2-pyrrolidinoethane hydrochloride, M.P. 168-171.
  • Example VIII 4-chloro-2-cyclohexylacetylpheno1 (230 g., 0.91 M), produced as in Example VII(A), was mixed with 2-diethylaminoethy1 chloride hydrochloride (186.7 g. 1.085 M), potassium carbonate (300 g., 2.18 M), potassium iodide (44.8 g., 0.265 M) and methyl iso-butyl ketone (1.8 l.) and the mixture was refluxed with stirring for 12 hours. The mixture was cooled to room temperature, and the undissolved material filtered 0E and washed with methyl iso-butyl ketone, the washings then being combined with the main filtrate.
  • Example IX Formulation of tablets and capsules of N,N-diethyl-2- [2 (2 cyclohexylvinyl)phenoxy1ethylamine' hydrochloride described in Example I is effected using the following ingredients:
  • the ingredients are blended and compressed.
  • the compressed pieces are then broken into granules and compressed into finished tablets.
  • Equlvnlcnt 10 mg. of free base.
  • the ingredients are blended and filled into hard gelatin capsules of suitable size.
  • R is alkyl or cycloalkyl of from 5 to 8 carbon atoms
  • Y is aminoalkyl of the formula in which R and R taken separately are each lower alkyl and Alk" represents a divalent alkyl group containing from 2 to 4 carbon atoms, the free valences being located on dilferent carbon atoms
  • R is hydrogen, halogen, lower alkyl or lower alkoxy.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US00122253A 1970-03-13 1971-03-08 N,n-dialkyl-2-(2-(2-cycloalkylvinyl)phenoxy)alkylamines Expired - Lifetime US3751470A (en)

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GB02111/70A GB1283451A (en) 1970-03-13 1970-03-13 Ortho-substituted phenol ethers, their preparation and compositions containing them

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US (1) US3751470A (enExample)
JP (1) JPS5214B1 (enExample)
BE (1) BE763744A (enExample)
DE (1) DE2109941A1 (enExample)
ES (2) ES389210A1 (enExample)
FR (1) FR2085705B1 (enExample)
GB (1) GB1283451A (enExample)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3910896A (en) * 1970-03-13 1975-10-07 Pfizer Substituted phenoxyalkylamines as gastric anti-secretory agents
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3910896A (en) * 1970-03-13 1975-10-07 Pfizer Substituted phenoxyalkylamines as gastric anti-secretory agents
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

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JPS5214B1 (enExample) 1977-01-05
ES389210A1 (es) 1973-06-01
FR2085705A1 (enExample) 1971-12-31
DE2109941A1 (de) 1971-11-25
BE763744A (fr) 1971-09-03
GB1283451A (en) 1972-07-26
ES389211A1 (es) 1973-06-16
FR2085705B1 (enExample) 1974-08-30

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