US3767819A

US3767819A - Alkylphenoxy alkylamines as gastric anti secretory agents

Info

Publication number: US3767819A
Application number: US00283396A
Authority: US
Inventors: P Leeming; P Cross; D Cox; J Augstein
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1969-06-12
Filing date: 1972-08-24
Publication date: 1973-10-23
Anticipated expiration: 1990-10-23
Also published as: FR2052952A1; US3709892A; FR2052952B1; GB1268951A; DE2026688A1; MY7300323A

Abstract

ORTHO-SUBSTITUTED PHENOXYALKYLAMINES HAVING GASTRIC ANTI-SECRETORY ACTIVITY ARE PREPARED. A TYPICAL EMBODIMENT IS N,N-DIETHYL - 2(2-(2-CYCLOHEXYLETHYL)PHENOXY) ETHYLAMINE.

Description

United States Patent Oflice 3,767,819 Patented Oct. 23, 1973 3,767,819 ALKYLPHENOXY-ALKYLAMINES AS GASTRIC ANTI-SECRETORY AGENTS Peter Rodway Leeming, Peter Edward Cross, and David Alexander Cox, Canterbury, and Joachim Augstein, Linford, England, assignors to Pfizer Inc., New York,

No Drawing. Original application June 8, 1970, Ser. No. 44,604, now Patent No. 3,709,892. Divided and this application Aug. 24, 1972, Ser. No. 283,396 Claims priority, application Great Britain, June 12, 1969, 29,780/69 Int. Cl. A61k 27/00 US. Cl. 424-330 2 Claims ABSTRACT OF THE DISCLOSURE Ortho-substituted phenoxyalkylamines having gastric anti-secretory activity are prepared. A typical embodiment is N,N-diethyl 2[2-(2-cyclohexylethyl)phenoxy] ethylamine.

CROSS REFERENCE TO RELATED APPLICATION This application is a division of application Ser. No. 44,604 filed .Tune 8, 1970, now Pat. No. 3,709,892.

BACKGROUND OF THE INVENTION The invention relates to compounds having anti-histamine activity, and is particularly concerned with a novel class of ortho-substituted phenoxyalkyl amines which have the property of blocking the actions of histamine at the so-called H receptor sites, eg those which influence gastric acid secretion, but have little or no ability to block the actions of histamine at the so-called H receptor sites, e.g., those which influence bronchial constriction.

SUMMARY OF THE INVENTION The novel compounds disclosed herein are selected from the group consisting of ortho-substituted phenoxyalkylamines of the formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl of from 7 to 9 carbon atoms, cyclohexylmethyl, cyclohexyl-ethyl, cyclohexyl-propyl or cycloheptylethyl;

Y is aminoalkyl of the formula Alk-NR R 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 pyrrolidine, piperidino, morpholino, thiomorpholino, piperazino, azepino, or diazepine 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 amino-cyclic group of the formula in which n is to 3 and Z is a divalent 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, lower alkoxy, lower alkanoyl or a-OXiminO-IOWeI alkyl.

In addition, there is disclosed a composition in dosage unit form useful for alleviating excess gastric acid secretion in a host comprising a pharmaceutical carrier and from about 12.5 mg. to about 500 mg., preferably from about 50 mg. to about 200 mg. (expressed as the weight of the free base) of a compound having the formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein R is alkyl of from 7 to 9 carbon atoms, cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl or cycloheptylethyl;

Y is aminoalkyl of the formula -AlkNR R 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 be located on different carbon atoms; or

Y is an amino-cyclic group of the formula in which n is 0 to 3 and Z is a divalent 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 alky, lower alkoxy, loweralkanoyl or u-oximino-lower alkyl.

The term loWer," applied to a substituent group, means containing from 1 to 4 carbon atoms, and halogen means fluorine, chlorine, bromine or iodine.

DETAILED DESCRIPTION OF THE INVENTION In the general formula, R may be a straight or branched chain group, or may contain a cyclic group. For example, it may be a straight or branched chain heptyl, octyl or nonyl group, or a cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl or cycloheptyl-ethyl group. Preferably, it is a primary hydrocarbyl radical, i.e., it is linked to the benzene ring by a methylene group. More preferably, it is a n-heptyl or 2-cyclohexyl-ethyl group.

When Y is a -Alk-NR R 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. When 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.

When Y is a AlkNR R group, Alk may be, for example, an ethylene, propylene, ethyl-substituted ethylene, dimethyl-substituted ethylene, trimethylene or tetramethylene group.

When Y is a C,,H may be for example a methylene ethylidene ethylene propylene or trimethylene group and the heterocyclic ring completed by Z may be, for example, a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine or diazepine ring, provided that any nitrogen atom in the ring is separated by at least 2 carbon atoms from the oxygen atom to which the group is attached.

3 Thus,

may be, for example, a 3-pyrrolidiny1 or 3- or 4-piperidinyl group, a 2- or 3-pyrrolidinylrnethyl or 2-, 3- or 4- piperidinylmethyl group, a 2-(2- or 3-pyrrolidinyl) ethyl or 2-(2- or 3-piperidinyl)ethyl group, or a 3-(2-pyrrolidinyl)-propyl or 3-(2-piperidinyl) propyl group. Any nitrogen atom in Z is preferably substituted with a lower alkyl or benzyl group while any carbon atom in 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 acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate, and ptoluene sulfonate salts.

Particularly preferred salts of compounds of this invention are the hydrochlorides and the addition salts formed with polycarboxylic acids, e.g., citric, tartaric, maleic, fumaric and oxalic acids.

PREPARATIVE METHODS (1) The compounds of the invention can be prepared from the appropriate ortho-substituted phenol, of the formula:

(a) reaction with an alkali metal compound in an inert solvent to form the alkali metal phenate and then with the appropriate halide, of the formula:

where hal represents a halogen atom, to yield the required product direct;

(b) reaction (under basic conditions) with a compound of the formula: halAlk--Q, where Q is halogen or other leaving group, e.g. an aryl sulfonyloxy group, such as benzene sulphonyloxy or p-toluene sulfonyloxy, to form a compound of the formula:

which is then reacted with the appropriate secondary amine HNR R (c) reaction with a halo-alkanol of the formula:

halAlk-OH,

under similar conditions to (b) to form a compound of the formula:

which is converted to the halide, eg., by reaction with thionyl chloride, and then reacted with the appropriate secondary amine as in (b); or

(d) reaction with an alkali metal compound to form the phenate as in (a) and then with a lower alkyl ester of a halogeno-acid of the formula: halAlk-COOR where R is a lower alkyl group, and AIR is a saturated aliphatic hydrocarbon group containing up to 3 carbon atoms, to yield a compound of the formula:

which is then converted to the appropriate amide (optionally via the free acid and acid chloride) by reaction with the amine HNR R and finally reduced with lithium aluminum hydride to yield the required product.

In the methods 1(a) and (d), the inert solvent may, for example be toluene or dimethyl formarnide. The formation of the phenate may be carried out by adding sodium hydride cautiously to the solution of the phenol and then heating. Reaction with the halide or halogeno-acid ester (e.g., the chloride or chloroester) may be carried out at reflux temperature.

In methods 10)) and 1(c), the reaction of the phenol with the compound halAlk-Q or with the halo-alkanol (e.g. bromo-alkanol) may be carried out under reflux in methanolic potassium hydroxide, ethanolic sodium ethoxide or acetone/potassium carbonate solution.

Subsequent reactions with the secondary amine may be carried out in any suitable inert solvent, e.g. ethanol, under reflux conditions. As a modification of these methods, a primary amine H NR may be used instead of the secondary amine HNR R and the product alkylated in conventional manner to yield a compound of the invention in which R and R are each a lower alkyl group.

(2) Compounds of the invention in which R is a primary hydrocarbyl radical, may also be prepared (a) when R is hydrogen, or a lower alkyl or alkoxy group, from a salicylaldehyde derivative of the formula:

E CHO by the Grignard reaction with magnesium and a halide of the formula hal-R where R CH is equivalent to R to yield a compound of the formula:

which is then reduced, e.g., with hydrogen in the presence of a suitable catalyst;

or (b) when R is hydrogen or a lower alkyl group, from a lower alkyl ether of salicylaldehyde itself, by similar reaction with the Grignard reagent and subsequent reduction, to yield a compound of the formula:

where R is lower alkyl, the ether being converted to the free phenol by conventional methods and then reacted according to any of the preparations (l)(a),

(b) or (c).

In the preparations (2)(a) and (b) of the Grignard reagent is prepared in the usual way from magnesium and the appropriate halide in a suitable solvent, e.g. 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. The subsequent reduction may be carried out with hydrogen in the presence of a palladium-on-carbon catalyst in an acid medium, e.g. at 50 and 50 psi. in ethanolic hydrochloric acid, or in the presence of Raney nickel as catalyst.

(3) Compounds in which R is a primary hydrocarbyl radical and R is hydrogen, halogen, or a lower alkyl or alkoxy group may also be prepared from ortho-acyl phenols of the formula:

(a) reduction with zinc and hydrochloric acid, with hydrazine in a suitable solvent, or with hydrogen in the presence of a suitable catalyst, followed by reaction according to any of the prepaartions (1) (a), (b) or or (b) reaction first according to any of the preparations (1) (a), (b) or (c) to yield a compound of the formula:

followed by reduction as in (a). In each case, the reduction with hydrogen may be carried out as in preparation (2), and in the cases Where R is halogen R may be simultaneously replaced by hydrogen.

The starting materials for preparation (3), Le. acyl phenols of the aforementioned formula, can be readily prepared from the corresponding phenyl carboxylate by the Fries rearrangement reaction, with aluminum chloride or similar Lewis acid catalysts:

R!- R (JO-R OCO-R5 OH when R is hydrogen, however, the reaction gives a mixture of ortho and para isomers which have to be separated to give the required ortho-acyl phenol.

In each preparation, the final product may be obtained as free base by precipitation or by removal of solvent under reduced pressure, and purified by addition of water, extraction into a suitable solvent, 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 to the liquid base, or to a solution thereof, and collection of the precipitate. Purification is carried out in the usual manner by recrystallization from a suitable solvent.

The compounds of the invention have been found to be potent H antagonists, i.e. blockers of the action of histamine at H receptor sites. This has been shown in tests in which their inhibiting effect on histamine-induced gastric acid secretion has been measured in experimental animals. In one of such tests, anaesthetised rats are sensitised 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. A 50% inhibition of the effect of histamine on pH, at a dose of mg./ kg. has been found for many of the compounds of the invention, while the most potent have a 100% inhibiting effect at 5 mg./kg. or a 50% inhibiting eflect at 2.5 mg./kg. or even less. The more potent compounds are also effective over a period of 3 to 4 hours after injection. In a similar test with anaesthetized cats, histamine is continuously infused before and during administration of the test compound.

By virtue of their Hf-blocking activity, the compounds of the invention are useful for reducing gastric hyper-acidity and therefore in the treatment of gastric ulcers and other conditions caused or exacerbated by gastric hyper-acidity. They are also useful for relieving other conditions due to the actions of histamine at H receptor sites.

On the basis of the results obtained, the preferred compounds have been found to be those having the formula:

in which R is heptyl or 2-cyclohexyl-ethyl group, R is a hydrogen or fluorine atom or a methyl or methoxy group, and 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.

Thus Y is preferably, for example: a group of the formula CH CH NR R in which R and R together contain from 4 to 7 carbon atoms; a group of the formula -CH CH(CH )-NR R where R and R together contain from 3 to 6 carbon atoms; or a 1- alkyl-2-piperidyl-methyl group in which the l-alkyl substituent contains up to 3 carbon atoms.

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. For example, 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 flavoring or coloring agents. They may be injected parenterally, for example, intramuscularly or subcutaneously. For 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 to make the solution isotonic.

' The invention is illustrated by the following examples.

EXAMPLE I N,N-diethyl-2- [2- (2-cyclohexyl-ethyl) phenoxy] ethylamine A 50% dispersion of sodium hydride (1.2 g.) was added in portions to a stirred solution of 2-(2-cyclohexylethyl) phenol (5.0 g.) in dry dimethylformamide (75 ml.) and the mixture then heated to for V2 hour. Z-(diethylamino) ethyl chloride (3.3 g.) in dimethylfo-rmamide (25 ml.) was slowly added, the mixture was refluxed for a period of 3 hours, then cooled and water (10 ml.) added. After evaporation of most of the solvent under reduced pressure, water (100 ml.) was added to the residue and the mixture is extracted twice with ether. The organic extract was washed with water, dried over sodium sulfate and filtered. Evaporation of the solvent then afforded the product as a pale yellow oil. Addition of an etheral solution of citric acid gave a precipitate of which 9.1 g. of the citrate salt of the product, which was recrystallized from ispropyl alcohol and had M.P. -131".

Analysis.Found (percent): C, 62.7; H, 8.2; -N, 2.95. galczdf.s for C H NO.C H O (percent): C, 63.0; 'H, 8.3;

EXAMPLES 2 TO 39 The compounds in the following examples were prepared as in Example I, from the appropriate substituted phenol and chloride Cl-Y. The analytical figures required by the empirical formula of each compound are given in brackets. Salt formation was carried out in the usual way, using the appropriate acid.

Elemental analyses (percent) Salt produced and MP. Example R Y (empirical formula) C H N 30 -do CH2CHN(C2H5)2 Citrate 1l2-113 63. 6 8. 4 2. 8

I (C21H35NO-CoHBO7). (63. 6 s. a 2. 75) CH:

31 d -CHCH2N(C2H5)2 Citrate 139-40 63. 6 8. 4 2. 75

H 2l 35NO-C6 EO1)- (63. 6 8. 2. 75)

32 .410 02H; Hydrochloride 187-188 71. 9 9. 8 3. 4

g (C2z a5N0-HCl). 72. 2 9. 9 a s) CH2CH 33 n-Nonyl. -CHzCH2-N(C2H5) 2"... H Oxalate 12l122 65.6 9. 0 3. 6

(CnHzzNO-CzHzOO. (66. 1 9. 3. 7)

34 2-cyclohexyl-ethyl. Same as above CH;C0- Citrate 118119 62. 4 7. 9 2. 4

(C2zH NOCuHa07); (62. 55 8. 1 2. 6)

35 -d0 (32H; Hydrochloride 159160 72. 0 9. 5 3. 8

I (CaiHaaNO-HCI). (71. 7 9. 7 4. 0) N CH 36 do C H2CH2N(C2H5)2 .:.:;'.2'...":':. F Citrate l29130 61. 0 8. 1 2. 4

(O2oHazFNO-CuH O1). (60. 8 7. 85 2. 7)

37 --d0. CH: Hydrochloride 170 71. 3 9. 7 3. 9

l (CmHzaNO -HC1). (71.65 9. 7 3. 9) N CH2-CH 38 Cycloheptyl-methyl.-. CH2CH2N(C2Hu)2 H Citrate 149.5150 63. 0 8. 1 3. 0

(CzoHaaNO -CuHsO1); (63. 0 8. 3 2. 8)

39 Cyclohexyl-methyl. 02H; Citrate 137138 64. 0 7. 8 2. 3

I (CnHuN O CQHBO1): (63. 9 8. 1 2. 8) N -CH2CH EXAMPLE 40 The maleate salt was formed in the usual manner and (A) 1-brom0-3- (2-n-heptylphenoxy) propane 2-n-heptylphenol (48 g.) was slowly added to a stirred solution of potassium hydroxide (14 g.) in methanol (100 ml.). 1,3-dibromopropane (202 g.) was then added in one portion and the mixture is refluxed on the steam bath for two hours before cooling and filtering the precipitated potassium bromide. Evaporation of the solvent left a residual oil which was distilled under reduced pressure, the pure product being the fraction (36 g.) collected between 138 and 146 at 0.6 mm./Hg pressure.

(B) 4-[3-(2-n-heptylphenoxy) propyll-l-methyl piperazine The product of (A) (5.0 g.) and N-methyl piperazine recrystallized from ethanol, to yield 3.5 g. of the dimaleate, M.P. l9l192 C.

A nalysis.-Found (percent): C, 61.8.; H, 7.7; N, 4.7. Calcd. for C H N O2C H O (percent): C, 61.7; H, 7.85; N, 5.0.

EXAMPLES 41 TO 44 Elemental analysis (percent) Salt produced and MP. Example R Y R (empirical formula) C H N 41 n-Heptyl -CHzCHzOH2-N(O2H5)2 H Oxalate 91-2 66. 8 9. l. 3. 2

(CzoHasNO 432E294) (66. 8 9. 4 3. 5) 42 (in Di-hydrochloride 22930 67. 4 9. 0 5. 3

-6 H 0 H 0 Hz-N /N 0 H2 CuHa (C27H40Nz0 -2HC1) (67. 3 8. 8 5. 8)

43 do H Oxalate 109-1l0 66. 8 8. 7 3. 3

CHaCHzC Hr-N (CzoHaaNO 0211204)- (67. 1 9. 0 3. 6)

44 2-cyclohexylethy1 CH7CHzCHr-N(C:H5)3 H Citrate 1356 63. 8 8. 1 5

(C21Ha5NO-CaHsO1). (63. 6 8. 5 2. 75)

(6.4 g.) in ethanol (100 ml.) were refluxed for 6 hours. EXAMPLE 45 After cooling and removal of solvent under reduced pressure, water (100 ml.) was added and the mixture made just basic with 2 N sodium hydroxide followed by extraction twice with ether. The combined organic extracts were dried, filtered and evaporated to give a residual oil that was held for 1 hour at C. and 1 mm. pressure in order to remove excess N-methyl piperazine.

The product of Example 34 was added to a solution 7 of hydroxylamine hydrochloride (1.0 g.) and sodium acetate (2.0 g.) in ethanol (50 ml.). The mixture is stirred, warmed on the steam bath for 1 /2 hours and cooled. The ethanol was then evaporated off under reduced pressure and water (50 ml.) added to the residue, which is extracted twice with ether (25 m1.) evaporated and dried 11 to give N,N-diethyl-Z-[2-(2-cyclohexylethyl)-4-( l-oximoethyl) phenoxy] ethylamine, as a colorless oil.

Addition of etheral citric acid gives the citrate salt, which is recrystallized from methanol/ethylacetate as a white solid (1.8 g.), M.P. 111-1l3.

AnaIysis.Found (percent): C, 60.8; H, 7.8; N, 4.9. Calcd. for C H N O -C H O (percent): C, 60.85; H, 8.0; N, 5.1.

EXAMPLE 46 (1) Sodium hydride (50% dispersion, 4.8 g.) was added portionwise to a solution of 2-(2-cyclohexylethyl) phenol (20 g.) in dry dimethyl formamide (100 ml.) and the mixture heated to 80 for 1 hour. Chloroethylacetate (12.1 g.) is then added and the mixture refluxed for 4 hours, cooled, poured into water, extracted with ether, evaporated and dried in the usual manner. High vacuum distillation gives 14.1 g. of ethyl 2-(2-cyclohexyl-ethyl) phenoxyacetate as a clear liquid.

(2) This ester (25 g.) is added to ethanolic sodium hydroxide (150 ml.) and warmed overnight on the steam bath. It is then evaporated to A volume, added to water, extracted with ether, acidified with hydrochloric acid, extracted three times with chloroform (50 ml.) and evaporated to give 18.5 g. of crude 2-(2-cyclohexy1-ethy1) phenoxyacetic acid.

(3) The acid is treated with thionyl chloride, and the acid chloride so formed (4.0 g.) was slowly added in benzene (30 ml.) to a solution of isobutyl piperazine (2.0 g.) in benzene (40 ml.). A rapid reaction takes place and a gelatinous precipitate was formed. The mixture was refluxed on a steam bath for 1 hour, cooled and then evaporated to near dryness under reduced pressure. Water (100 m1.) is then added to the residue, basified with NaOH and the mixture extracted with chloroform (50 ml.). Working up the chloroform extract in the usual manner aflorded 4.6 g. of 1-isobutyl-4-[2-(2-cyclohexylethyl)phenoxyacetylIpiperazinc as a dark brown oil.

(4) This amide (4.6 g.) was slowly added to lithium aluminum hydride (1.1 g.) in dry ether (200 ml.) and the mixture stirred and refluxed for 6 /2 hours. 5 N aque ous sodium hydroxic solution (1.8 ml.) was then added to decompose the excess LiAlI-I, and the mixture filtered. The filter cake is well washed with ether, the filtrates combined, dried and evaporated to give a mobile yellow oil. Addition of ethereal HCl gave 2.8 g. of 1-isobutyl-4-[2-(2- {2 cyclohexylethyl}phenoxy)ethy1]-piperazine di-hydrochloride which was recrystallized from isopropyl alcohol, M.=P. 255-256".

Analysis-Found (percent): C. 64.45; H, 9.3; N, 6.1. Calcd. for C H N QZHCI (percent): C, 64.7; H, 9.5; N, 6.3.

EXAMPLE 47 (1) Cyclohexylmethylmagnesium bromide (35.4 g.) 0.2 mole was prepared in ether (610 ml.) in the usual manner from cyclohexylmethyl bromide and magnesium. Z-diethylaminoethoxy benzaldehyde (44.2 g., 0.2 mole) in ether (60 ml.) was added slowly to the cooled Grignard reagent. At the completion of the addition the mixture was heated under reflux for 3 hours, and then decomposed with 5 N hydrochloric acid in the presence of ice. The free base of the product was liberated by the addition of ammonium chloride (42.8 g.) and dilute ammonia and the separated ethereal layer removed. The aqueous phase was extracted twice further with ether (150 ml. total) and the ether extracts pooled and washed with dilute ammonia. Ether was removed by evaporation on a water bath and the residual oil distilled in vacuo. The fraction of B.P. 180-186/03 mm. (29.8 g.) was collected and shown to consist of 95% pure N,N-diethyl-2-[2-(2-cyclohexyl-l-hydroxyethyl)phenoxylethylamine as free base.

(2) The product of (1) (20 g.) was dissolved in ethanol (100 ml.); 36% w./v. hydrochloric acid (8 ml.) and 5% palladium on carbon catalyst (5 g., i.e. 2.5 g. of catalyst wetted with an equal weight of water) was added.

The suspension was hydrogenated at 50 p.s.i.g. and 50 C. for 2 /2 hours, when hydrogen uptake ceased. Catalyst was filtered oil and the filtrate was treated with an excess of 20% w./v. sodium carbonate solution (50 ml.). Most of the remaining ethanol was removed by distillation in vacuo and the residue extracted with ether (3 X 50 ml.). Evaporation of the ether yielded 16.4 g. of N,N-diethyl- 2-[2-(2-cyclohexylethyl)phenoxy]ethylamine as an oil. This was dissolved in ether 150 ml.) and a solution of citric acid monohydrate in ethyl methyl ketone (11.4 g. in 75 ml.) added slowly to the stirred solution. A colorless voluminous precipitate separated which was filtered, washed with ether and dried in vacuo at 40 C. to yield 25.8 g. of the citrate, M.P. 128-130, identical with the product of Example 1.

Analysis.Found (percent): C, 63.60; H, 8.50; N, 2.71. Calcd. for C H NO.C H O-; (percent): C, 63.01; H, 8.34; N, 2.83.

EXAMPLE 48 (1) Z-cyclohexylacetyl-4-chlorophenol (225.5 g., 1.0 mole) in dimethylformamide (600 ml.) was added over 1 hour to a suspension of sodium hydride oil dispersion (48 g., 1.0 mole) in dimethylformamide (400 ml.) at and the mixture obtained was stirred at 90-400 for a further 1 /2 hours. Z-dimethylaminoethylchloride (142 g., 1.05 mole) in dimethylformamide (200 ml.) was then added at 90 over 0.5 hour and the reactants heated at 90100 for 3 hours. After cooling the reaction to 25", water (1 litre) was added cautiously, the solution obtained with extracted with chloroform (4X 750 ml.) the chloroform solution was backwashed with water (3 X 500 ml.) and concentrated to an oil which was dissolved in dilute (5 N) hydrochloric acid (750 ml.) and backwashed with ether (3X 250 ml.). The aqueous solution was adjusted to pH 9.5 with sodium hydroxide solution and extracted with chloroform (3 X 250 ml.). The chloroform solution on concentration gave 345 g. of N,N-diethyl2-(2-cyclohexylacetyl-4-chlorophenoxy) ethylamine as an oil. Purification of this product was achieved by formation of the citrate which was twice recrystallized from isopropanol and had M.P. 123-125.

(2) The product of (1) as citrate (11.2 g., 0.02 mole) dissolved in methylated spirit mls.) was hydrogenated over 10% palladium on carbon (6 g.) at 60 p.s.i.g. and 80 until hydrogen uptake was complete (2 hours). The catalyst was filtered oil and the solution concentrated to an oil which was suspended in water, adjusted to pH 9.5 with sodium hydroxide solution and extracted with chloroform (3x 50 mls.). The chloroform solution was dried over magnesium sulfate and concentrated to an oil to yield 5 g. of N,N-diethyl-2-[2-(2-cyclohexylethyl)-phenoxy]ethylamine as free base, B.P. 183-9 at 3.5 mm. Hg. This was converted by conventional means to the hydrochloride, M.P. 161-2".

Analysis.Found (percent): C, 70.92; H, 10.12; N, 4.09;; Cl, 10.75. Calcd. for C H NoHCl (percent): C, 70.78; H, 10.10; N, 4.13; Cl. 10.45.

EXAMPLE 49 Formulation of tablets and capsules of N ,N-diethyl-Z- [2 (2 cyclohexylethylJphenoxy] ethylamine hydrochloride described in Example 48 is eifected using the following ingredients:

Tablets: Mg./tablet N,N diethyl 2-[-(2-cyclohexyl-ethyl)phenoxy] ethylamine hydrochloride 1 56.0 Dicalcium phosphate -2 120.0 Corn starch 20.0

Magnesium stearate 1.6 Sodium lauryl sulfate 0.2

1 Equivalent to 50 mg. of free base.

The ingredients are blended and compressed. The compressed pieces are then broken into granules and compressed into finished tablets.

Capsules Mg./ tablet N,N diethyl 2 [Z-cyclohexyl-ethyDphenoxy] ethylamine hydrochloride 1 56.0

Corn starch 127.0

Microcrystalline cellulose 127.0

Magnesium stearate 5.4

Sodium lauryl sulfate 0.6

and the pharmaceutically acceptable acid addition salts thereof wherein R is alkyl of from 7 to 9 carbon atoms, cyclohexylmethyl, cyclohexyl-ethyl, cyclohexyl-propyl or cycloheptyl-ethyl; 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 pyrrolidine or piperidino group and Alk is a divalent alkyl group containing from 2 to 4 carbon atoms, the free valences being located on different carbon atoms; or Y is an amino-cyclic group of the formula in which n is 0 to 3 and Z is a divalent group which completes a pyrrolidine or piperidine ring, the nitrogen atom in said ring being separated from the oxygen atom to which the aminocyclic group is attached, by a chain of from 2 to 4 carbon atoms; and R is hydrogen, lower alkyl, lower alkoxy or lower alkanoyl.

2. The composition of claim 1 wherein said compound is N,N-diethyl-2-[2-(2-cyclohexyl-ethyl)phenoxy] ethylamine.

References Cited UNITED STATES PATENTS 3/1972 Bach et al. 260-3265 ALBERT T. MEYLERS, Primary Examiner F. E. WADDELL, Assistant Examiner US. Cl. X.R.