N-substituted -alpha-methyl-3,4-(methylenedioxy) Phenethylamines

Abstract

N-substituted-.alpha.-methyl-3,4-(methylenedioxy)phenethylamines of the formula: ##SPC1## Wherein R is cyclopropyl or cyclopropylmethyl. The compounds are useful as appetite depressants. 3 Claims, No Drawings

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 770,126, filed Oct. 23, 1968 now abandoned.

Description

DISCLOSURE

The problems caused by obesity are now well recognized and are quite generally considered to be of sufficient importance that some effort should be made to remedy the condition. Ordinarily, obesity is caused simply by the caloric input to the body exceeding the caloric output; adjustment may be achieved by reducing the input or increasing the output. However, for many individuals such as the aged or those suffering from infirmities, an increase in caloric output is impossible or at least inadvisable. Therefore, some way must be found to reduce the caloric input.

Because of the nature of the obesity problem, any product to reduce the individual's appetite must be of such a character that administration can safely and comfortably extend over a prolonged period. Products such as amphetamine and 2-amino-1-phenylpropane, have been used for this purpose, but when administered in sufficient quantities to induce anorexia, the patient may experience a number of undesirable side effects. For example, the stimulating effect may be that an appetite depressant dose taken shortly before the evening meal may make it difficult for the patient to sleep without sedation. Work on this problem has, therefore, been directed toward isolation and separation of anorexia effects from those which produce an anti-depressant or hypertensive activity.

It also has been noted recently that a number of the compounds which are active as appetite depressants cause monoamine oxidase inhibition and produce the side effects and toxic reactions associated with such inhibition. These include such effects as constipation, difficulty in micturition, blurred vision, dryness of mouth and impotence. Ordinarily these effects are noted only with a marked overdose, but their appearance at normal therapeutic doses in sensitive individuals is a distinct probability. Other side effects such as fluid retention, skin alterations, sweating, nausea and headache have been reported.

Some patients receiving compounds causing monoamine oxidase inhibition experienced hypertension and severe headaches after ingesting quantities of aged cheese and other foods containing tyramine such as certain beers, wines and yogurt.

It is highly desirable, therefore, that a compound to be used as an appetite depressant produce a minimum hypertensive and stimulant response. It is also desirable that an appetite depressant not cause monoamine oxidase inhibition.

It is an object of this invention, therefore, to provide a compound which is a good appetite depressant while exhibiting a minimum of side effects.

It is a further object of this invention to provide a compound which is an appetite depressant and causes very little stimulant type side effects.

It is a still further object of this invention to provide a compound which is an appetite depressant and relatively free from monoamine osidase inhibitory activity.

These and other objects are achieved in general through the provision of a substituted phenethylamine having the structural formula wherein R and R.sub.1 are each hydrogen, halogen, trifluoromethyl, diloweralkylamino, loweralkoxy and loweralkyl; R.sub.2 is hydrogen, phenyl and loweralkyl; R.sub.3 is hydrogen, straight and branched loweralkyl, aryl and trifluoromethyl; R.sub.4 is hydrogen, loweralkyl, loweralkanoyl and lowercarbalkoxy; and X is cycloalkyl, cycloalkyl-loweralkyl, and its non-toxic acid addition salts.

In addition to the above definitions, this invention contemplates compounds, wherein R and R.sub.1, when at the 2- and 3-positions respectively, together form a phenyl ring, which have the structural formula and compounds wherein R and R.sub.1 when at the 3- and 4-positions respectively, together form a methylene dioxy ring system of the formula

Generally, these compounds are prepared by reacting an amine derivative of the formula NH.sub.2 --X wherein X is as previously described, with an apporpriately substituted phenylacetone of the structural formula wherein R, R.sub.1, R.sub.2 and R.sub.3 are each as previously described. This reaction is carried out in an inert solvent, by which is meant a solvent system which neither reacts with the reactants or products, nor otherwise interferes with the reaction, and yields a com-pound of the formula This compound is then reduced by an appropriate reducing agent such as sodium borohydride or lithium aluminum hydride, or by catalytic reduction, or by other known reducing agents, to yield the product of Formula I wherein R.sub.4 is hydrogen. Other radicals may be substituted for hydrogen in the position indicated by R.sub.4 by acylation or by acylation followed by reduction. An ester or alkanoyl halide may be used for the acylation.

The compounds of this invention exhibited activity as anoretic agents when administered orally or subcutaneously to rats in an amount equal to from about 0.001 and about 0.1 millimoles per kilogram of body weight. The compounds may be administered orally, for example, as the base or as the hydrochloride salt in a saline solution or in a capsule; administration may also be as a powder in a capsule or in tablet form, these preparations being made according to the usual procedures.

In order to better illustrate this invention, the following examples are presented to demonstrate a few specific embodiments of this invention and are not intended to limit same thereby.

EXAMPLE 1

p-Chloro-N-(cyclopropylmethyl)-.alpha.-methyl-phenethylamine

To 600 ml. of benzene is added 50.0 grams of p-chlorophenyl-acetone and 22.8 grams of cyclopropylmethylamine. The mixture is heated to reflux employing a Dean-Stark water separator and refluxed until no more water separates. The reaction mixture is then concentrated and the crude ketimine isolated. The crude ketimine is dissolved in 600 ml. methanol and the solution is cooled in an ice bath. To this cooled solution is added 22.4 grams of sodium borohydride portionwise with stirring, and the reaction mixture is refluxed for 4 hours. The solution is concentrated and 400 ml. of water is added.

The mixture is rendered alkaline with 60 ml. of 45 percent aqueous potassium hydroxide and 60 grams potassium hydroxide pellets and the resulting oily mixture is extracted three times with ether. The combined ether solutions are washed once with water and dried over anhydrous magnesium sulfate. The solution is then filtered, concentrated and distilled yielding 47.3 grams of p-chloro-N-(cyclopropylmethyl)-.alpha.- methyl-phenethylamine having a boiling point of 107.5.degree.-109.degree. C, at 1.3 mm, n.sub.D.sup.25 1.5233.

The acid-addition salts of these compounds are prepared by dissolving the base obtained in accordance with the procedure outlined above, in anhydrous ether and adding the acid corresponding to the salt desired. For example, the hydrochloride salt of the compound prepared according to Example 1 is prepared by dissolving the 47.3 grams of p-chloro-N-(cyclopropylmethyl)-.alpha.-methyl-phenethylamine in 700 ml. of anhydrous ether and the mixture is cooled in an ice bath. To this solution is added ethereal hydrochloric acid dropwise with stirring precipitating the hydrochloride salt out of solution. The acid is added until no more precipitate forms. In like manner, other acid-addition salts may be prepared such as the phosphate, sulfate, fumerate and oxalate, among others.

The procedure of Example 1 may be followed to prepare other phenethylamine derivatives by reacting the appropriately substituted phenylacetone with the desired amine derivative and reducing the product of this reaction to yield the desired compound. Following below in Table 1 is a list of compounds prepared in accordance with this invention showing the respective definitions of R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and X, with reference to Formula I, and the identifying physical constants. ##SPC2## ##SPC3## ##SPC4## ##SPC5##

The compounds of Examples 37 through 40 are prepared according to the method of Example 1 by substituting the correspondingly substituted phenylacetone as the starting material. For example, to prepare the compound of Example 37, the para-chlorophenylacetone is replaced with 3,4-methylene dioxy phenylacetone and the starting material for the compound of Example 38 is 1-naphthylacetone.

EXAMPLE 41

p-Chloro-N-(cyclobutylmethyl)-.alpha.-methyl-phenethylamine

A solution of 25.0 grams (0.188 mole)cyclobutylcarbonyl chloride in 200 ml. anhydrous ether is added dropwise with stirring to a cold solution of 32.0 grams (0.188 mole) of p-chloro-.alpha.-methylphenethylamine and 19.0 grams (0.188 mole) tri-ethylamine in 200 ml. anhydrous ether. The mixture is allowed to reach room temperature and stirred for 1 hour. The reaction mixture is then filtered and the resulting solid washed with water. The crude amide is then recrystallized from a methanol-water solution yielding 37.9 grams of N-(p-chloro-.alpha.-methyl-phenethyl)- cyclobutanecarboxamide.

A solution of 33.1 grams (0.131 mole) of the amide in 600 ml. anhydrous ether is added dropwise with stirring to a suspension of 9.92 grams (0.262 mole) lithium aluminum hydride in 500 ml. anhydrous ether and the mixture is refluxed for 20 hours. The excess lithium aluminum hydride and the product complex are decomposed by the successive addition of 9.9 ml. water 9.9 ml. 15 percent sodium hydroxide and 29.7 ml. water. The salts are then filtered, washed well with ether and the filtrate is dried over magnesium sulfate and concentrated. The crude product is distilled at 1 mm. pressure of mercury, the fraction boiling at 124.degree.--126.degree. C, n.sub.D.sup.25 1.5222 collected as p-chloro-N-(cyclobutylmethyl)- .alpha.-methyl-phenethylamine at a yield of 80.2 percent or 25.0 grams. Elemental analysis for C.sub.14 H.sub.20 CIN: Calculated: C=70.72%; H=8.48%; N=5.89% Found: C=70.66%; H=8.64%; N=5.77% The hydrochloride salt of the phenethylamine prepared according to Example 41 is prepared by treating a solution of the phenethylamine in anhydrous ether with ethereal hydrochloric acid. The hydrochloride salt is recrystallized from a methanol-ether solution.

EXAMPLE 42

p-Chloro-N-(cyclopentylmethyl)-.alpha.-methyl-phenethylamine

Following the procedure of Example 41, the p-chloro-N- (cyclopentylmethyl)-.alpha.-methyl-phenethylamine is prepared by sub-stituting cyclopentylcarbonyl chloride for the cyclobutylcarbonyl chloride. The resulting amide is then reduced to the amine as described in the foregoing procedure. The resulting p-chloro-N-(cyclopentylmethyl)- .alpha.-methyl-phenethylamine has a boiling point of 132-134.degree.C at a mercury pressure of 1 mm., N.sub.D.sup.25 1.5228. elemental analysis for C.sub.15 H.sub.22 CIN: Calculated: C=71.55%; H=8.81%; N=5.56% Found: C=73.11%; H=9.06%; N=6.02% The hydrochloride salt of the N-cyclopentylmethyl phenethylamine derivative of Example 42 is prepared in the same manner as described for the N-cyclobutylmethyl phenethylamine derivative.

The following example illustrates the acylation step employing an ester to replace the hydrogen at R.sub.4 of Formula I with a formyl group.

EXAMPLE 43

p-Chloro-N-(Cyclopropylmethyl)-N-Formyl-.alpha.-Methyl-phenethylamine

A mixture of 22.3 grams (0.1 mole) of p-chloro-N-(cyclo-propylmethyl)- .alpha.-methyl-phenethylamine prepared according to Example 1 and 11 grams (0.15 moles) of ethylformate were refluxed for 24 hours. The excess of formate was removed and the residue was distilled at reduced pressure to give 12.5 grams of oil boiling at 117.degree.-119.degree. C at 1.4 mm., N.sub.D.sup.25, 1.5385. elemental analysis for C.sub.14 H.sub.18 ClNO: Calculated: C=66.79%; H=7.21%; N=5.56%; Cl= 14.08% Found: C=66.86%; H=7.39%; N=5.61%; Cl- 14.07% The introduction of other substituents in the R.sub.4 position is illustrated by the following examples.

EXAMPLE 44

Preparation of p-Chloro-N-(Cyclopropylmethyl)-.alpha.-Methyl-phenethyl

Carbamic Acid Ethyl Ester

A solution of 21.6 grams (0.20 moles) of ethyl chloroformate in 200 ml. of ether was added dropwise with stirring in a period of about 15 minutes into a solution of 44.8 grams (0.2 mol) of p-chloro-N-(cyclopropylmethyl)- .alpha.-methyl-phenethylamine prepared according to Example 1 and 20.2 grams (0.2 mole) of triethylamine in 200 ml. of dry ether. A white precipitate formed immediately. The mixture was stirred for one hour at room temperature and filtered. The solid was dissolved in water and the aqueous solution extracted with ether. The ethereal solutions were combined, washed with water and dried over magnesium sulfate. Isolation of the product by filtration and concentration of the ethereal solution gave 44.6 grams of an oil as the crude ester. This was distilled to give 38.9 grams of p-chloro-N-(cyclopropyl-methyl)-.alpha.-methyl-phenethyl carbamic acid ethyl ester with a boil-ing point of 154.degree.- 157.degree.C at 1 mm., N.sub.D.sup.25, 1.5140. elemental analysis for C.sub.16 H.sub.22 ClNO: Calculated: C=64.97%; H=7.49%; N=4.73% Found: C=64.84%; H=7.49%; N=4.74%

EXAMPLE 45

Preparation of p-Chloro-N-(Cyclopropylmethyl)-N-Methyl-.alpha.-

Methyl-phenylamine

A solution of 33.35 grams (0.113 mole) of the carbamic acid ethyl ester of Example 44 in 200 ml. of dry ether was added dropwise with stirring to a suspension of 8.56 grams (0.226 mole) of lithium aluminum hydride in 1 liter of dry ether at a rate sufficient to maintain gentle reflux. When the addition was complete, the reaction mixture was refluxed and stirred for 2 hours. The complex was then cautiously decomposed by the successive addition of 8.56 ml. of water, 8.56 ml. of 15% NaOH and 28.78 ml. of water. The reaction mixture was filtered and dried over magnesium sulfate. The ether, after filtration from the drying agent, was evaporated and the residue was distilled to yield 22.5 grams of p-chloro-N-(cyclopropylmethyl)-N-methyl-.alpha.-methyl-phenylamine boiling at 114.degree.--116.degree. C at 1 mm. pressure, N.sub.D.sup.25, 1.5226. elemental analysis for C.sub.14 H.sub.20 ClN: Calculated: C=70.72%; H=8.48%; N=5.89% Found: C=70.81%; H=8.43%; N=5.80% The hydrochloride salt of the foregoing compound was prepared from the base with gaseous HCl in ether.

The compounds of this invention exhibit good biological activity, specifically as anoretic agents. It has been found that a dose comprising a minor proportion of the compounds of this invention in a major proportion of carrier when administered orally or subcutaneously to rats produces a marked reduction of food intake of the test rats over the controls. Water soluble compounds are usually administered subcutaneously in a saline solution containing 0.01 to 0.05 millimoles per ml.; water insoluble compounds are suspended in gum tragacanth (0.3 percent gum in water) and the effective dose administered orally in water suspension at the rate of 2 ml./kg.

The test procedure utilized to illustrate this biological activity is a relatively simple test. Two groups of four rats each are placed on a 5-hour feeding schedule, that is, the total feeding period for a 24 hour period is 5 hours for each group at the same time of the day, 7 days a week. Approximately one-half hour before the feeding time is to commence, the control group is administered saline solution and the test group is administered a dosage of the test compound. In this experiment, two different dosage levels of 0.011 and 0.044 mM./kg. of body weight were administered to different test groups. A measured amount of feed is given to both groups (the same amount for each group) and at the end of the 5 hour feeding period, the food remaining is measured to determine intake. The test animals are compared to the controls in accordance with the following scoring system: % Food Intake Less Rating than Controls 0 5 or less .+-. 6-19 1+ 20-39 2+ 40-59 3+ 60-89 4+ 90 & over

Following below is Table II showing the activity of a few species of the compounds of the instant invention based upon the above-mentioned scoring system. Except where noted, the rating is at a dose of 0.011 mM./kg. and at 0.044 mM./kg.

The side effects of the compounds also were observed and notes made of responses such as increased irritability, ataxia, salivation, convulsions, tail-lash and the like. These are noted as mild, moderate and severe; a rating of mild, however, also includes zero side effects and does not necessarily indicate the presence of some side effects.

Monoamine oxidase inhibition was also noted at dosage levels of 5, 10, 25, 50 and 100 mg./kg. of body weight. That those compounds of Formula I wherein X has four or more carbon atoms cause surprisingly little monoamine oxidase inhibition is apparent from the results shown in Table II.

TABLE II

Appetite Depressant Activity of Substituted Phenethylamines Compound Rating 0.011 0.044 Side MAOI* mM/kg mM/kg Effects _________________________________________________________________________ _ 1. p-chloro-N- cyclobutyl- .alpha.-methyl- 3+ 4+ mild phenethyl- amine 2. p-chloro-N- cyclopentyl- .alpha.-methyl- 1+ 3+ mild Neg. phenethyl- at 50 amine.sup.. HCl 3. p-chloro-N- cyclopropyl- methyl-.alpha.- 3+ 4+ mild Neg. methyl-phen- at 50 ethylamine.sup.. HCl 4. p-fluoro-N- cyclopropyl- methyl-.alpha.- 2+ 2+ methyl-phen- ethylamine 5. N-cyclopropyl- .alpha.-propyl-phen- .+-. 3+ ethylamine 6. p-chloro-N- cyclopropyl- 3+ 4+ .alpha.-methyl- phenethylamine 7. p-dimethylamino- N-cyclopropyl-.alpha.- 2+ 3+ moderate Neg. methyl-phen- to at 50 ethylamine severe 8. p-chloro-N- (3-hydroxy- propyl)-.alpha.- 1+ 2+ methyl-phen- ethylamine.sup.. HCl 9. p-dimethyl- amino-N- cyclobutyl- 3+ 3+ mild Neg. .alpha.-methyl- at 25 phenethyl- amine 10. m-trifluoro- methyl-N- cyclopropyl- methyl-.alpha.- 3+ 3+ mild Neg. methyl-phen- at 50 ethylamine.sup.. HCl 11. m-trifluoro- methyl-N- cyclopropyl- 1+ 3+ moderate .alpha.-methyl- to phenethyl- severe amine.sup.. HCl 12. m-trifluoro- methyl-N- cyclobutyl- 3+ (1) mild Neg. .alpha.-methyl- at 100 phenethyl- amine 13. N-cyclopropyl- methyl-p- (dimethylamino)- 3+ (2) mild Neg. .alpha.-methyl- at 50 phenethylamine 14. N-cyclopropyl- .alpha.-methyl-p- (trifluoro- 3+ (2) mild Neg. methyl)phen- at 10 ethylamine 15. p-chloro-N- (cyclopropyl- methyl)-N- 2+ 3+ mild Neg. methyl-.alpha.- methyl-phen- ethylamine

FOOTNOTE: * Monoamine oxidase inhibition - dose indicated in mg./kg.

FOOTNOTE: (1) at 26 mg./kg. administered orally--------------------------- ------------------------------------------------(2) at 12-13 mg./kg. administered subcutaneously

The compounds of this invention may be administered as bases, or more conveniently as acid-addition salts. The route of administration may be oral, intraperitoneal, subcutaneous, and intravenous, among others. As can be observed from the Table above, these compounds exhibit marked activity as appetite depressants without undesirable side effects.

Claims

1. A compound of the formula wherein R is cyclopropyl or cyclopropylmethyl, or a pharmaceutically

2. A compound in accordance with claim 1 wherein R is cyclopropyl,

3. A compound in accordance with claim 1 wherein R is cyclopropylmethyl, N-cyclopropylmethyl-.alpha.-methyl-3,4-(methylenedioxy)phenethylamine.