Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.


  1. Advanced Patent Search
Publication numberUS3689504 A
Publication typeGrant
Publication dateSep 5, 1972
Filing dateDec 24, 1970
Priority dateDec 24, 1970
Publication numberUS 3689504 A, US 3689504A, US-A-3689504, US3689504 A, US3689504A
InventorsBruce Wayne Horrom
Original AssigneeAbbott Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
N-substituted -alpha-methyl-3,4-(methylenedioxy) phenethylamines
US 3689504 A
N-substituted- alpha -methyl-3,4-(methylenedioxy)phenethylamines of the formula:
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent Horrom 1 Sept. 5, 1972 [54] N-SUBSTITUTED -ALPHA-METHYL- 3,4-(METHYLENEDIOXY) PHENETHYLAMINES [72] inventor: Bruce Wayne Horrom, Waukegan,


[73] Assignee: Abbott Laboratories,

Chicago, ill.

[22] Filed: Dec. 24, 1970 [21] Appl. No.: 101,441

Related US. Application Data [62] Division of Ser. No. 770,126, Oct. 23, 1968,


North [56] References Cited UNITED STATES PATENTS 1,073,966 9/1913 Decker ..260/340.5

OTHER PUBLICATIONS Horrom Chemical Abstracts, Vol. 71, 1969, Col. l2786g Primary Examiner-Alex Mazel Assistant Examiner-James H. Turnipseed AttorneyRobert L. Niblack [57] ABSTRACT N-substituted-a-methyl-3 ,4-( methylenedioxy)phenethylamines of the formula:

wherein R is cyclopropyl or cyclopropylmethyl. The compounds are useful as appetite depressants,

3 Claims, No Drawings N-SUBSTITUTED -ALPHA-METHYL-3 ,4- (METHYLENEDIOXY) PHENETHYLAMINES CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional application of US. Ser. No. 770,126, filed Oct. 23, 1968 now abandoned.

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 individuals 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-l-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 antidepressant 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 phencthylamine having the structural formula Ra Ra R4 a II H-N-X 7 u 7 II and compounds wherein R and R when at the 3- and 4- positions respectively, together form a methylene dioxy ring system of the formula I CH: III

Generally, these compounds are prepared by reacting an amine derivative of the formula NI-I X wherein X is as previously described, with an apporpriately substituted phenylacetone of the structural formula uail.

wherein R, R R and R 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 is hydrogen. Other radicals may be substituted for hydrogen in the position indicated by R, by acylation or by acylation followed by reduction. An ester or alkanoyl halide may be used for the acylatron.

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. 1

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)-a-methylphenethylamine is added stanes whyd P r ions 1.

with stirring, and the reaction mixtureis refluxed for 4 hours. The solution is concentrated and 400 ml. of water isadded.

The mixture isrendered alkaline with 60 ml. of percent aqueous potassium hydroxide and 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)-a-methylphenethylamine having a boiling point of l07.5l09 C, at 1.3 mm, n 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)-a-methyl-phenethylamine in 700 ml. ofanhydrous 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, fumera te and oxalate, am or rg others. i w

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. Followingbelow in Table 1 is a list of compounds prepared in accordance with this invention showing the respective definitions of R, R R R R and X, with reference to Es vl nd e ntifyin P a in t TABLE I B.P. in 0., Example R R1 R2 R3 R4 X Salt M.P. in 0. mm.

2 H H H CH; H H01 205-207 109-11215 3 4-01 5-01 H CH1 H 125 127/0.e

4 4-F H H CH3 H 116-119l6 5 5-CF; H H -CH3 H H01 197. 15-199 82-84/0.6

6 4-N(CH;) H H CH3 H CH 1 2(HC1) 235-236 127-130/1 7 H H H H 20s 210/1 2 a n H H CH CHzCHa H G 1181'20/5.3

0 11 H H CH,CH; H q 107-110 10..v 4-1 ll 431-17011, 0II,CH, 1! 1 1101 177-177. rs mums u ll 4 (,I H [1 --Ull II In? Ito/z lOl052 050l Table l-Continued B.P. in 0., Example R R1 R1 R9 R4 X Salt M.P. in 0. mm. 12 -01 H H CH3 H 3 H01 129-130 13 2-01 H H --CH3 H H01 119-120 11s.5-120/4.s

14 461 H "H H 1645-16613 16 4-Cl H Q CH3 H q Mil-164.8 16 4-01 5-C1 H CH H H01 172-173 122-124/1.2 17 4-F H H CH3 H 6 H01 138-138.6 1213-1214/06 1s H H H OF; H H01 122-123 8991/9.2

19 S-CF; H H CH3 H H01 124-126 100-101/5.4

20 H H -CH; H H 1 H01 139-140 99-100/5.3 21 H H Q H H Q HCl 134-1345 144-145/1.4

22 N 4-OCH; E-OCH; H CH:CH; H l 152-156/3 23 4-0CH B-OCH; H CH3 H 4 H01 129-132 130132/125 24 000113 H H -CH; H 4 H01 142-143 147-151/02 25 11-01 H H c H 1 H01 161.5162.5 102403 26 4-N(CH3) H H CH3 H q 124/0.9 27 L01 1 H mm fig H --CH4.C=CH H01 199-1995 115-117 1, 2s 4-01 H H CH3 H -CH2CH2CH2OH H01 122-123 137-14150, 29 4-N(CH;)2 H H CH3 H 2(HC1) 236-236 127-130/1 3o 4-01 H H C a H 1119-1015 05 31 4-01 H H OH1 H H01 -172 114-119 03 32 401 H H C a H H01 224-225 1111-122 09 H3. 0-0 F; H H CH3 H H01 133-130 77-30/0. 7

34 5-02; H H CH3 H I H01 159.5-160.5 114-12 35 5-01 3 H H CH3 H H01 187187.5 134-137 5 30 4-N(OH3)2 H H -CH1 H 2(H01) 184 127-130/07 37 3,4-methyl0n9 dioxy H CH1 II 123-1361 CHr- TABLE I-Continued n.1 in e (1., Example R R1 R9 R3 R4 Salt. MA. in min.

38 2,3-phenyl H CHa H 144-145/0.9

39 2,3-phenyl H a H 150-154/1A5 40 3, -methylene dioxy H CH: H HCl 186-187 110111/0.7

*In the above table, each boiling pointisexpressed in C. at a particular pressure of mercury expressed in millimeters (mm.) of pressure.

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 parachlorophenylacetone is replaced with 3,4-methylene dioxy phenylacetone and the starting material for the compound of Example 38 is l-naphthylacetone.

EXAMPLE 41 p-Chloro-N-(cyclobutylmethyl)-a-methylphenethylamine 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-a-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-(pchloro-a-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. 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 l24- 126 C, n,, 1.5222 collected as p-chloro-N-(cyclobutylmethyl)-a-methyl-phenethylamine at a yield of 80.2 percent or 25.0 grams.

Elemental analysis for C I-I CIN: Calculated: =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)-a-methylphenethylamine Elemental analysis for C l-l ClNz Calculated: C=7 1.55%; l-l=8.8 1%; N=5.56% Found: C=73.l 1%; 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., of Formula I with a formyl group.

EXAMPLE 43 p-Chloro-N-(Cyclopropylmethyl)-N-Formyl-a-Methylphenethylamine A mixture of 22.3 grams (0.1 mole) of p-chloro-N- (cyclo-propylmethyl)-a-methyl-phenethylamine prepared according to Example I 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 l l7-l 19 C at 1.4 mm., N 1.5385.

Elemental analysis for C H CINO: Calculated: C=66.79%; H=7.2l%; N=5.56%; Cl=l4.08% Found: C=66.86%; H=7.39%; N==5.6l%; Cl-l4.07%

The introduction of other substituents in the R position is illustrated by the following examples.

EXAMPLE 44 Preparation of p-Chloro-N-(Cyclopropylmethyl)-a- Methyl-phenethyl Carbamic Acid Ethyl Ester A solution of 2l .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)-a-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 Elemental analysis for C H ClNO:

C=64.97%; H=7.49%; N=4.73% C=64.84%; H=7.49%; N=4.74%

. EXAMPLE 45 Calculated: Found:

Preparation of p-Chloro-N-(Cyclopropylmethyl)-N- Methyl-a- 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 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-a-methyl-phenylamine boiling at ll41 16 C at 1 mm. pressure, N 1.5226.

Elemental analysis for C H ClN: Calculated: C=70.72%; H=8.48%; N=5.89% Found: C=70.81%; l-l=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 0.01 l 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 determineintake. 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 l+ 20-39 2+ 40-59 3+ 60-89 4+ & 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 0.01 l 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 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 Compound 0.01 1 mM/ kg MAOI l. p-chloro-N- cyclobutyla-methylphenethylamine 2. p-chloro-N- cyclopentyla-methylphenethylamine-l-ICI 3. p-chloro-N- cyclopropylmethyl-amethyl-phenethylamine- I-lCl 4. p-fluoro-N- cyclopropylmethyl-amethyl-phenethylamine 5. N-cyclopropyla-propyl-phenethylamine 6. p-chloro-N- cyclopropyla-methylphenethylamine 7. p-dimethylamino- N-cyclopropyl-amethyl-phenethylamine 8. p-chloro-N- 3+ 4+ mild 3+ mild Neg.

3+ moderate severe Neg. at 50 propyD-mmethyl-phenethylamine-HCI 9. p-dimethylamino-N- cyclobutyla-methylphenethylamine l0. m-trifluoromethyl-N- cyclopropylmethyHzmethyl-phenethylarnine- I l. m-trifluoromethyl-N- cyclopropyla-methylphenethylamineHCl 1 fm -tnfluoromethyl-N- cyclobutyla-methylphenethylamine I 3. N-cyclopropylmethyl-p- (dimethylamino)- a-methylphenethylamine l4. N-cyclopropyla-methyl-p- (trifluoromethyDphenethylarnine l5. p-chloro'N- (cyclopropylr'nethYlI-N- methyl-amethyl-phenethylamine mild mild

moderate severe mild mild

Neg. at 25 Neg. at 50 Neg. at I Neg. at 50 Neg. at


* Monoamine oxidase inhibition dose indicated in mgJkg. l at 26 mgJkg. administered orally (2) at 12-! 3 mgJkg. administered subcutaneously wherein R is cyclopropyl or cyclopropylmethyl, or a pharmaceutically acceptable acid addition salt thereof.

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

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

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US1073966 *Nov 25, 1912Sep 23, 1913Farbenfab Vorm Bayer F & CoAlkylhomopiperonylamins and the process of making them.
Non-Patent Citations
1 *Horrom Chemical Abstracts, Vol. 71, 1969, Col. 12786g
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3886284 *May 15, 1973May 27, 1975Millmaster Onyx CorpAmino derivatives of terrasubstituted benzene compounds
US3898281 *Apr 25, 1974Aug 5, 1975Syntex CorpNaphthyl acetaldehyde imines
US3944675 *Jul 16, 1973Mar 16, 1976Schering CorporationSubstituted aryl and aralkyl amides in the treatment of parkinsonism
US3968246 *Jul 10, 1975Jul 6, 1976Millmaster Onyx CorporationDisinfecting with N-trimethylbenzyl ethylenediamine
US4034113 *Apr 15, 1976Jul 5, 1977Shulgin Alexander TTreatment of senile geriatric patients to restore performance
US4035508 *Dec 18, 1975Jul 12, 1977Sandoz, Inc.Hypolipidemic agents
US4053509 *Mar 15, 1973Oct 11, 1977Schering CorporationAdamantane-carboxamides or cyclopropane-carboxamides, cns drugs on
US4876282 *Nov 25, 1987Oct 24, 1989Eli Lilly And Company1-Phenylalkylamines as selective serotonin uptake inhibitors
US4996235 *Nov 25, 1987Feb 26, 1991Eli Lilly And Company3,4-diphenylbutanamines
US5008292 *Nov 25, 1987Apr 16, 1991Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T.Pesticidal method
U.S. Classification549/440, 564/374, 564/381, 564/378, 560/27, 564/248, 564/382, 549/442, 564/219
International ClassificationC07D317/58
Cooperative ClassificationC07D317/58
European ClassificationC07D317/58