US2784141A - Tranquilizing composition comprising alkyl aminoethyl esters of benzilic acid and salts thereof - Google Patents

Description

March 5, 1957 E. s. A. JAcoBsl-:N 2,784,141

TRANQUILIZING COMPOSITION COMPRISINGl ALKYL AMINOETHYI.. ESTERS OF BENZILIC ACID AND SALTS THEREOF INVEN TOR. ER/K 5.4. JACosE/v www ATTRA/EY March 5, 1957 E. s. A. JAcoBsEN 2,784,141

TRANQUILIZING COMPOSITION COMPRISING ALKYL AMINOETHYL ESTERS OF BENZILIC ACID AND SALTS THEREOF fR/A 5. A. J/ICOBSE/V United States Patent O TRANQUILIZING COB'IPOSITION COB/[PRISING ALKYL AMINOETHYL ESTERS F BENZILIC ACID AND SALTS THEREF Eril: S. A. Jacobsen, Copenhagen, Denmark, assigner, by mesne assignments, to Merck & Co., Inc., Rahway, NJ., a corporation of New Jersey Application August 27, 1954, Serial No. 452,626 Claims priority, application Denmark May 13, 1954 6 Claims. (Cl. 167-65) This invention relates to therapeutic compositions useful for treating diseases of the central nervous system.

More particularly, it has now been discovered that novel compositions containing, as the active medicament, one or more of the dialkylaminoethyl esters of benzilic acid, their hydrohalides, their salts with mineral acids such as sulfuric or phosphoric acids, or their salts with any of the commoner organic acids such as acetic, citric or tartaric acids, are valuable therapeutic agents, capable lof oral administration as sedatives and for the treatment of diseases of the central nervous system.

Although the dialkylaminoethyl esters of benzilic acid, as, for example, the dimethylaminoethyl, diethylaminoethyl, and di-isopropylaminoethyl esters, may be ad ministered parenterally in the form of solutions, this invention is particularly concerned with the preparation of dosageaunit forms of these therapeutically active esters, or of their equivalent therapeutically-eifective salts, in which dosage-unit form the active`medicament is combined with a solid pharmaceutical carrier.

For the treatment of diseases of the central nervous system it has been found advantageous to administer approximately 0.5 to 2.0 milligrams of the benzilic acid ester (or its therapeutically equivalent salt) three times daily. However, the dosage of the particular dialkylaminoethyl ester of benzilic acid used will vary considerably, such as with the age of the patient, the condition of the patient, and the character and degree of progression of his disease. Eiective therapeutic dosages may sometimes be as low as 0.1 milligram, and in series disease conditions the dosage may advantageously be as high as 10 milligrams. The frequency of administraf tion may vary widely.

The benzilic acid ester utilized, more particularly one of the Vspecific dialkylaminoethyl esters herein specified, or the salt of the benzilic acid ester such asany' of its hydrohalides, or its salts with thecommoner mineral acids such as sulfuric acid or phosphoric acid, or with the commoner organic acids such as acetic, citric, or tartaric-acids, may be dispensed in any of the usual dosageunit forms utilized for orally administered pharmaceutical preparations. For example, the dialkylaminoethyl ester of benzilic acid (or mixture of two or more of such esters), or salt thereof, may be dispensed as tablets, capsules, or pills, or in any other desirable pharmaceutical form, preferably compounding the particular dosageunit form so that it contains a dosage within the therapeutically-etfective amounts indicated. The active medicament may be in dosage-unit form for a single daily therapeutic dose, in smaller units for multiple doses, or in larger units for division into single doses. Obviously, in addition to the therapeutically-eftective agent or medicament (i. e., the benzilic acid ester or its salt) there may also be present excipients, binders, llers, extenders, and other therapeutically-inert ingredients necessary in the formulation of the active medicament into a pharmaceuticalpreparation in dosage-unit form.

, hydrochlorides),

Y 2,784,14l Patented Mar. 5, 19:57

In accordance with the invention a therapeutic composition can be prepared in which the benzilic acid ester (or its salt) is the predominant and primary active me-v` dicament, and in which it is supported or suspended in a.

solid, substantially non-toxic pharmaceutical carrier, such as lactose, starch, sugar and/or dextrin, together with other inert excipients commonly used in the preparation of tablets such as stearic acid, magnesium stearate, gelatin and/or acacia. The dosage of active medicament in each tablet of a dosage-,unit form of the therapeutic composition may range from 0.1 milligram of the ester of benzilic acid to l0 milligrams of the therapeutically-active ester, tablets containing about 0.5 milligram of the dialkylaminoethyl ester of benzilic acid (or of its salt) being a preferred therapeutic form of the invention.

A dosage which has been found satisfactory for the treatment of diseases of the central nervous system is from 2 to 3 of such tablets containing 0.5 milligram of the benzilic acid ester (or its salt) together with other inert non-toxic medicinal carrier ingredients of the type specified above. Usually 2 or 3 of such tablets, capsules, pills, etc., containing a quantity of active medicament within the range specified, will constitute a daily dose for patients suffering with disorders of the central nervous system.

As the benzilic acid ester constituting the active medicament in the novel dosage-unit forms comprising the invention, it is preferred to use an ester of the structural formula:

wherein R1 and R2 represent methyl, ethyl, or isopropyL;

V tically-equivalent salts) although the dimethylaminoethyl and di-isopropylaminoethyl esters possess about the same order of activity. Since the diethylaminoethyl ester of benzilic acid, and its salts, especially the hydrochlorides, have been subjected to the most extensive clinical study, this ester is preferred for use in preparing the novel dosage-unit forms.

In addition to utlizing the basic esters themselves, equally satisfactory results are secured by the use of salts of these esters, such as the hydrohalides (especially 'the salts with readily-tolerated mineral acids such as sulfuric acid or phosphoric acid, and salts with the commoner organic acids such as acetic, citric and tartaric acids. Y i' The pharmacological or therapeutic effects in question, the manner in which they may be ascertained and evaluated, the procedure by which the activity of the agents in question can be tested or evaluated, the types of diseases or disorders against which the compositions vprepared in accordance with the invention are effective, the conditions under which the desired therapeuticelects will be secured, and the doses tobe used will nowr'be discussed. They will also be illustrated by examples of biological and clinical experiments and tests. A i" The invention is not, however, to be limited to the use of the therapeutic compositions of the invention only in the cases mentioned, nor in cases which are directly analogous thereto or derivable therefrom. These biologiused, and which will being' utilizedV forA statisticalI treatment.

Many susbtances which act specifically on certain of the functions of the central nervous system are already known to medicine. For example, morphine acts upon the centers dealing with pain perception; apomorphine acts upon the emetic center; and a number of hypnotics are known which are active principally on the sleeping centers.

Several of the known substances which are active as regards functions of the central nervous system show a similarity to atropine, insofar as their action on peripherie organs concern. The action of these substances on the central nervous system has been the subject of but little systematic research.

It has been known from prehistoric times, however, that parts of plants subsequently proven to contain atropine give rise to physical confusion. Moreover, the sedative action of salts of scopolamine has been utilized in psychiatry for a considerable period of time. Nevertheless, it is still not known which parts of the central nervous system are specifically acted upon by atropine or scopolamine.

Recently a considerable number of substances which actin a manner similar to that of atropine, insofar as their action on peripherie organs is concerned, have been prepared, these substances also having the property of inuencing centers of the central nervous system. Several of these substances appear to act specifically on certain individual functions of the central nervous system, in contradistinction to the more diffuse action of atropine and scopolamine. By way of example, the following su stances may be mentioned: pethidine, which acts upon the centers dealing with pain perception, and diphenhydramine and similarly-acting substances which have an effect upon certain functions within the equilibrium system so that they are capable of repressing seasickness. Among the latter group of substances certain, such as diphenhydramine itself, also are active on the sleeping center. Others act upon the extra pyramidal system, so that they can be used as therapeutic agents against the rigidity associated with paralysis agitans.

it is known that atropine, as well as substances which act in a similar manner on the peripherie organs as atropine, have in common the capability of depressing the reaction power of the receptive organs against acetylcholine. The dialkylaminoethyl esters of benzilic acid and their salts which are used to prepare the therapeutic compositions herein described and claimed also have these properties. It has been known for a long time, however, that even substances which are closely related to each other chemically may have different specific actions upon the various organs belonging to the peripherie system. Thus, the action of methyl atropine upon the excretion of saliva is up to 1.5 times that of atropine, whereas its mydriatic action is only one-tenth that of atropine. An analogous difference in the specic action on various centers of the central nervous system can be observed by comparing substances having such action even in cases where this specific action has hitherto remained unknown, or but little known, and in cases where it is observed with respect to centers other than those already mentioned, including those centers which it has not hitherto been possible to inuence specifically in a pharmacodynamic manner. By this, substances possessing hitherto unknown pharmacodynamic activity may be discovered.

One purpose of the present invention is the preparation of therapeutic compositions which contain chemical substances which, upon administration, are capable of influencing, i. e., depressing certain centers in the frontal part of the thalamus. Such influencing is important for obtaining effects similar to those aimed at in lobotomy, which is a surgical operation in which all nerves in the foremost part of the cerebrum are cut. It is assumed that the therapeutical effect is due mainly to breaking the connection between the cerebral cortex of the front lobe and the above-named centers, which means that a superior 4 i function which has developed in these centers is brought under control. On account of the surgical risk, and because the effect of the operation cannot as yet be completely predicted, lobotomy operations will not be undertaken on patients the symptoms of which are not severe, or where they are assumed to be of a temporary nature.

Another purpose of the present invention is the preparation of therapeutic compositionsV containing substances capable of inlluencing the vegetative centers of the hypothalamus. These centers directly control the functions of the autonomous nervous system. In addition, they exercise control by way of the hypophysial part of the hormonal system. It is assumed that these centers are connected with the superior centers of the brain. It is thereby explainable that various psychical processes may be accompanied by various reactions of the autonomous nervous system of which blushing for shame, whitening with anger, sweating in state of terror, etc. are well known examples. Psychosomatic diseases are presumably'developed by means of these centers, and often result in a biased balance within the functions of the autonomous nervous system and the hormonal system which may give rise to chronic diseases. Among these, there may be mentioned various forms of gastric ulcers, eczema, increased blood pressure and asthma.

Obviously if substances could be selected or produced, or means specified, by which some or more of the said centers ofthe frontal part of thalamus or hypothalamus could be specifically depressed so that on appropriate dosing no substantial or disturbing influence on the central or peripheral part of the nervous system, outside of said centers, would occur, or so that the action on specific centers within the said groups could be further specialized,

important pharmacotherapeutic eifects of a hitherto un attainable character could be secured. These effects could be utilized in human therapy, and it is the main purpose of the present invention to produce compositions having these therapeutic effects, useful in both human and veterinary therapy.

rl`hese desirable pharmacotherapeutic effects are exhibited by the dialkylaminoethyl esters of benzilic acid and their salts, as previously pointed out. These esters of benzilic acid have the type formula:

wherein R1 and R2 represent methyl, ethyl, or isopropyl, and R1 and R2 may be the same or different alkyl radicals chosen from this group.

The esters are preferably used in the form of their salts, for instance salts with hydrohalic acids such as the hydrochloride, hydrobro'mide, etc., or salts with the commoner mineral acids such as sulfuric acid or phosphoric acid, or with the commoner organic acids such as acetic, citric or tartaric acid. Since the salts are the full equivalent of the esters themselves, and may be used interchangeably therewith, it is the intention of this disclosure that the term ester or esters may be construed as including the salts of these esters.

As mentioned above, these substances have `the common effect of depressing the reaction power of peripherally recepting organs to acetyl choline. @n isolated sections from the intestines, in Vitro, these esters of benzilic acid and their salts exhibit atropine-'like effects,

Moreover, it is a property, common to all the esters in question, that they are capable of prolonging the period ol' anesthesia in, for example, mice alter the intraperitoneal administration of enhexymal. This effect has previously been observed for a number of substances which produce, as an additional effect, a strong desire to sleep on the part of the patient. However, it has been found that the anesthesia-prolongi'ng` effect may be associated Vwith substances which do not produce sleepiness in man, and the benzilie acid esters -utilized in preparing the therapeutic compositions of this invention, as well as their salts, appear to have these desirable properties. There has been found no parallel effects between their anesthesiaprolonging elfect, `and their action against seasickness. Those substances in which the anesthesia-prolonging eect is not associated with the effect of counteracting seasickness are of special importance in connection with the present invention. v

The anesthesia-prolonging effects observed are thus representative of attack in functions other than the abovenamed ones. That the point of attack in spite of the greater specificity includes the foremost centers in the thalamus is in accord with the fact that atropine does not show the anesthesia-prolonging eifect in question. Scopolamine, which has been used as a sedative for many years in psychiatrics, on the other hand, must be assumed to act upon the centers ythe influencing of which is also the aim of the present invention (although the action of scopolamine is not nearly as speciiic as that of the esters ot benzilic acid and their salts comprising the therapeutically-active constituent in the novel products of this invention). Scopolamine has a weak, but clearly ascertainable, effect in the prolongation of anesthesia.

The therapeutic effectiveness of the dialkylaminoethyl esters yof benzilic acid and their salts may be directly demonstrated by tests with experimental 'animals which require them to carry out, under a certain psychical strain, actions in which they have been previously trained The strain `is increased to a point at which certain objective signs of disquietude or other psychical imbalance or neurosis can be observed and measured, and under these conditions the inuence of the substances in question and of other sedatives of known kind may be Atried out and compared.

Two representative experiments of ythis kind will now be described, the explanation being best understood with reference tothe curves shown in the drawing.

EXPERlMENT I Feeding experiments on cats The cats are trained to open a box and extract a morsel of fodder from the same on the sound of a bell which is actuated by the cats themselves by treading on a pedal placed at a certain distance from the fodder box within the spacy feeding cage. When a cat has been trained sufliciently in this behavior for the purpose Iof the experiment it will actuate the bell signal regularly during the meal and then walk rto the box open the same, extract the morsel, walk back to the pedal, a-ctuate the signal, walk to the box, etc., the whole cycle being carried out vin a regular manner and requiring only 3-10 seconds. The experiment is planned so that 50 to 100 morsels lare required for a meal and it will not be until the cat is nearly satisfied that it will start using longer time for the lactuating of the signal prior to eventually discontinuing completely the described cycle. Now the box is so constructed that a blow of air can be produced directed against the head of the cat when immersed into the box to extract a morsel. The cats are strongly impressed by these blows of air.

yIn the drawing Fig. l -shows diagrams corresponding 1l feeding operations with one and the same cat on the days stated on each individual diagram. The labscissa corresponds to the number of signals and subsequent 'openings ot' the box, whereas the orinate indicates the time lapse between two subsequent openings of the box including the time used by the animal to actuate the signal. At the times indicated by P a blow of air has been released.

One hour prior to each of the feeding operations il-l lustrated the cat has received an injection, theV composition of which is unknownto the assistant but which has been stated on the diagram'. "B'e'nzytyl" means hydrochloride' of diethylaminoethyl ester of benzilic acid; trasentin means diphenylacetoxyethyl dethylamine in the form of its hydrochloride. All injections are 1 ml. It will be seen that lafter injections of salt water or -trasentin the cat is distinctly inquieted by the 'blows of air, whereas after an injection of benzytyl it behaves practically vas if no blows of air had been given. Numerous experiments of this kind have given similar results in all cases.

EXPERIMENT Il Rats in an electrical cage Yfor instance curved back, stretched forelegs, raised Ifur and erected tail are evaluated two points each whereas expressions of relax such as natural attitude, relaxed tail, cleaning itself and examining Ithe cage are charged each- 2 points. After 13 to 15 impulses an injection with a 4substance, the composition of which is unknown to the lassistant, is given, and the experiment is continued until 56 impulses have been given.

Fig. 2 shows 8 diagrams concerning such experiments carried out, on the dates started, with one and the same rat. The abscissa represents the number of impulses, each subsequent impulse being represented `by a point on the yaxis 1 mm. to the right of the one representing the previous impulse. The ordinate states the number of points charged in consequence of the appearance and behavior of the rat between the impulses, the maximum number of points, viz. l0, meaning that the rat showed simultaneously all the expressions of strain which are comprised by the observation.- Fields filled in with black at the Y foot of the diagram indicate the cases where the rat has responded to the acoustic signal by jumping into the other hall:` -of the cage (conditioned reaction), whereas an electrical .impulse has been necessary in order to make the rat jump through the passage connecting the half of the cage in all cases where the lield has no-t been filled in. An arrow shows in the 2nd, 3rd, and 4th, andthe 6th, 7th, and 8th diagram. the time when an injection was given, and the nature of the injected uid is stated on each of the diagrams. In the experiments represented by the first and 5th diagram, no injection was given. The meaning of the designation benzytyl has been stated above, whereas amidryl means benzhydryl-oxyethyl-dimethylamine (diphen'hydramine) in the 'form of its hydrochloride. All injections are of 1 ml. lt will be seen that benzytyl has exerted a strong sedative effect and that injections of this substance tend to produce an increase in the number of conditioned reactions. Below, the results of experiments on animals, carried out with a number of different substances, have been stated in the form of a table .the columns of which are designated l-XIII which designations have the following significations:

I: LD50 for mice, calculated as milligram per 20 grams Vof body weight. In-the case of benzhydryl-oxethyl-trimethylammonium bromide the determination has, however, been carried out with the corresponding iodide.

II: Anesthesia-prolonging effect in mice after the intraperitoneal injection of enhexymal according to Winther and co-workers (I. Pharm. 94, 7, 1948), the effect of the'r antihistaminic substance, diphenhydramine, being fixed to 2.5. v Y Y III: Evaluation of the sedative effect in rats during the experiments in 'electrical cage described above, taking into consideration the necessary doses. 'The' evaluation O--no eiect. i=moderate effect on comparatively great doses.

From the data tabulated, it appears that the therapeutic effects described are characteristic of the particular esters of benzilic acid, and their salts, as enumerated. In the experiments carried out with rats (but not in the experiments with cats) as described above, a small effect has l: ood eiect on com a ativel r s. D

g p r y g eat dose been observed when using comparatively large doses of -moderate eect on smaller doses. f 3=g0od effect on Smaller doses trasentin. However, other substances which are char- 10 g00d effect on Very Smau doses acterized generally by sedative or pain-depressing effects are without effect in :these experiments, or exert only a IV-VIII: Evaluation of the sedative effect in experi- 10 trace of eiect when used in large doses. ments with rats in accordance with experiment II using An exception to this is scopolarnine, which is extremely the dose stated in the subsequent line, the evaluation being active, even in doses smaller than those necessary with expressed by the numbers 0-3 and calculated in each the benzilic acid esters (and their salts) of the present individual case as the average of many experiments. invention. However, the eiect of scopolamine on the TABLE A I II III IV V VI VII VIII IX X XI XII XIII Doses; Mg 10 5 2 1 0.5 0.25 0.1 0.05 0.02 0.01

Dimethylaminoethyl ester of Benzlllc Acid i HG1 31.4 3.5 a 1.5 2.5 1.6 1.7 0.7 0.5 Diethylaminoethyl ester ofBeuzilic Acid HCl 21.6 8 3 2.2 2.2 1.6 1.5 0.5 0.5 Dl-lscpropylaminoethyl ester of Benzilic Acid TABLE B 25 central nervous system is more diffused, producing confusion and hallucinations. This is not the case with the Bemhydryloxyethyldimemamme HC1 2.5 2.5 0 0 3 0 dialkylaminoethyl esters of benzilic acid and their salts. genzixygiyoxyeyiiethyi HCIHC 3 g 0.3 Experiments 1n man have shown that doses sucient for enz y ry oxyc y. i-n-propy Bemhydryloxycthydmspmpyl HC1" 1 6 05 0 0.7 producing a clear .effect on the central` nervous system genzyryioxyeyipiperu H g5 g 8 ag 0.3 30 will produce but little or no atropine-like eiect on the enz y ry oxye ymorp o e 2-Benzhydryloxyethylpropyldietliylamine perlpherlcal SYSU H01 1.2 i.5 0.5 0.2 Upon the administration :of about 4 milligrams by Bemfydr 2 3 0. 5 0 0 0 mouth, or subcutaneously, the most characteristic effect in Belzhvlyloxyethyltrimetllvlammonium 3 05 0 o o 2 0 normal human beings is a peculiar inhibition of thinking. BeiigilidrifEiiiiiintiiihifi' 35 It appears to be difficult for the person involved in the monium Bi'ornlde 2. 33 0 0 0 0 Bemhydryloxyethylmethyldiethylam experiment to maintain sequence of thought, but the per monium iodide 1.60 0 0 0.5 sons are conscious of the situation, and of the fact that BfgifreyloxfffifthYffffflfff 1 1 D 0 0 0 they would be able to carry out normal thought processes Tritylxyethyidiethyiamine HC1 1) 0 0 but that .this would require a greater effort than `that nor- 40 mally required.

TABLE C I II III IV V VI VII VIII IX X XI XII XIII Doses, Mg 10 5 2 1 0.5 0.25 0.1 0.05 0.02 0.01

Diphenylacetoxyethyl diniethylamine HC1" 0 0 0 0 Dlphenylacetoxyethyl dlethylnmine 'rIO1 0.25 1 2.2 l 0.6 0 CyclohexylphenylacetoXvethyldiethylamine HC1 0.5 1 a 0.8 0.5

ium Bromide 0 0.6 0.5 Diphenylacetoxyethyltrlethyla Bromide 0 0 0 0. 2

Atropine su1phate. 0 1 1.3 0.4 0 Scopolamne brornid (0.25) l0 Pheuemale, sodium sa 0 Pentymale 0 Alcohol g Demerol, H l Met-linden 3 TABLE D I II III IV V VI VII VIII IX X XI XII XIII Doses, Mg 10 5 2 1 0.5 0.25 0.1 0.05 0.02 0.01

Potassium benvll'lte 0 0 w-Diethylamino pchloropropiophenone 0 0 w-Dimcthylarninopropophenone 0 0 a-(2#D.i0thylamlnoethyl)-beuzhydrnl 0 0. 2 Benzilc acid hydrazlde, HCl 0 0. 2 1,1Diphenyl-l-propene3diethy1amine 0 0.5 5,5-DiphenyI-ZA-oxazolidinedone -l- 0.5 0.5 Benz'ilic acid lsobutenylhydrfwip Q 0.2 Tiarnaotil 0 0 0 D When the experimental subjects are tested by means of the usual intelligence tests, the results appear to be uninfluenced, but the experimental person has the feeling that the time required for the solution of any problem is considerably greater than it actually is in fact. Gidd-iness may be felt at times, but generally there is a subjective feeling of comfort without any pronounced euphoria. No sleepiness is produced in a person under the inuence of the substance. In the electroencephalogram there is a flattening of the alpha waves, which appears simultaneously with occurrence of subjective symptoms yand disappears with the disappearance of the same. The objective effects resulting from the administration in human beings of the esters of benzilic acid an-d their salts, in accordance with the invention, correspond to the tindings in the experiments with rats and cats, and they may be readily ascertained, particularly by certain reactions in the autonomous nervous system, such as changes in skin temperature, perspiration, and the like, which in the experimental person are associated with certain psychical processes. Such reactions are eliminated or clearly depressed under the influence of suitable doses of the dialkylaminoethyl esters of benzilic acids and their salts as enumerated above, these substances being orally administered in the dosage-unit forms herein described.

In some cases elimination or repression of stammering has been observed, so that persons who have Ia tendency to stammer under the inuence of excitement cease to stammer under similar excitative conditions after administration of suitable doses of the benzilic acid esters or their salts such as the hydrohalides, salts with phosphoric or sulfuric acid, or salts with the organic acids, acetic, citric and tartaric acids. A suitable dose may be, in adults, tablets containing from 1 to 2 milligrams of the active material, for a total dosage of 2 to l0 milligrams per day.

In neurotic patients it has been possible in all cases t depress or remove neurotic symptoms upon the administration of similar doses. A businessman had been an invalid for more than one year because of neurosis with sensations of terror and somatic headache. He had been afraid to walk in the streets, to drive his car, to go to his oce, or even to take part in informal and customary social affairs. After medication with 2 or 3 tablets containing, as the active medicament, 1.5 milligrams of the diethylaminoethyl ester of benzilic acid daily for a few months, he was capable of attending to his ordinary business atfairs. It was necessary, however, on some occasions to take up to six of such tablets daily.

A female neurotic patient was in great pain, and suffered neurosis involving anxiety associated with terror of suicide. She had been admitted to a hospital in the belief that this was the beginning of mental disease. After medication of a similar kind with tablets containing 1.5 milligrams of the diethylaminoethyl ester of benzilic acid in the form of its hydrochloride, up to six such tablets being orally taken daily, she was discharged as capable of working after only two weeks. Neurotic patients suffering with similar mental conditions have been under similar treatment for periods of 6 to 8 months.

Occasionally, when the symptoms appeared to have disappeared, it has been tried to stop medication by administering placebos. In all cases examined, however, the symptoms have returned after a few days upon cessation of the treatment, and `the oral administration of tablets of the dialkylaminoethyl esters of benzilic acid (or their salts) had to be begun again.

In near psychiatric patients the active esters of benzilic acid described exhibit la sedative action, the patients being less strained. Hallucinations that they may be suter- 10 ing appear to leave a lessened impression on `the patents mind. The dose necessary for obtaining this effect is substantially greater in mentally diseased patients than that necessary to secure `the same eect in normal persons. For mentally diseased patients dosages of from l0 to 90 milligrams per day may be administered, individual administrations being up to l5 milligrams of the benzilic acid ester or its salt.

The therapeutic effect of the dialkylaminoethyl esters of benzilic acid may be described by stating that they appear to raise the threshold at which irritation duc to psychical causes begins.

Since various changes and modifications may be made in the invention, certain preferred embodiments of which have been herein described, it is the intention that such changes and moditications as are Within the scope of the appended claims shall be considered as part of the invention.

I claim:

1. A tranquilizing composition in dosage-unit form adapted for the treatment of neurotic conditions comprising a solid pharmaceutical carrier and from 0.1 milligram to 15 milligrams per dosage unit of a medicament active on the central nervous system selected from the group which consists of compounds having the formula 06H5 0H /Ri C-COO-CH2CH5*N 04H5 R2 wherein R1 and R2 represent methyl, ethyl and isopropyl,

and pharmacologically acceptable acid addition salts thereof.

2. A tranquilizing composition in dosage-unit form adapted for the treatment of neurotic conditions comprising a solid pharmaceutical carrier and from 0.1 milligram to l0 milligrams per dosage unit of a pharmacologically acceptable acid addition salt of the dimethylaminoethyl ester of benzilic acid.

3. A tranquilizing composition in dosage-unit form adapted for the treatment of neurotic conditions comprising a solid pharmaceutical carrier and from 0.1 milligram to 10 milligrams per dosage unit of the diethylaminoethyl ester of benzilic acid.

4. A tranquilizing composition in dosage-unit form adapted for the treatment of neurotic conditions comprising a solid pharmaceutical carrier and from 0.1 milligram to l0 milligrams per dosage unit of a pharmacologically acceptable acid addition salt of the diethylaminoethyl ester of benzilic acid.

5. A tranquilizing composition in dosage-unit form adapted for the treatment of neurotic conditions comprising a solid pharmaceutical carrier and from 0.1 milligram to 10 milligrams per dosage unit of a pharmacologically. acceptable acid addition salt of the aminoethyl ester of benzilic acid.

6. A tranquilizing composition in dosage-unit form adapted for the treatment of neurotic conditions comprising a solid pharmaceutical carrier and from l milligram to 2 milligrams per dosage unit of the hydrochloric acid addition salt of the diethylaminoethyl ester of benzilic acid.

References Cited in the tile of this patent FOREIGN PATENTS Switzerland June 2, 1936 Switzerland Feb. 16, 1937 OTHER REFERENCES di-isopropy1-'

Claims (1)

1. A TRANQUILIZING COMPOSITION IN DOSAGE-UNIT FORM ADAPTED FOR THE TREATMENT OF NEUROTIC CONDITIONS COMPRISING A SOLID PHARMACEUTICAL CARRIER AND FORM 0.1 MILLIGRAM TO 15 MILLIGRAMS PER DOSAGE UNIT OF A MEDICAMENT

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