US3895110A

US3895110A - Methods for the treatment of psychic disturbances

Info

Publication number: US3895110A
Application number: US503733A
Authority: US
Inventors: Turan M Itil; Werner Martin Herrmann
Original assignee: Schering AG
Priority date: 1973-09-06
Filing date: 1974-09-06
Publication date: 1975-07-15
Anticipated expiration: 1992-07-15
Also published as: GB1474749A; DE2345377A1

Abstract

Cyproterone and its 17-esters are administered to persons with a psychic disturbance of the affective or behavioral type to evoke an anxiolytic response.

Description

United States Patent Itil et al.

METHODS FOR THE TREATMENT OF PSYCHIC DISTURBANCES Inventors: Turan M. Itil, Nyack, N.Y.; Werner Martin Herrmann, Berlin, Germany Assignee: Schering Aktiengesellschaft, Berlin,

Germany Filed: Sept. 6, 1974 Appl. No.: 503,733

Foreign Application Priority Data Sept. 6, 1973 Germany 2345377 US. Cl. 424/242 Int. Cl. A61K 27/00 [451 July 15,1975

2/1966 Wiechert et al. 260/239.55 R

Primary Examiner-Stanley J. Friedman Attorney, Agemy or FirmMillen, Raptes & White [5 7 ABSTRACT Cyproterone and its l7-esters are administered to persons with a psychic disturbance of the affective or behavioral type to evoke an anxiolytic response.

5 Claims, No Drawings METHODS FOR THE TREATMENT OF PSYCHIC DISTURBANCES BACKGROUND OF THE INVENTION This invention relates to medicinal agents comprising cyproterone or a l7-ester thereof and to their use.

Cyproterone (6-chloro- 1 a,2oz-methylene-4,6- pregnadien-l7a-ol-3,20-dione) and the 17-esters thereof are known, for example, from US. Pat. No. 3,234,093.

Several steroids are known to exert a depressant effect on the central nervous system and possess hypnotic and/or anesthetic effects. These steroids are not useful as psychotropic agents due to their known side effects and depression of the central nervous system.

Minor tranquilizers of the benzodiazepines type have become popular as medicinal agents having an anxiolytic and sedative effect. However, these active agents have the disadvantage that their use can cause a psychic dependency (WHO Bull. 43 Suppl., 1970, 49). Furthermore, the muscle-relaxant properties of these substances, for example, can lead to undesired side effects (AMA Drug Evaluations, American Medical Assoc. Chicago, lst ed. 1971, pp. N 47 ff.). Also, the conventional anxiolytic (minor tranquilizer) and anti depressant (thymoleptic) substances have sedating properties which are undesirable during waking hours, e.g., during work or activity which requires a person to be alert.

It has now been found that cyproterone and the esters thereof have a broader spectrum of effectiveness, compared to conventional minor tranquilizers, with the additional advantage that they do not exhibit the above-described adverse side effects, but instead have additionally an antidepressant effect. This result has been obtained for the first time with a substance having a steroid structure.

SUMMARY OF THE INVENTION According to this invention, cyproterone or a 17- ester thereof is administered systemically to a patient with a psychic disturbance of the affective or behavioral type in an amount effective to evoke an anxiolytic response.

DETAILED DISCUSSION The preferred 17-esters of cyproterone are esters of hydrocarbon carboxylic acids of l-8 carbon atoms, preferably 2-8 carbon atoms, e.g., a monobasic alkanoic acid, e.g., formic, acetic, propionic butyric, isobutyric, oz-ethylbutyric, valeric, isovaleric, a-ethylvaleric, trimethylacetic, 2-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, enanthic, octanoic, a cyclic acid, preferably a cycloaliphatic acid, e.g., cyclopropylideneacetic, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, B-cyclopentylpropionic, cyclohexylcarboxylic, cyclohexylacetic, a carbocyclic aryl or an alkaryl acid, e.g., benzoic, 2-, 3- or 4- methylbenzoic acid.

A preferred class of acyl groups are those of straight or branched chain monobasic alkanoic acids, preferably of 28 carbon atoms, e.g., acetyl, propionyl, butyryl, isobutyryl, of which acetyl is most preferred.

Since the exact chemical nature of the acyl radical of the 17-ester group is not critical, as long as it is not physiologically toxic and it can be formed on the cyproterone l7-hydroxy group, contemplated equivalents of the preferred esters described above, insofar as they can be formed, are those formed with other aliphatic and aromatic unsubstituted and substituted and monobasic, dibasic and polybasic carboxylic acid, saturated or unsaturated aliphatic, araliphatic and aromatic carboxylic acids containing up to 18 and preferably up to 8 carbon atoms, e.g.,undecylic, palmitic, B-cyclohexylpropionic acid, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, cinnamic, naphthoic, 3-methyl-a-naphthoic, B-phenyL propionic, diphenylacetic, biphenylacetic or a-naphthylacetic acid, or a dibasic alkanoic acid, e.g., oxalic, maleic, fumaric, succinic, malonic, glutaric, a-methylglutaric, B-methylglutaric, B,B-dimethylglutaric, adipic, pimelic and suberic acid, a dibasic aryl acid, especially those capable of forming a cyclic anhydride, e.g., phthalic acid, or a carbamic acid, e.g., carbamic acid, phenylcarbarnic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic and allophanic acid; or of a heterocyclic acid, e.g., B-furylcarboxylic pyrrole carboxylic, B-pyrrolidylpropionic, N-methylpyrrolidyL 2-carboxylic, -0z-picolinic, nicotinic, indole-2- carboxylic, 6-hydroxyindolyl-3-acetic and N- methylmorphol'yl-2-carboxylic and pyrrolyl-2- carboxylic acidfor a sulfonic acid of 118, preferably 1-12, carbon atoms, including alkanesulfonic, e.g., methaneand ethanesulfonic, and aryl sulfonic, e.g., benzeneand p-toluenesulfonic acid.

Such contemplated equivalents can also be esters with an acid containing one, two or more simple substituents in the molecule, e.g., hydroxy, halo, alkoxy, acyloxy, sulfonyloxy, amido, sulfato, nitro, mercapto and cyano, in the molecule, e.g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannoic, gluconic and salicylic acid; of an amino acid, e.g., glycine, aminopropionic, diglycollamic, triglycollamic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic, paraaminobenzoic, ethylmercaptoacetic, benzylmercaptoacetic, chloroacetic, fiuoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, m-nitrobenzoic, 2,3,4- trimethoxybenzoic, phenoxyacetic and a-naphthoxyacetic acid.

Cyproterone acetate was tested in a placebocontrolled double blank experiment by quantitative pharmaco-electroencephalography (CEEG) and by the method of evoked potentials on humans (T.M. Itil et a]. Quantitative Pharmaco-Electroencephalography [The use of computerized cerebral biopotentials in psychotropic drug research] in Psychotropic Drug and the Human EEG, Modern Problems of Pharmacopyschiatry Series, Basel, New York: S. Karger, 1974).

Moreover, the effects and side effects were determined by various rating scales, e.g., for neurological and psychosomatic symptom spectra, by self-rating scales for sedation, fear and depression, as well as by interviews with physicians. In clinical tests, the effectiveness of cyproterone acetate was proven in premenstrual anxiety and tension conditions. The effectiveness was described by physicians judgments and placed into objective form in ratings. In the practical application of cyproterone and the esters thereof, the effect according to this invention occurs soon after administration, which is surprising since it is generally known from endocrine-active steroids that such effects are observed only after a longer treatment period. In the case of cyproterone acetate, in its previous applications for its known effects, such effects were known to occur only after weeks of treatment. Whereas, the desired psychotropic effects of cyproterone or its l7-esters, occur within hours after administration.

A particular advantage of the medicinal agents based on cyproterone or a l7-ester thereof in the present field of application of this invention is that, even during long-term usage, dependency does not arise and no tolerance requiring higher dosages is observed, as occurs, for example, in the case of the benzodiazepines. Additionally, even with high doses, there is no danger of impairing the functional power and reaction capacity, or of lowering the level of consciousness to produce a type of drowsiness, for example during driving or working.

Furthermore, it is also advantateous that cyproterone and the l7-esters thereof, even in a massive single oral dose of the order of 2 g., do not ordinarily produce adverse neurological, vegetative or other side effects, or any disturbance of consciousness. Therefore, even an overdose does not lead to serious muscle relaxation and impairment of consciousness.

During the further development of psychopharmaceuticals based on benzodiazepines, a dissociation between the sedative and anxiolytic properties was sought.

With cyproterone and its l7-esters, a class of compounds has been found for the first time which has the typical activity profile of an anxiolytic agent, but does not have any significant sedating properties.

Cyproterone and its l7-esters exhibits a neuropsychotropic effect of the type of the minor tranquilizers and especially anxiolytic, antidepressant (thymoleptic) and sedative activity.

Accordingly, cyproterone and the l7-esters thereof possess the advantage that they overcome the deficiency of lack of dissociation between sedative and anxiolytic properties present in the known psychopharmaceuticals based on benzodiazepines.

In its method of use aspect, this invention relates to the treatment of psychic disturbances in the affective and behavioral ranges, especially anxiety and tension conditions, with and without depression, unrest and disturbances resulting from stress situations or excess stimulation, as well as pathological aggressiveness, employing cyproterone or a l7-ester thereof.

In medical practice, the drugs based on cyproterone and l7-esters thereof according to the present invention can be administered subcutaneously, intramuscularly or orally with effectiveness by injection or oral administration being about equal. The daily dosage is 0.05 500 mg., preferably 0.1- 50 mg. This dosage can be administered in a single oral dose. It is advantageous to remain below the threshold value of endocrine effectiveness, especially under the threshold value for an antiandrogen effect in males and females of 50 to 100 mg per day.

The formulation of the medicinal agents of this invention is accomplished in a conventional manner, by processing cyproterone and the esters thereof, especially the esters with l-8 carbon atoms, together with the vehicles, diluents and flavor-ameliorating substance, customary in galenic pharmacy, and then converting the compositions into the desired forms of application, such as, for example, tablets, dragees, capsules and solutions suitable for oral or parenteral administration.

Especially suitable for injections are oily solutions, such as solutions in sesame, castor and cottonseed oil.

If desired, diluents or solubilizers, such as, for example, benzyl benzoate or benzyl alcohol, can be added to increase solubility. To obtain a protracted effect, cyproterone and the esters thereof can also be utilized in microencapsulated form. For oral application, especially suitable are capsules, tablets, dragees, pills, suspensions and solutions. The amount of active agent in the thusformulated medicinal agents is 0.05 500 mg., preferably 0.1 50 mg., per unit dose.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

EXAMPLE I 50.0 mg. of 6-chloro-17-acetoxy-l0:,20z-methylene- 4,6-pregnadiene-3,20-dione (cyproterone acetate) is mixed homogeneously with 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil, 2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearate and compressed, without previous granulation, into round, biplanar tablets with a breaking notch and a final weight of 225 mg.

EXAMPLE 2 To produce an injection solution, 100.0 mg. of cyproterone acetate is dissolved in 618.6 mg. of benzyl benzoate (USP XVII) and 353.4 mg. of castor oil (DAB [German Pharmacopoeia] 7, USP XVII); the solution is filtered under sterile conditions and filled aseptically into 3-ml. ampoules.

EXAMPLE 3 Respectively 0.1 mg. of cyproterone acetate (micronized, particle size 2-8 IL) is mixed homogeneously with mg. of lactose (DAB 7, USP XVII) and filled into hard-gelatin capsules (5 X 15 mm.).

EXAMPLE 4 Analogously to Example 1, 10 mg. of cyproterone is compressed, with 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil, 2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearate, into tablets having a final weight of mg.

EXAMPLE 5 This study was set up in a group of five very young male patients in the age range of 18-26, who are suffering from symptoms of anxiety and they were included in this study. All patients received anxiolytics or similar treatment but not systematically and no longer period of time before cyproterone acetate treatment. All patients are characterized by nervousness, restlessness, anxiety, headache, and tachycardia. Before cyproterone acetate medication, all drugs were discontinued and during the study no additional medication was allowed. The treatment period was 2 weeks and the daily dosages ranged from 1-6 mg (mean 3.7-4.7 mg) (total dosage 55-57 mg).

In two patients complete remission with the improvement of symptoms of anxiety, somatic symptoms, headache was observed (Patient 2 and 3). In one patient a moderate degree of improvement was observed in dosages 3-4 mg daily (Patient 4). When the dosage was increased patient got restless. In two other patients (Patient l and 5), only slight improvement was observed in symptoms such as restlessness, parasthesia, difficulty in swallowing, tachycardia, and insomnia.

EXAMPLE 6 Cyproterone acetate was administered to 10 female patients in the age range of 25-55. All patients had clinical symptoms of anxiety, depression or psycho-physiological complaints which appear either in the premenstrual period or if already present, showed marked exacerbation after midcycle.

The patients were medicated for two cycles, one with placebo and one with cyproterone acetate. Treatment was started immediately following the appearance of clinical symptoms and continued until a few days before the estimated date of the beginning of the next cycle. Cyproteronc acetate and placebo were given at 100 mg once a day in the morning. All patients showed a significant remission of anxiety-tension and depression during the premenstrual period.

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

l. A method for the treatment in a affected person of psychic disturbances of the affective or behavioral type which comprises administering systemically to the af fected person an amount of cyproterone or a 17-ester thereof with a hydrocarboncarboxylic acid of l-8 carbon atoms effective to evoke an anxiolytic response.

2. A method according to claim 1 wherein cyproterone is administered.

3. A method according to claim 2 wherein the cyproterone is administered orally.

4. A method according to claim 1 wherein cyproterone acetate is administered.

5. A method according to claim 4 wherein the cyproterone acetate is administered orally.

Claims

1. A METHOD FOR THE TREATMENT IN A AFFECTED PERSON OF PSYCHIC DISTURBANCES OF THE AFFECTIVE OR BEHAVIORAL TYPE WHICH COMPRISES ADMINISTERING SYSTEMICALLY TO THE AFFECTED PERSON AN AMOUNT OF CYPROTERONE OR A 17-ESTER THEREOF WITH A HYDROCARBONCARBOXYLIC ACID OF 1-8 CARBON ATOMS EFFECTIVE TO EVOKE AN ANXIOLYTIC RESPONSE.

2. A method according to claim 1 wherein cyproterone is administered.

4. A method according to claim 1 wherein cyproterone acetate is administered.