SK12962000A3 - USE OF D1/D5 ANTAGONISTS FOR TREATING OBSESSIVE COMPULSIVEì (54) DISORDERS, SOMATOFORM DISORDERS, DISSOCIATIVE, EATING DISORDERS,ì (54) IMPULSE CONTROL DISORDERS AND AUTISM - Google Patents

Abstract

A method for treating obsessive compulsive disorders, somatoform disorders, dissociative disorders, eating disorders, impulse control disorders, and autism is disclosed. These disorders are treated by administering an effective amount of a D1/D5 antagonist.

Description

Technical field

The invention relates to the use of a D1 / D5 antagonist as an active ingredient of a pharmaceutical composition for the preparation of a medicament for the treatment of diseases including obsessive compulsive disease, somatoform diseases, dissociative diseases, eating disorders, impulsive behavioral disorders and autism, anorexia nervosa, bulimia, pathological gambling.

BACKGROUND OF THE INVENTION

Obsessive-compulsive disease (OCD) is classified as the most common psychiatric disease and occurs in 2-3% of the US population. OCD is characterized by anxiety-inducing and fixed notions (eg fear of contamination and germs, fears and uncertainties about possible future harm, need for symmetry, etc.) that lead to ritual and and / or irrational behavior (eg constant control, washing, touching, heart rate monitor, etc.). See Hollander et al., J. Clin. Psychiatry 57 (Suppl.8), pp.3-6 (1996).

Somatoform diseases (e.g., dysmophophobia and hypochondria) are characterized by an abnormal interest in self-image or health. For example, in dysmorphophobia, this interest is centered on the notion of its appearance or focuses on a minor defect in appearance. Many of the people suffering from dysmorphophobia are severely affected by their bias in social, occupational and other areas of daily life. See Phillips, J. Clin. Psychiatry, 57 (suppl.8), pp.61-64 (1996). Hypochondria are characterized by the persistent conviction of the affected person that he is ill or is likely to become ill. Many hypochondriacs are unable to engage in routine activities due to their bias for the suspected disease.

Dissociative diseases (eg depersonalization) are characterized by sudden, transient changes in identity, memory, or consciousness, separating normally integrated memory or personality components from an individual's dominant identity. Depersonalization, which is a dissociative disease, is characterized by one or more depersonalization episodes (feeling unnatural and alienated to oneself or to their physical depiction).

Eating disorders (for example, anorexia nervosa, bulimia and morbidity) are characterized by an abnormal need to eat or uncontrolled incentives to consume an abnormally high amount of food. These disorders complicate not only the social life of disabled people but also their good health.

Diseases involving impulsive behavioral disorders (such as pathological gambling, compulsive shopping and sexual behavior, and kleptomania) are characterized by a passion and inability to get rid of repeated participation in various types of activities that are either socially unacceptable or abnormally excessive within social standards.

Autism is a disease characterized by a self-centered disease with a significant deterioration in reaction or contact with reality in a normal way. Many autistic people are not even able to communicate with other people.

In view of the severe and life-attenuating effects of these diseases, the need for drug therapy is an effective treatment for the disease.

Data on the effects of D1 antagonists are described in the literature, including: inhibition of self-damaging behavior in rats neonatally treated with 6-hydroxypropamine; blocking amphetamine-induced physical activity and apomorphine-induced stereotyped rat behavior; inhibition of self-treatment and oral activities induced by administration of D1 agonists to monkeys of the m. inhibition of apomorphine-induced stereotyped behavior in mice; and reverse extrapyramidal side effects in monkeys treated with haloperidol. See Criswell et al., Neuropsychopharmacology 7, (2), p. 95-103 (1992); Kerkman et al., European Journal of Pharmacology, 166 (3), 481-91, (1989); Gnanaligham et al., Psychopharmacology, 117 (4), pp. 403-12 (1995); Acri et al., Drug Dev. Res., 37 (1), pp. 39-47 (1996); McHugh et al., European Journal of Pharmacology, 202, pp. 133-134 (1991); Coffin et al., Neurochem. Int., Vol. 20, Suppl., Pp. 141S-145S (1992); Waddington, Gen. Pharmac., Vol. 19, No.1, pp. 55-60 (1998); and Beaulieu, Can. J. Neural. Sci., 14: 402-406 (1987).

SUMMARY OF THE INVENTION

The invention provides a method of treating a human suffering from obsessive-compulsive disease, somatoform disease, dissociative disease, eating disorder, impulsive behavior disorder or autism, by administering an effective amount of a D1 / D5 antagonist.

DETAILED DESCRIPTION OF THE INVENTION

The following terms used herein have this meaning.

A D1 / D5 antagonist is a compound that selectively binds to D1 and / or D5 receptors in the brain, thereby reducing or preventing dopamine binding at these sites. A compound binds selectively to D1 and / or D5 receptors when it binds more to either D1 or D5 receptors than to the D2 receptor. D1 / D5 antagonists include compounds that bind only to the D1 receptor (purify D1 antagonists), only the D5 receptor (D5 antagonists), and compounds that bind to both the D1 receptor and the D5 receptor.

Examples of D1 / D5 antagonists include, but are not limited to: SCH 39166, [(-) - trans-6, 7, 7a, 8, 9, 13b-hexahydro-3-chloro-2-hydroxy-N-methyl -SHbenzo [d] naphtho [2,1-b] azepine HCl]; SCH 23390, [(R) - (+) - 8-Chloro-2,3,4,5-tetrahydro-34-methyl-5-phenyl-1H-3-benzazepin-7-ol maleate; BTS-73-947, [(S) -1- (1- (2-chlorophenyl) cyclopropyl) -7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline]; A69024, [1- (2-Bromo-4,5-dimethoxybenzyl) -7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline]; JHS-271, [8-chloro-3- [6- (dimethylamino) hexyl] -2,3,4,5-tetrahydro-5-phenyl-1 H -3-benzazepin-7-ol]; JHS 198, [8-chloro-3- [6 (dimethylamino) hexyl] -2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepin-7-ol in a 1: 1 complex with cyanoborane ]; JHS-136, [8-chloro-3- [4- (dimethylamino) butyl] -2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepin-7-ol]; and NNC-22-0010, [S (+) - 8-Chloro-5- (5-bromo-2,3-dihydrobenzofuran-7-yl) -7-hydroxy-3-methyl-2,3,4,5-tetrahydoO] -1-benzazepin-3]. The above D1 / D5 antagonists can be prepared by known methods such as those described in U.S. Pat. 5,302,716, WO 93/13073, WO 93/1702, WO 95/25102, and in J. Med. Chem. 38 (21), p. 4284-93 (1995), the disclosures of which are incorporated herein by reference. Particularly preferred methods are disclosed in SCH 39166 and SCH 23390, with the method of SCH 39166 being most preferred.

It will be clear to those skilled in the art that effective dosages for treatment, e.g. obsessive compulsive diseases, somatoform diseases, dissociative diseases, eating disorders, impulsive behavioral disorders and autism will vary depending on the individual being treated and the severity of his condition. Preferably, D1 / D5 antagonists are administered in daily doses of from 0.01 to 500 mg / kg body weight, more preferably from 0.01 to 150 mg / kg, most preferably from 0.01 to 10 mg / kg. The daily dose may be administered in a single dose or divided into several doses.

In preparing the pharmaceutical compositions of the D1 / D5 antagonists of the invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid dosage forms include powders, tablets, dispersible granules, capsules, cachets, and lace. The powders and tablets may contain 5 to 70 percent of the active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sucrose, and lactose. Tablets, powders, cachets, and capsules are solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and then the active ingredient is dispersed homogeneously into the melt while stirring. The molten homogeneous mixture is then poured into suitably shaped molds and allowed to cool while solidifying.

Liquid dosage forms include solutions, suspensions, and emulsions. By way of example, aqueous or water-propylene glycol solutions for parenteral injection may be mentioned.

Liquid dosage forms also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may be in the form of a solution or in the form of solids in powder form which may be combined with a pharmaceutically acceptable carrier, such as an inert compressed gas.

The dosage forms of the invention also include solid dosage forms intended shortly before use for transformation into liquid forms for oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

D1 / D5 antagonists may also be administered by the transdermal route. Compositions suitable for transdermal administration may be in the form of creams, aerosols and / or emulsions, which may be incorporated into the transdermal patch or into a matrix or reservoir used in the art for this purpose.

Preferably, the DI / D5 antagonists are administered orally.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of pharmaceutical compositions containing SCH 39166 as active ingredient:

ε- component mg / capsule mg / capsule 1 SCH 39166 5.0 25.0 2 lactose, USP 114.0 94.0 3 Sodium salt of glycolate starch NF 6.0 6.0 4 povidone, USP (K29 / 32) 4.0 4.0 5 magnesium stearate, NF 1.0 1.0 Full com 130.0 mg 130.0 mg

The ingredients designated 1-4 are mixed for 10-15 minutes in a suitable mixer. Component number 5 is then added and stirring is continued for an additional 1-3 minutes. The mixture is then dispensed into suitable hard, two-piece gelatin capsules in a suitable capsule filling machine.

Example 2

The capsules prepared according to the method of Example 1 (containing 5.0 mg SCH 39166) are administered once daily for six months to a patient diagnosed with obsessive compulsive disease, thereby reducing or eliminating the observable symptoms of the disease.

Example 3

The capsules prepared by the method of Example 1 (containing 25.0 mg of SCH 39166) are administered once daily for six months to a patient diagnosed with autism, thereby reducing or eliminating the observable symptoms of the disease.

Ί

The invention is described by the specific examples above, but it will be apparent to those skilled in the art that other alternative embodiments, modifications and variations are possible. It is intended that all of these alternative embodiments, modifications and variations be included within the spirit and scope of the invention.

Claims (3)

PATENT CLAIMS ·· I · · · · · · · · Use of the D1 / D5 antagonist as an active ingredient of a pharmaceutical composition for the preparation of a medicament for the treatment of diseases including obsessive compulsive disease, somatoform diseases, dissociative diseases, eating disorders, impulsive behavioral disorders and autism, anorexia nervosa, bulimia, morbidity as well as pathological gambling. The use of claim 1, wherein the D1 / D5 antagonist is selected from the group consisting of (-) - trans-6,7,7a, 8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methylSH- benzo [d] naphtho [2,1-blazepine-HCl, (R) - (+) - 8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7 -ol maleate, (S) -1- (1- (2-chlorophenyl) cyclopropyl) -7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, 1- (2-bromo) -4,5dimetoxybenzylH-hydroxy-e-methoxy-N-methyl ^ .SAtetrahydroizochinolín I, 8-chloro-3 [6- (dimethylamino) hexyl] _-2,3,4-l 5-tetrahydro-5-phenyl-1 H-3 bezazepin-7-ol in a 1: 1 complex with cyanoborane, 8-chloro-3- [4- (dimethylamino) butyl] 2,3,4,5-tetrahydro-5-phenyl-1H-3-bezazepine- 7-ol and S - (+) - 8-chloro-5- (5-bromo-2,3-dihydrobenzofuran-7-yl-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3) benzazepine Use according to claim 1, wherein the amount of D1 / D5 antagonist is 0.01 to 150 mg per kilogram of weight, preferably 0.01 to 10 mg.