SK5812000A3 - Method of reducing craving in mammals - Google Patents

Abstract

A method of reducing craving in a mammal to food or an addictive substance is disclosed. The method comprises administering to the mammal an effective amount of a D1/D5 antagonist or a D1/D5 partial agonist alone or in combination with other specified CNS compounds.

Description

A method of reducing the need for food and addictive substances in mammals and use

Technical field

The present invention is directed to reducing the need for food and addictive substances in mammals. More specifically, the present invention relates to reducing the need of mammals for each dopamine mediated by needs that include food or addictive substances.

BACKGROUND OF THE INVENTION

Significant research has focused on obesity, nicotine addiction and substance abuse. The company's medical expenses related to obesity, tobacco consumption and drug and alcohol abuse are very high. However, many individuals who decide to lose weight, stop smoking and / or abuse drugs or alcohol will often fall back into their established stereotypes of behavior in a short time after completing the treatment program. Often, this may be due to subtle signals in the surrounding area that initiate an individual's need for food or the substance they abuse. Accordingly, it would be desirable to provide a substance that suppresses food and / or substance abuse needs in a susceptible mammal.

It is known to use _D} antagonists in the treatment of addiction drugs. U.S. Pat. Nos. 4,973,586 and 5,302,716 disclose the use of Dj antagonists in the treatment of drug addiction. A dosage range of from 0.02 mg / kg to 10 mg / kg has been proposed, with 2.0 mg / kg divided into 1 to 3 administrations per day being particularly suitable.

Spealman et al., Neurochem. Int. Vol. 20 Suppl., 99147S152S (1992) discloses that cocaine is a potent enhancer and is often used as a standard to improve the enhancing effects of other drugs. When SCH 39166 was administered to monkeys, a triple or greater increase in cocaine dose was usually necessary to restore the characteristic self-administration activities.

Barrett-Larimore and Spealman in the Society for Neuroscience Abstracts 22 (2): 92 5 (1996) reported that all of the compositions containing the D 39 antagonist D _T antagonist and the D ₂ antagonist and D ₃ / D ₄ antagonist would be capable of alleviating behavior , in which a model with a deterioration in health found cocaine.

Clifton, 1995 and Clifton, 1991 indicated that DJ antagonists SCH 39166 and SCH 23390 had no effect on total food intake, food volume or feed fraction up to 3 mg / kg.

Caine and Koob in The Journal of Pharmacology and Experimental Therapeutics Vol. 270, No. 1, p. 209-218 (1994) disclose tests of Di antagonists SCH 39166 and SCH 23390 for cocaine and food self-enhancement. D 1 antagonists have been found to act on food self-enhancement.

Chausmer and Ettenberg in Pharmacology Biochemistry and Behavior Vol. 57, no. 4, p. 681-685 (1997) conducted tests for D ₁ and D ₂ antagonists in response to restoring food reward properties. They found that the D ₂ raclopride antagonist was sufficient to block the effects of the reboot reaction, but the Di SCH 39166 antagonist did not.

Nathan, Breskin and Batki in CNS Drugs 1998, Jul 10 (1), p. 43-59 summarize the results in the treatment of cocaine addiction using various drugs.

Lancet, Volume 347, p. 504-508 (February 14, 1996) discloses that haloperidol was tested for the desired reduction in substance abuse. However, the formulation is said to have significant adverse effects such as dysphoria, restlessness or stiffness, which reduces the desire for individuals to receive them.

It has been difficult to develop a substance that avoids the need for food or addictive substances in mammals, especially humans, because of the lack of reliable animal models that are well suited to human behavior.

Substances that are administered to reduce the need for food or addictive substances should not produce significant physiological effects such as mood stimulation or increased blood pressure or heart rate. This would lead to the replacement of one substance being abused by another. Also, substances that attenuate the need for a substance should not aggravate the physiological symptoms of the substance if the individual has a re-deterioration in health and takes the substance. Also, substances administered to reduce the need for food or an addictive substance should not cause significant adverse harm such as dysphoria, restlessness or stiffness.

Accordingly, it is desirable to provide a composition and method of treatment that will be active in reducing the need for the substance to be abused, and which will not impair the magnitude of the sympathetic response caused by the substance, and which have beneficial pharmacodynamic effects.

It is also desirable to provide a composition and method of treatment that blocks the euphoric and dysphoric effects of the substance being abused.

SUMMARY OF THE INVENTION

The present invention relates to the use of D1 / D5 antagonists, D1 / D5 partial agonists, or mixtures thereof, or in combination with other CNS compositions for the preparation of a medicament to reduce a need in a mammal, particularly a nutritional need and an addictive substance such as tobacco, alcohol, or abused. drugs. In a preferred composition, the antagonists of the D1 / D5 partial agonists of Di / _D5 administered in the range of 0.01 mpk and 500 mpk per day, preferably from 1 mpk and 150 mpk per day to a mammal susceptible to the needs of food and addictive substances. Suitable D 1 / D 5 antagonists are SCH 23390, SCH 39166, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 and A 69024, when SCH 39166 is particularly suitable. A suitable partial agonist Di / D ₅ is SKF 38393.

Antagonists Di / _D5 partial agonists or D? / D ₅ may be used in combination with agents selected from the following classes of CNS:

A. anti-obesity agents;

B. 5-hydroxytriptamine receptor agonists and antagonists;

C. antipsychotics / anxiolytics;

D. antidepressants;

E. dopaminergic agonists;

F. anticonvulsant / mood stimulants;

G. cocaine-like agonists;

H. cocaine catalytic antibodies; and

I. alcohol and opioid antagonist drugs.

Fig. 1 depicts the effects of a D1 / D5 antagonist and a D1 / D5 antagonist in control movement as a dose function.

Fig. 2 shows the effects of antagonist Di / _D5 antagonist DJ / Ds as in the control of movement operation of the dose after the administration of cocaine.

Fig. Figures 4 and 5 show systolic and diastolic blood pressure in humans before and after administration of cocaine as a function of time with different doses of a suitable D1 / D5 antagonist and placebo.

Fig. 5 and 6 show heart rate and body temperature, each before and after administration of cocaine with different doses of a suitable D1 / D5 antagonist and placebo.

Fig. Figures 7 and 8 show subjective euphoria and anxiety each before and after administration of cocaine with different doses of a suitable Di / Ds antagonist and with placebo.

Fig. 9 depicts the subjective need to take cocaine as a time function after a suitable Di / D ₅ antagonist or placebo has been administered.

Fig. 10 and 11 represent the subjective evaluation of good therapeutic effects, respectively. poor therapeutic effects such as time function and dose to individuals before and after cocaine administration.

Fig. Figures 12 and 13 show a positive and negative behavioral response as a function of time after administration of amphetamine and also after administration of a suitable D1 / D5 antagonist or placebo.

Fig. 14 and 15 show the chemical structures of the selected compositions.

An addictive substance is any substance that triggers dopamine release in susceptible mammals. Addictive substances include, but are not limited to, nicotine, alcohol, psychomotor stimulants such as amphetamines, opiates, benzodiazepines, and barbiturates.

The need is an intense and long-lasting desire or lust for a meal or addictive substance often in response to surrounding stimuli. The first dose of an addictive substance can trigger a deterioration in the health of a mammal who has previously suppressed the search for habit formation. A dopamine D 1 site blockage that avoids the need associated with withdrawal has been found to be triggered by either a low dose of addictive substance and / or associated stimuli. Pretreatment of a mammal with small doses of the antagonist Di / _D or partial agonist Di / _D5 inhibits or blocks the need for food or addictive substance.

While the examples presented below focus on D ₁ / D ₅ antagonists, it is contemplated that pure D ₁ antagonists, pure D ₅ antagonists, pure D ₁ partial agonists and pure D ₅ partial agonists, and pure D / D ₅ partial agonists will also demonstrate efficacy while reducing the need. As used herein, the term D 1 D 5 antagonist includes compositions that bind only to the D ₁ receptor (pure D ₅ antagonists, only the D ₅ receptor (pure D ₅ antagonists)), as well as those that bind to both receptors. ? Ds include compositions that bind only to the D 1 receptor (pure partial agonists of DJ, only to the D ₅ receptor (pure partial agonists of D ₅ ) as well as compositions that bind to both receptors and mimic dopamine under certain conditions. is defined to include mixtures of two or more Di / D ₅ antagonists, two or more Di / D ₅ agonists, and one or more Di / D ₅ antagonists with one or more Di / D ₅ agonists. Ds include:

SCH 39166, which has the chemical name (-) - trans6,7,7a, 8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo [d] naphtho- [2,1- b] azepine;

SCH 23390, which has the chemical name (d) -7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate;

BTS-73-947, which has the chemical name 1- [1- (2-chlorophenyl) cyclopropyl] -1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-2-methyl- (S) -isoquinolinol;

NNC-22-0010, which has the chemical name (+) - 5- (5-bromo-2,3-dihydro-7-benzofuranyl) -8-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3- benzazepin-7-ol;

JHS-271, which has the chemical name 8-chloro-3- [6 (dimethylamino) hexyl] -2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepin-7ol;

JHS-198, which has the chemical name 8-chloro-3- [6 (dimethylamino) hexyl] -2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepine-7-ol with boron carbonitrile (1: 1) ;

JHS-136, which has the chemical name 8-chloro-3- [4- (dimethylamino) butyl] -2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepine-7-ol; and

A-69024, which has the chemical name 1 - [(2-bromo-4,5-dimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoquinolinol.

A suitable partial Di / D ₅ agonist is SKF 38393, whose chemical name is 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol. The structures of these means are shown in FIG. 14 a

15th

The compositions are suitably administered at a dosage of from 0.01 mg / kg to 500 mg / kg per day, preferably from 1 mg / kg to 150 mg / kg per day. The effectiveness of representative means in suppressing needs may be apparent from the following tests.

Ί

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Example 1 illustrates that the D ₁ / D ₅ antagonist is effective in reducing the need for an addictive substance, cocaine, while the D ₂ / D ₃ antagonist was more or less effective. Cocaine-induced increases in locomotor activity are blocked by antagonists D1 / D5 antagonists but not by D ₂ / D _3, only if using relatively large doses. In this example, selective D1 / D5 antagonists, SCH 39166 and selective D ₂ / D ₃ antagonist, raclopride (raclopride) were studied for cocaine-induced movement stimulation in male CF-1 mice. Mice were administered oral doses of SCH 39166, raclopride (raclopride) or vehicle, followed by subcutaneous (sc.) Dose of cocaine or vehicle for 20 minutes. Movement activity was measured 10 minutes later for 8 minutes and is shown in FIG. SCH 39166 or raklopride (raclopride), when administered alone, produced a dose-dependent decrease in physical activity as shown in FIG. However, while SCH 39166 blocked cocaine-induced elevation in physical activity at all doses of test cocaine, raklopride (raclopride) had an adverse effect only on cocaine-induced elevation in physical activity at relatively large doses.

Example 2

This example demonstrates that the preferred D1 / D5 antagonist was effective and did not exhibit significant adverse effects when administered to individuals following cocaine injections. The individuals selected for these tests were people who had previously demonstrated cocaine addiction and were volunteers in the program. For two blind studies, these subjects received placebo, 10 mg SCH 39166, 25 mg SCH 39166, or 100 mg SCH 39166 two hours before the injection of 30 mg / kg cocaine. Systolic and diastolic blood pressure were measured in subjects from 2 hours before cocaine injection to 4 hours after cocaine administration. As can be seen in FIG. 3 and 4 respectively, the Di / Ds antagonist SCH 39166 did not adversely affect cocaine-induced increases in systolic and diastolic blood pressure. Fig. 5 shows that the lower heart rate at beats per minute did not deteriorate after cocaine administration after SCH 39166, while FIG. 6 shows that the increase in body temperature attributed to cocaine administration has not worsened.

In the same study, cocaine requirement was measured as a time function after placebo or various doses of SCH 39166. Cocaine requirement was measured using the Visual Analog Scale test. This method of testing is described in British Journal of Medical Psychology, Vol. 47, p. 211-217 (1984). In this test, subjects are subjected to a subjective measure of feelings of taking cocaine on a 0-100 scale, where 0 represents no need at all and 100 represents the strongest feelings. As can be seen in FIG. 7, the amount of euphoria following cocaine administration was lower in patients who had been pretreated with SCH 39166, in particular at a dose of 100 mg. Fig. 8 shows that dysphoric effects, such as anxiety, were lower after administration of cocaine in those patients who had been pretreated with SCH 39166. As seen in FIG. 9, the need for cocaine compared to placebo was significantly lower in subjects receiving SCH 39166. The greatest reduction in cocaine need occurred in subjects receiving 100 mg of SCH 39166.

Similarly, in a second transient study in healthy volunteers given 15 mg d-amphetamine after previous treatment with 100 mg SCH 39166 or placebo, attenuation of amphetamine euphoric (Fig. 12) and dysphoric (Fig. 13) effects was also observed in SCH 39166 in compared to placebo.

Even if the compositions of the present invention were effective in reducing the need for addictive substances or food, individuals would probably not benefit from the need for reducing drugs if they had tolerable side effects. Fig. 10 shows that the good effects of the drugs, i. individuals' feelings towards this formulation were not significantly lower than placebo, even at a dose of 100 mg at 1.5 hours after administration, as measured by the Visual Analog Scale test. Fig. 11 shows that the poor drug effects for all doses of SCH 39166 at the same time point, as judged by the Visual Analog Scale test, were not significantly different from placebo. Therefore, the use of this formulation should not be adversely affected by the negative views of the subjects receiving the drug, nor should it stimulate subsequent administration.

Studies on food needs and re-deterioration of food status following food restriction in both rodent and primate samples have shown that the D1 / D5 antagonist SCH 39166 can block re-deterioration of health in association with food effects and food related environmental stimuli. While it is undesirable to remain limited by any theory, Di / D ₅ antagonists and / or partial D1 / D5 agonists can prevent recurrence of the diet-related deterioration in the treatment of obesity by blocking the beneficial effects of dopamine at Dj / Ds sites associated with food or substance use needs.

Examples 3-5 provide further illustrations of the effect of the D1 / D5 antagonist in reducing food needs in a mammal.

Example 3

In this example, an adult male rat (genus: CD) was kept closed behind a pressure barrier according to a fixed schedule of 30 (FR 30). The rat was to push the septum 30 times to receive one 45 mg tablet of food. Each training session was 30 minutes long. Total reaction rate (total # pushes per barrier / 30 minutes), i. the rate at which the rats pushed the septum was measured and then analyzed in animals initially given saline (control animals) followed by doses of D1 / D5 antagonists SCH 23390 or SCH 39166. Each group of six animals received a single dose of drug administered subcutaneously. in a volume of 1 ml / kg 30 minutes before the start of the training session. The doses of SCH 23390 were 0.003 mg / kg, 0.005 mg / kg, 0.01 mg / kg and 0.03 mg / kg (mpk), while the doses of SCH 39166 were 0.001 mg / kg, 0.003 mg / kg, 0. , 01 mg / kg, 0.03 mg / kg, 0.1 mg / kg and 0.3 mg / kg (mpk). A dose of 0.01 mg / kg (mpk) of both SCH 23390 and SCH 39166 significantly reduced the baffle rate relative to that of saline-treated control animals. Both drugs elicited a decrease in the dose-response rate until the responses were eliminated to the highest dose.

Example 4 Male Genetically Obese Mice, i. ob / ob mice, 16 weeks of age, were individually housed in Nalgen metabolic cages on an inverted light cycle throughout the study period. Mice were provided with food and water ad libitum. Mice were divided into 5 groups of 4-5 mice each based on food intake baseline and body weight. Mice were dosed intraperitoneally (ip) with 0.003 mg / kg, 0.03 mg / kg, 0.3 mg / kg, or 3.0 mg / kg of SCH 39166 at the beginning of the night cycle, and provided a known amount of standard rodent feeding. Food consumption was measured after five hours and a further ip injection of the drug carrier was given. Food intake was measured again 24 hours after the initial injection. These injections and measurements were continued for a further 72 hours. 72 hours of cumulative food intake was reduced by 17% at 3.0 mg / kg (p <0.02).

Example 5

In this experiment, baseline food intake (in grams) was measured at intervals of 2 hours, 4 hours, or 24 hours after introcerebral ventricular administration (i.c.v.) of neuropeptide Y (NPY), a composition that stimulates an animal to consume food. A volume of 3 μς / 5 μΐ NPY was administered to adult male Sprague-Dawley rats (SD). In the daily test, three groups of rats (five rats per group) were pretreated with SCH 39166 according to the following dosing schedule:

A dose of SCH 39166 was injected intraperitoneally (ip). 30 minutes later, i.c.v. injection of 3 mg NPY. Control animals received an ip injection of the methylcellulose carrier. Thirty minutes later, the animals received NPY (3 mg). The second group received ip 1 mpk of SCH 39166 and 30 minutes later received 3 mg NPY. A third group of animals received ip 3 mpk of SCH 39166 and 30 minutes later received 3 mg NPY. Food intake was measured 2 hours, 4 hours and 24 hours after NPY administration. Animals receiving 3 mpk SCH 39166 pre-treatment showed a significant decrease in food intake following NPY administration.

Example 6

In a multicentre, double-blind study, a preliminary analysis of approximately 160 cocaine-dependent patients was given daily doses of 10 mg, 25 mg or 100 mg of SCH 39166 or placebo for eight weeks of the duration of the test. While the study did not demonstrate the efficacy of SCH 39166 in reducing cocaine use, it demonstrated that SCH 39166 was effective in reducing weight, alcohol consumption and tobacco smoking.

Table 1 shows the number of patients who received a placebo or indicated dose of SCH 39166 for 28 days to 25 days. Body Mass Index (BMI) and patient weight were measured at the start and end of the study. BMI is determined by weight (kg) / height ² (meters). Weight of patients with BMI from 20.0 to 24.9 is considered normal, while BMI over 25.0 is considered overweight.

Table IA shows the percentage of patients in each category with a weight reduction of at least 5 pounds. Table 1B shows the percentage of patients with an original BMI of 22 or less and the percentage of patients with a BMI of at least 26 who reduced the unit of BMI by at least 1. From these tables it can be seen that SCH 39166, especially at 100 mg / day weight loss in obese people, i with BMI 26 and higher.

Table IA

Effects of ecopipam ('ecopipam) on body weight (Cocaine-dependent patients who completed> 28 days of treatment)

treatment n = Basic BMI lines Change weight (Lbs) Patients with weight loss > 5 lbs placebo 34 25.5 + 2,3 15% 10 mg 30 25.2 - 1,4 27% 25 mg 32 25.5 - 0,9 22% 100 mg 29 26, 3 - 3,3 45%

Table 1B

treatment n = Patients with weight loss> 1 BMI Initial BMI <22 Initial BMI> 26 placebo 34 3/8 (39%) 3/14 (23%) 10 mg 30 2/9 (21%) 2/10 (21%) 25 mg 32 2/10 (21%) 4/14 (30%) 100 mg 29 1/7 (17%) 10/15 (71%)

The Di / D ₅ antagonists or partial D1 / D5 agonists of the present invention can be used alone in the treatment of food needs or in combination with the treatment of behavior; an overweight program; with other CNS agents described herein, in particular anti-obesity agents including beta 3 agonists, lipase inhibitors such as orlistat, NPY agonists and antagonists, 5HT-2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotropin releasing factor, leptin mimic agents and blockers, and nicotinic agonists.

Suitable beta 3 agonists include:

BMS 196 085, which has the chemical name [R- (R *, R *)] [4- [2 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] phenoxy] methanesulfinic acid; and

SR 58611A, which has the chemical name ethyl ester hydrochloride [R- (R *, S ')] - [[7 - [[2- (3-chlorophenyl) -2-hydroxyethyl] amino] -5,6,7,7-8] tetrahydro-2-naphthalenyl] oxy] ethane.

The structures of these means are shown in FIG. 15th

The Di / D ₅ antagonists or partial Di / D ₅ agonists of the present invention can be used in combination with other agents that have been shown to alter the use or desire to eat, including sibutramine, fluoxitin, flenfluramine and analogs, amphetamine and analogs, fenetramine, diethylproprione and mazindole.

Table 2 shows the reduction in alcohol consumption in patients measured in days without any alcohol consumption.

Table 2

Dose SCH 39166 (mg) % of patients who did not drink alcohol for at least 1 day % of patients who did not drink alcohol for at least 3 days 0 (placebo) 35 29 10 43 23 25 41 31 100 59 48

D1 / D5 antagonists or partial agonists of Di / D _and according to the present invention may be used alone in the treatment of alcohol needs or in combination with the treatment of conduct, and / or with other CNS compounds described here, particularly alcohol antagonistic drugs.

Table 3 shows that low doses of SCH 39166 were also effective in reducing cigarette smoking.

Table 3

Dose SCH 39166 (mg) % of patients at least 1 day after the last cigarette % of patients at least 3 days after the last cigarette 0 32 3 10 57 27 25 53 19 100 38 17

D1 / D5 antagonists or partial agonists of Di / _D5 of the invention may be used alone to treat the needs of nicotine or combined with treatment behavior, with the smoking cessation, nicotine replacement therapy, such as patches and gum, alone or in combination with other CNS agents described herein, particularly busporin and buproprion.

The compositions of the present invention may be administered alone or in combination with other specified compositions, including:

A. anti-obesity agents including beta 3 agonists, sibutramine, lipase inhibitors such as orlistat / agonists and NPY antagonists, 5HT-2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotropin releasing factor, leptin mimic agents and blockers, and nicotine agonists;

B. serotonin receptor agonists such as buspirone, gepirone and ipsapirone or serotonin receptor antagonists such as ritanserin, ketanserin, ondansetron, granisetron, sumitriptan, rizatriptan and eletriptan;

C. antipsychotic drugs such as haloperidol, flupentixol, chlorpromazine and anxiolytics such as diazepam, lorazepam, triazolam, alprazolam and buspirone;

D. antidepressant drugs such as despiramine, imipramine, amitryptyline, clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, buproprion and citalopram;

E. dopaminergic antagonists such as bromocriptine, amandatin;

F. anticonvulsants and mood stabilizers such as carbamazepine, phenytoin, lithium, C ₈ H ₆ O ₂ (acid valproic), vigabatrin, lamotrigine, tiabagine and zonisamide;

G. cocaine-like agonists such as mazindole, methylphenidate;

H. cocaine catalytic antibodies; and

I. alcohol and opiate antagonist drugs such as disulfilram, acamprosate and naitrexone.

Use of Di / D ₅ antagonists or partial agonists

The Dj / D · of the present invention in combination with the other CNS compositions noted above may allow lower doses of each composition to be used, thereby providing increased efficacy while reducing side effects.

Suitable antagonist D1 / D5 agents are SCH 39166, SCH 23390, NCC-22-0010 and BTS-73-947. A suitable partial agonist of Di / D ₅ is (+) SKF 38393.

Since the present invention may, in certain embodiments, comprise administering a combination of two compositions, the compositions may be administered together or sequentially or in a single pharmaceutical composition. When the compositions are administered separately, the number of doses of each composition administered per day may not necessarily be the same, for example, when one composition has a longer duration of activity, it will therefore be administered less frequently. The compositions may be prepared using conventional pharmaceutical carriers and excipients and using conventional techniques. The compositions may be administered in conventional oral or extracorporeal form such as a capsule, tablet, powder, wafer, suspension or solution. When the composition is administered to the CNS in combination with antagonist Di / _D5 partial agonist or Di / Ds, the composition of the CNS všeobenosti administered in the known dosage ranges for the composition. The precise dose administered will be determined by the attending physician and will depend upon the strength of the composition administered, the age, weight and response of the patient.

The compositions may be administered to a mammal by any route of administration which provides the necessary concentration of a D1 / D5 antagonist or a D1 / D5 partial agonist. When the drug is administered orally by capsule or tablet, the daily dose will range from 0.1 mg / kg daily to 500 mg / kg daily, more preferably from 0.1 mg / kg to 150 mg / kg daily and most preferably from 0.1 mg / kg to 10 mg / kg daily. The compositions are preferably administered 1 to 3 times daily.

Tablet SCH 39166 may have the following composition, even though i other formulations are suitable: ingredients 5 mg 25 mg 100 mg The core SCH 39166 5, 0 25, 0 100.0 Lactose monohydrate NF 114.0 94.0 79.4 very fine powder Starch sodium glycolate NF 6, 0 6, 0 8.0 Povidone USP (K29 / 32) 4.0 4.0 10, 0 Magnesium stearate 1.0 1.0 2.0 Purified water USP / EP (evaporates) (evaporates) (evaporates) Weight of the tablet core 130 mg 130 mg 200 mg

The tablet may be coated by standard techniques using any approved dye. It is also contemplated that a sustained release of the composition could also be used to administer the composition over time.

Since the present invention may comprise separate administration of two compositions, the present invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. The kit will suitably include separate administration instructions.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and variations will therefore be apparent to those skilled in the art. All of these alternatives, modifications and variations are intended to be within the meaning and scope of the present invention.

Claims (6)

PATENT CLAIMS 1. The use of a D1 / D5 partial agonist Dj./D _5, or mixtures thereof for the preparation of a medicament for the reduction of the needs of food or addictive substance in a mammal. The use according to claim 1, wherein the D1 / D5 antagonist or Dj / Ds partial agonist is administered at a daily dose ranging from 0.01 mg / kg to 500 mg / kg. Use according to claim 1 or 2, wherein the addictive substance is cocaine, amphetamine, nicotine, opiates, tobacco or alcohol. Use according to claims 1 to 3, wherein the D1 / D5 antagonist is SCH 39166, SCH 23390, BTS-73-947, NCC-22-0010, JHS-271, JHS198, JHS-136, or A 69024 and the D1 / D5 partial agonist is SKF 38393. Use according to any one of claims 1 to 4, wherein the D 1 / D ₅ antagonist is SCH 39166. Use of a D1 / D5 antagonist or Dj / Ds partial agonist in combination with one or more means selected from the following classes for the preparation of a medicament for reducing a food or addictive drug need in a mammal: A. anti-obesity agents; B. 5-hydroxytriptamine receptor agonists and antagonists; C. antipsychotics / anxiolytics; D. antidepressants; E. dopaminergic agonists; F. anticonvulsant / mood stimulants; G. cocaine-like agonists; H. cocaine catalytic antibodies; and I. alcohol and opioid antagonist drugs. The use of claim 6, wherein the D1 / D5 antagonist is selected from SCH 39166, SCH 23390, BTS-73-947, NCC-22-0010, JHS271, JHS-198, JHS-136 or A 69024. 8th The use 39,166th according to claim 7, where a Di / D ₅ antagonist is SCH 9th The use food u SCH 39166 na mammals. training drug to reduce needs 10 . Application of SCH 39166 to nicotine in a mammal. training drug to reduce needs 11 report to reduce food and addictive needs substances, characterized in that it comprises D1 / D5 antagonists or a partial Di / D ₅ agonist in combination with one or more agents selected from the following classes: A. anti-obesity agents; B. 5-hydroxytriptamine receptor agonists and antagonists; C. antipsychotics / anxiolytics; D. antidepressants; E. dopaminergic agonists; F. anticonvulsant / mood stimulants; G. cocaine-like agonists; H. cocaine catalytic antibodies; and I. alcohol and opioid antagonist drugs. The kit of claim 10, wherein the D1 / D5 antagonist is SCH 39166. Use of SCH 39166 in combination with an anti-obesity agent for the preparation of a medicament for reducing food needs in a mammal. Use according to claim 13, wherein the anti-obesity agent is selected from beta 3 agonists, sibutramine, lipase inhibitors, NPY agonists and antagonists, 5HT-2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotropin releasing factor l, agents and blockers, fat absorbing blockers, and nicotinic agonists. The use of claim 14, wherein the lipase inhibitor is orlistat. Use according to claim 14, wherein the anti-obesity agent is sibutramine. The use of claim 14, wherein the anti-obesity agent is a beta 3 agonist. Preliminary international survey report Group IV The problem underlying the present application is to provide medicaments that suppress the needs of a food or other addictive substance in a susceptible mammal. See. p. 1, 2nd paragraph of the application. The proposed solution to the problem is a decrease in dopamine mediated by interaction needs receptors Di / D ₅ modulators Di / D _5th However, the role of dopamine in the need as well as the use of Di modulators to reduce drug retrieval is well known in the prior art cited in the exploratory report and application (page 1), which discloses the ability of Di modulators such as SCH 23390, SCH 39166 and SKF 38393 to reduce food consumption. , cocaine, amphetamine, and ethanol. Consequently, there is no required uniformity of the invention (PCT Regulation 13.1) to the extent that a technical relationship involving one or more corresponding special technical features within the meaning of PCT Regulation 13.2 does not exist among the subject matter of the 4 groups of dependent claims defined in the exploratory report. See. PCT / ISA / 210 (special sheet). It should be noted that each of the individual causing agents (e.g., food, cocaine, nicotine, ethanol) leads to specific problems that require individual management of the disease and the individual side effects of the agent. This concept has also been expressed in the present application where treatment with a Di / D ₅ modulator is intended to reduce both the desire to take an addictive substance and the possible interference with other addictive substance-specific effects. See. for example 2. Thus, the examination of each of the four patients, as mentioned above, must necessarily be based on a prior art that is different for each of the addictive substances. Group V 1) The following documents (D) cited in the International Exploration Report are referred to in this report; the list shall be attached at the end of the Protocol: D1 = PSYCHOPHARMACOLOGY, (1995 JUL), 120 (2): 227-35 D2 = PSYCHOPHARMACOLOGY, (1994 JAN) 113 (3-4): 328-33 D3 = AMERICAN J. OF PHYSIOLOGY, (1995), 269 (4 PT 2): R896-903 D 4 = WO-A-96 13257 D5 = WO-A-9746239 D6 = BRAIN RESEARCH, (1995 MAR), 673 (2): 242-50 D7 = BRAIN RESEARCH, (1995 AUG), 731 (1-2): 31-8 D8 = NIDA RES. Monogram. (1992), 119 (PROBL. DRUG. DEPEND. 1991): 185-9 D9 = EUROPEAN J. PHARMACOLOGY, (1985), 111 (2): 167-76 D10 = PHARMACOLOGY, BIOCHEM. & BEHAVIOR., (1994 JUL) 48 (3): 817-20 D11 = ALCOHOL, (1993), 10: 207-212 D12 = PHARMACY (1995), 50 (12): 815-18 Unless otherwise indicated, the reference refers to the important passages highlighted in the exploratory report 1.1 Preliminary document D5 discloses the use of D 1 agonists such as SKF 38393 (cf. claim 4 of the present application) to reduce food intake. 2) Novelty The subject-matter of claims 1 to 12 is not new. 2.1 Claims 1, 2, 4, 5, 9 relate to the use of Di / Ds modulators such as SCH 39166 to reduce food needs. The use of SCH 39166, SCH 23390 (antagonists) and SKF 38393 (agonists) to reduce food intake as described in Examples 3-5 of the present application is known from D1, D2 and D3. D1 further suggests use in the treatment of obesity, cf. Example 6 of the present application. 2.2 Claims 1 to 5, 10 relate to the use of Di / D ₅ modulators such as SCH 39166 to reduce the need for addictive substances such as cocaine, amphetamine, nicotine and alcohol. Documents D6, D7 and D8 describe the debilitating effects of D1 / D5 modulators such as SCH 39166, SCH 23390 and SKF 38393 on cocaine reactions, suggesting that the results of the investigation could have consequences for the treatment of cocaine needs. D9 discovers the beneficial effects of SCH 23390 inter alia on amphetamine stimulus. D10 concerns the reduction of nicotine discrimination by SCH 23390. D11 and D12 describe reducing alcohol intake and eliminating ethanol symptoms with SCH 23390 and SKF 38393. 2.3 Claims 6 to 8, 11, 12 relate to combinations containing Di / Ds modulators and other active agents, and the use of these combinations to reduce food or dietary needs, respectively. addictive substance. The use of SCH 39166 and SCH 23390 or SKF 38393 with other active agents is known from D2 and D3. Kits that include SCH 23390 and receptor NER modulators are disclosed in D4. A combination of modulators Di / D ₅ with other active ingredients are also found in documents D6 and D9, D12 and Dll that show positive correlations between Di and other dopaminergic and / or glutaminergickými systems in terms of the behavior of the discovery of an addictive substance. 3) Industrial applicability The subject matter of the claims relates to pharmaceutical products and their individual medical uses, which is in accordance with Article 33 (4) of the PCT. Group VI D5 = WO-A-97 46239, Publication date 11.12.98, Date of completion 06.06.97, Priority date 06.06.96. Group VII 4) Contrary to the requirements of regulation 5.1 (a) (ii) of the PCT, the relevant background of the prior art disclosed in documents D1 to D4, D6 to D12 is not mentioned in the description and these documents are also not found here. Group VIII 5) It is not clear which means are meant by the term partial agonist, even when read in the context of the definition provided on p. 5 (mimic dopamine under certain conditions). Note that D2, D3 and D5, for example, designate SKF 38393 as a D 1 agonist. 6) The claim 12 depends on claim 11 rather than claim 10 as mentioned. Dear Sir, In reply to the Preliminary International Survey Report of 12 July 1999, the applicant adds claims to the aforementioned patent application. The deadline for tabling amendments expires on 12 September 1999. Please add new claims: Use of SCH 39166 in combination with an anti-obesity agent for the preparation of a medicament for reducing food needs in a mammal. Use according to claim 13, wherein the anti-obesity agent is selected from beta 3 agonists, sibutramine, lipase inhibitors, 5HT-2c agonist agonists, melanocortin and NPY antagonists, peptide glucagon-like receptor 1, cholecystokinin, leptin mimic and peptide, corticotropin , agents and blockers, fat absorbing blockers by nicotinic agonists. 15. Use of orlistat. according to claim 14, wherein the lipase inhibitor is Use according to claim 14, wherein the anti-obesity agent is sibutramine. The use of claim 14, wherein the anti-obesity agent is a beta 3 agonist. notes The applicant has supplemented the claims of the aforementioned patent application as imposed by Article 19 of the PCT in the Preliminary International Survey Report received two months ago by adding claims 13 to 17 in the appendix designated as new page 20A. These claims are not beyond the disclosure in the international patent application. Exact help for additional claims 13 to 17 can be found on p. 12, lines 24-31, and p. 13, lines 17-23 of PCT published patent application. 20Α Use of SCH 39166 in combination with an anti-obesity agent for the preparation of a medicament for reducing food needs in a mammal. The use of claim 13, wherein the anti-obesity agent is selected from beta 3 agonists, sibutramine, lipase inhibitors, NPY agonists and antagonists, 5HT-2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotropin release factor 1, agents and blockers, fat absorbing blockers, and nicotinic agonists. The use of claim 14, wherein the lipase inhibitor is orlistat. The use of claim 14, wherein the anti-obesity agent is sibutramine. The use of claim 14, wherein the anti-obesity agent is a beta 3 agonist.