CN1283116A - Method of reducing craving in mamals - Google Patents

Method of reducing craving in mamals Download PDF

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CN1283116A
CN1283116A CN98812730A CN98812730A CN1283116A CN 1283116 A CN1283116 A CN 1283116A CN 98812730 A CN98812730 A CN 98812730A CN 98812730 A CN98812730 A CN 98812730A CN 1283116 A CN1283116 A CN 1283116A
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antagonist
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addiction
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cocaine
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V·科芬
P·W·格吕
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Merck Sharp and Dohme Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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

Reduce the method for craving in mamals
Background of invention
The present invention is directed to and reduce mammiferous addiction.More specifically, the present invention is directed to and reduce mammal comprising food or cause the addiction of addiction material the mediation of any dopamine.
People have carried out big quantity research at obesity, nicotine addiction and substance abuse.The loss of the health relevant with obesity, tobacco consumption, medicine and alcohol abuse is very big to the loss that society causes.Yet when many people select fat-reducing, stop smoking and (or) when stopping Drug abuse or ethanol, during they receive treatment through being everlasting or treat in the behavioral pattern before firm end will be returned to its treatment soon again and go.This often is to be caused by some the delicate signals in the environment, and these signals can excite individual patients to food or they addiction of indiscriminate exhausted material once.Therefore, if a kind of material that can suppress the mammal that is easy to be addicted to the addiction of food and/or abuse material can be provided, will be very good.
The application of D1 antagonist in use in drug-abuse therapy known.United States Patent (USP) the 4973586th and announced the application of D1 antagonist in the medicine dependency for No. 5302716.Its recommended doses scope is 0.02-10mg/kg, and particularly preferred dosage is 2.0mg/kg every day, divides to give for 1-3 time.
Spealman etc., Neurochem.Int.Vol.20 Suppl., 99147S-152S (1992) have announced that cocaine is a kind of strong reinforcing agent, are often used as the standard of estimating the other drug reinforced effects.When using SCH 39166, need increase by 3 times or highlyer could recover its distinctive self administration behavior to the dosage of cocaine usually to monkey.
Barrett-Larimore and Spealman are at Society for NeuroscienceAbstract 22 (2): some kinds of chemical compounds of report in 92 5 (1996), comprise D1 antagonist SCH 39166, a kind of D2 antagonist and a kind of D3/D4 antagonist, all can weaken the behavior of the searching cocaine in the cocaine recurrence model.
Clifton, 1995 and Clifton, 1991 when pointing out D1 antagonist SCH 39166 and SCH23390 dosage up to 3mg/kg, and food total amount, meal amount size or the eating speed of picked-up are not all had influence.
Caine and Koob have described the enhanced experiment of 23390 pairs of cocaines of D1 antagonist SCH 39166 and SCH and food oneself at The Journal of Pharmacology and ExperimentalTherapeutics Vol.270 in the No.1 209-218 page or leaf (1994).Find that the D1 antagonist influences cocaine self administration behavior.
Chausmer and Ettenberg be at Pharmacology Biochemistry andBehavior Vol.57, No.4, in the 681-685 page or leaf (1997) to D1 and D2 antagonist the recovery characteristics of replying in the food award test.They find that D2 antagonist raclopride can block food effectively and strengthen the restitution of replying that causes, but D1 antagonist SCH 39166 is not all right.
Nathan, Breskin and Batki have summarized the result who causes addiction with different pharmaceutical treatment cocaine at CNS Drugs 1998 in Jul 10 (1) the 43-59 pages or leaves.
At Lancet the 347th volume, the 504-508 page or leaf has reported in (on February 14th, 1996) that haloperidol is used to alleviate serious hope to Drug abuse by test.Yet, it is reported that this chemical compound has harmful side effect clearly, for example irritated, uneasy or stiff, this has reduced individual patients and has adopted their interest.
Owing to lack the reliable animal model very relevant with behavior of men, the material of therefore developing some addictions that can suppress mammal (especially human) is very difficult.
The material that is used to reduce addiction should not produce tangible physiological reaction, quickens such as excited, hypertension or heart rate.It is another kind of to cause a kind of abuse material to replace like this.Be used to prevent and have a liking for the chemical compound of addiction also should not aggravate to abuse material when individuality recovers and use the abuse material physiological reaction abusing material.The material that is used to reduce addiction should not produce significant side effects, such as irritated, uneasy or stiff.
Therefore, be necessary to provide a kind of chemical compound and Therapeutic Method, make it can reduce addiction effectively, and can not aggravate, and have good drug effect by the orthosympathetic speed of replying that causes of abuse material to the abuse material.
Equally also being necessary provides a kind of chemical compound and Therapeutic Method, is used to block by abusing glad and irritated that material causes.
Summary of the invention
What the present invention is directed to is to use D1/D5 antagonist, D1/D5 partial agonist or their mixture separately, perhaps they are combined with other CNS chemical compounds, reduce mammiferous addiction with the preparation medicine, especially to food or cause the addiction of addiction material, for example Nicotiana tabacum L., ethanol or Drug abuse.In a preferred embodiment, give administration D1/D5 antagonist or the D1/D5 partial agonist be easy to be addicted, the dosage scope be every day about 0.01 to about 500mpk, be preferably 1-150mpk every day.Preferred D1/D5 antagonist is SCH 23390, SCH39166, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 and A69024, and wherein SCH 39166 is particularly preferred.Preferred D1/D5 partial agonist is SKF 38393.
D1/D5 antagonist or D1/D5 partial agonist can be used in combination with the chemical compound of selecting from following CNS family:
A: obesity chemical compound;
B:5-seretonine receptor 5 agonist and antagonist;
C: psychosis/antianxiety drugs;
D: antidepressant;
E: dopaminergic agonist;
F: anticonvulsant drug/amitriptyline;
G: the agonist of cocaine sample;
H: the catalytic antibody of cocaine; And
I: ethanol and Opiate antagonist pharmaceuticals.
The accompanying drawing summary
Fig. 1 has described the effect of the controlled motion that a kind of D1/D5 antagonist and a kind of D2 antagonist change with dosage.
Fig. 2 has described after using cocaine, the effect of the controlled motion that a kind of D1/D5 antagonist and a kind of D2 antagonist change with dosage.
When Fig. 3 and 4 had described the preferred D1/D5 antagonist of using various dose and a kind of placebo, before using cocaine and afterwards systolic pressure and diastolic pressure were over time.
When Fig. 5 and 6 has described the preferred D1/D5 antagonist of using various dose and a kind of placebo respectively, before using cocaine and heart rate afterwards and body temperature.
When Fig. 7 and 8 has represented to use the preferred D1/D5 antagonist of various dose and a kind of placebo respectively, before using cocaine and subjective afterwards glad and anxiety curve.
Fig. 9 is illustrated in and has used after a kind of preferred D1/D5 antagonist or a kind of placebo, to the subjective wishes of cocaine picked-up in time and the curve that changes
Figure 10 and 11 is illustrated respectively in and uses before the cocaine and afterwards the subjective estimation of good drug influence and bad drug influence is reached change curve to patient's dosage in time.
Figure 12 and 13 be illustrated in use amphetamine and use a kind of preferred D1/D5 antagonist or a kind of placebo after positive and psychoreaction passiveness over time.
Figure 14 and 15 has shown the chemical constitution of selected compounds.
Detailed Description Of The Invention
Cause the addiction material and refer to any material that susceptible mammal dopamine discharges that triggers. Cause the addiction material and include, but are not limited to, nicotine, alcohol and psychomotor excitant, for example amphetamine, opiate, benzodiazepine * and group of barbiturates.
Sensual desires be often to environment hint response a kind of to food or cause strong, the lasting serious hope of addiction material and yearning. A kind of ignition dosage that causes the addiction material can cause that before repressed searching of mammal causes addiction agent behavior recurrence.
Have been found that dopamine D1The sealing in site can block the sensual desires relevant with abstinence from alcohol and by low dose cause the addiction material and (or) sensual desires that triggers of coherent signal. Can suppress or block sensual desires to food or Abused drug with the D1/D5 antagonist of low dosage or D1/D5 partial agonist.
Although the embodiment that below enumerates for be the D1/D5 antagonist, people expect that simple D1 antagonist, simple D5 antagonist, simple D1 partial agonist and simple D5 partial agonist and D1/D5 partial agonist also can reduce sensual desires effectively. Terminology used here " D1/D5 antagonist " only comprise with the compound (simple D1 antagonist) of D1 receptors bind and only with the compound (simple D5 antagonist) of D5 receptors bind, the while also comprises the compound of all being combined with two kinds of acceptors. Equally, term " D1/D5 partial agonist " only comprise with the compound (simple D1 partial agonist) of D1 receptors bind and only with the compound (simple D5 partial agonist) of D5 receptors bind, the while also comprises the compound of all being combined with two kinds of acceptors and can imitating under given conditions dopamine. Term " its mixture " is defined as the mixture of the mixture that comprises two kinds of (or more) D1/D5 antagonists, two kinds of (or more) D1/D5 partial agonists and the mixture of a kind of (or more) D1/D5 antagonist and a kind of (or more) D1/D5 partial agonist. Wherein preferred D1/D5 antagonist is:
SCH 39166, and chemical name is (-)-trans-6,7,7a, 8,9,13b-, six hydrogen-3-chloro-2-hydroxy-n-methyl-5H-benzo [dextrorotation]-naphthols-[2,1-b] azepines;
SCH23390, chemical name are (dextrorotation)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydrochysene-1H-3-Benzazapine (benzazepine) maleate;
BTS-73-947, chemical name are 1-[1-(2-chlorophenol) cyclopropyl]-1,2,3,4-tetrahydrochysene-7-hydroxyl-6-methoxyl group-2-methyl-(S)-isoquinolin;
NNC-22-0010, chemical name are (+)-5-(5-bromo-2,3-dihydro-7-benzofuran)-8-chloro-2,3,4,5-tetrahydrochysene-3-methyl isophthalic acid H-3-Benzazapine-7-alcohol;
JSH-271, chemical name are 8-chloro-3-[6-(dimethylamino) hexyl]-2,3,4,5-tetrahydrochysene-5-phenyl-1H-3-Benzazapine-7-phenol;
JSH-198, chemical name are 8-chloro-3-[6-(dimethylamino) hexyl]-2,3,4,5-tetrahydrochysene-5-phenyl-1H-3-Benzazapine-7-phenol and monoborane nitrile borate (boranecarbonitrile) (ratio is 1: 1);
JSH-136, chemical name are 8-chloro-3-[4-(dimethylamino) butyl]-2,3,4,5-tetrahydrochysene-5-phenyl-1H-3-Benzazapine-7-phenol reaches;
A-69024, chemical name are 1-[(2-bromo-4, the 5-dimethoxy benzene) methyl]-1,2,3,4-tetrahydrochysene-6-methoxyl group-2-methyl-7-isoquinolin.
A kind of preferred D1/D5 partial agonist is SKF 38393, and its chemical name is 2,3,4,5-tetrahydrochysene-1-phenyl-1-H-3-Benzazapine-7,8-diphenol.Figure 14 and 15 has shown the structure of these chemical compounds.
The preferred application dosage of these chemical compounds be every day about 0.01 to about 500mg/kg, more preferably every day about 1 is to about 150mg/kg.Can see that from following test these exemplary compounds can suppress addiction effectively.
Embodiment 1
Embodiment 1 has illustrated that the D1/D5 antagonist is effectively in reducing the addiction that causes addiction material cocaine, and the effectiveness of D2/D3 antagonist is much lower.The rising of the locomotor activity that cocaine causes can be blocked by the D1/D5 antagonist, but can not be by D2/D3 antagonist blocking-up (unless using high relatively dosage).In this example, (Kui third quinoline raclopride) is used for male CF-1 mice, stimulates with the inductive behavior of research cocaine with a kind of optionally D1/D5 antagonist (SCH39166) and a kind of optionally D2/D3 antagonist.Use SCH 39166, Kui third quinoline or the excipient of oral dose to mice, subcutaneous (sc) uses the cocaine or the excipient of doses after 20 minutes.Measured the motor capacity of mice later in 10 minutes, be 8 minutes measuring period, and measurement result is seen Fig. 1.As shown in Figure 2, when using SCH 39166 or Kui third quinoline separately, can cause the dose-dependent motor capacity of mice to reduce.Yet, when the cocaine of attempting with various dosage, the reduction of SCH 39166 motor capacity that causes by cocaine all capable of blocking, and Kui third quinoline can only just can influence the reduction of the motor capacity that cocaine causes when higher relatively dosage.
Embodiment 2
Present embodiment is used preferred D1/D5 antagonist to individual patients after being presented at the injection cocaine, and this antagonist is effectively and not to show significant side effects.These test selected individual patients once had cocaine to have a liking for addiction history and aspiration to participate in this plan in the past.In a double-blind study, before injection 30mg/kg cocaine two hours, use the SCH 39166 of SCH 39166,25mg of placebo, 10mg or the SCH39166 of 100mg to the patient earlier.During about 4 hours, measure the systolic pressure and the diastolic pressure of individual patients at preceding 2 hours of cocaine of injection after use cocaine.Can see the systolic pressure that D1/D5 antagonist SGH 39166 can not reverse influence be caused by cocaine and the rising of diastolic pressure respectively from Fig. 3 and 4.Fig. 5 is presented at and uses after the cocaine, and average heart rate (per minute heart beating number of times) can not aggravate because of using of SCH 39166, and Fig. 6 then shows by using the fervescence that cocaine causes and can not worsened.
In same research, as the time function after using placebo or the pharmacological action after giving the SCH 39166 of various dose, measured serious hope degree to the picked-up cocaine.(Visual AnalogScale VAS) tests and to measure by visualization analog scaling chi to the serious hope degree of picked-up cocaine.This test procedure is described in British Journal ofMedical Psychology, the 47th volume, 211-218 page or leaf (1974).In this test, require individual patients in the graduated scope of 0 to 100 (mm) subjective evaluation its want to absorb the degree of cocaine sensation, 0 (mm) expression does not have hope, 100 (mm) to represent strong desire fully.As can see from Figure 7, carrying out among the pretreated patient with SCH 39166 (especially dosage is 100mg), it is lower to use afterwards glad " highly " (" high ") of cocaine.Fig. 8 is presented at SGH 39166 and carries out among the pretreated patient, uses the cocaine influence of dysphoria (for example anxiety) afterwards and decreases.As seen from Figure 9, compare with placebo, the individual patients of using SCH 39166 obviously reduces the serious hope degree of absorbing cocaine.The individual patients of using 100mg SCH 39166 is maximum to the serious hope reduction of picked-up cocaine.
Similarly, in another crossing research that the healthy volunteer is carried out, do pretreatment with 100mg SCH39166 or placebo, use 15mg d-amphetamine again, can be observed, compare with placebo, use SCH 39166 influence of amphetamine glad (Figure 12) and anxiety (Figure 13) is weakened.
Even the chemical compound among the present invention produces effect aspect the addiction of abuse material and food in reduction, the patient also is unwilling to adopt the medicine that reduces addiction, unless these side effects of pharmaceutical drugs can be stood.Figure 10 has shown " good drug effect ", just, after medication 1.5 hours, show by visualization analog scaling chi experimental measurement, the patient to the good feel of this chemical compound (even dosage reaches 100mg) not than the obvious reduction of placebo.As shown in figure 11, judge that by the test of visualization analog scaling chi on identical time point, the bad drug effect of the SGH 39166 of all dosage does not all have obviously different with placebo.Therefore, the passive viewpoint of using the patient of this medicine should not influence using of this medicine, and after using this medicine, this medicine can not cause excitement yet.
To studies have shown that of the bounce-back of the addiction after the food addiction of Rodents and primate model and the erstricted diet, the recurrence that the influence of D1/D5 antagonist SCH 39166 ambient signal relevant with food and food capable of blocking is correlated with.Yet, be not bound by any theory, the D1/D5 antagonist and (or) the D1/D5 partial agonist in the treatment obesity, can stop the bounce-back of appetite by the positive influences of dopamine on the blocking-up D1/D5 site relevant with addiction.
Embodiment 3-5 provides other examples about the effect of D1/D5 antagonist in reducing mammal food addiction.
Embodiment 3
In the present embodiment, (plant system: CD) press batten with the adult male rat of 30 plans of fixed frequency (fixed-ratio schedule of30, FR 30) training to obtain food.A rat must be pressed batten 30 times for the food pellets that obtains a 45mg.Be 30 minutes each cycle of training.Measure total speed (press batten total degree/30 minutes) of replying, just rat is pressed the speed of batten, the animal that normal saline solution the time is used in beginning is analyzed (control animal) then, then the D1/D5 antagonist SCH 23390 that uses various dose or the animal of SCH39166 is analyzed.Began preceding 30 minutes a training period, give the medicine of six every group animal subcutaneous injection 1ml/kg dosage.The dosage of SCH 23390 is 0.003,0.005,0.01 and 0.03 mg/kg (mpk), and the dosage of SCH 39166 is 0.001,0.003,0.01,0.03,0.1 and 0.3 (mpk) simultaneously.Compare with the control animal of handling, press the frequency of batten obviously to reduce through the animal that the SCH 23390 and the SCH 39166 of 0.01mpk dosage handle through normal saline solution.Two kinds of medicines all can cause the dose-dependent speed of replying to reduce, and reach until dosage and reply disappearance when the highest.
Embodiment 4
In whole research process, 24 fat male mices (16 age in week) of planting system's (being the ob/ob mice) of heredity are closed in the Nalgene metabolic cage separately respectively, during whole research, be placed in the room of light periodically-varied.Mice is pickuping food and water arbitrarily.According to the foundation level of food intake and the difference of body weight mice is divided into 5 groups, every group of 4-5 only.When the dark cycle begins, give the SCH39166 of injection of vehicle or 0.003,0.03,0.3,3.0mg/kg in the mouse peritoneum, provide the solid type food of rodent standard of known quantity to it.Measure the consumption of food after 5 hours, continue intraperitoneal injection excipient or medicine that another is taken turns.Behind the initial injection 24 hours, measure food-intake again.This injection and measurement continue 72 hours.When dosage was 3.0mg/kg, 72 hours accumulative total food intake reduced by 17% (p＜0.02).
Embodiment 5
In this test, give rat brain indoor (interocerebral ventricular, i.c.v) injection neuropeptide " Y " (NPY, a kind of chemical compound that stimulates the animal feed) afterwards, 2, the 4 or 24 hours measuring basis food-intakes (in gram) in every interval.(Sprague-Dawley SD) uses the NPY of 3 μ g/5 μ l dosage to give the bull rat.Testing the same day, using three groups of rats of SCH 39166 pretreatment (5 every group) according to following drug dosage schedule:
The SCH 39166 of intraperitoneal (ip) injection doses.After 30 minutes, intracerebral ventricle injection 3mg NPY.Give control animal ip injection of vehicle methylcellulose.After 30 minutes, use NPY (3mg) to animal.The SCH of second group of ip injection 1mpk is ip injection 3mg NPY after 39166,30 minutes.The SCH of the 3rd treated animal ip injection 3mpk is ip injection 3mg NPY after 39166,30 minutes.Injection NPY measured food intake later on every 2 hours, 4 hours and 24 hours.Accepting 3mpk SCH 39166 pre-treated animal showed tangible food intake in 2 hours later on and reduces using NPY.
Embodiment 6
In a polycentric double-blind study, the patient that about 160 cocaines are relied on carries out transition (interim) and analyzes, and acceptable dose is 10mg, 25 or SCH 39166 or the placebo of 100mg to these patients every day in the test period in 8 weeks.Though this research does not show the effect of SCH 39166 aspect minimizing cocaine consumption, 39166 pairs of reductions of its proof SCH body weight, minimizing alcohol consumption and smoking have positive effect.
Table 1 was presented in time of 28-25 days, accepted patient's the quantity of the SCH39166 of placebo or predetermined close.Measure in the beginning of research with when finishing body-mass index (BodyMass Index, BMI) and weight in patients.BMI is by body weight (kilogram)/height (rice) 2Determine.The BMI value is normal for the patient of 20.0-24.9 is considered to body weight, and the BMI value is higher than 25.0 patient and then is considered to overweight.
Table 1A lists patient's percentage rate that each apoplexy due to endogenous wind body weight reduces by 5 pounds at least.Table 1B shown initial BMI value be 22 or lower and BMI value be at least among 26 the patient and reduce by 1 percentage rate that BMI unit is shared at least.As can be seen, SCH 39166 (especially dosage is 100mg/kg) is especially effective to the body weight that reduces obese people (just the BMI value is 26 or higher) from these forms.
Table 1A
Ecopipam is to the influence (patient that the cocaine of finishing 〉=treating in 28 days relies on) of body weight
Treatment n= Benchmark BMI Body weight changes (pound) Body weight reduces (〉=5 pounds) patient
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= The initial BMI in the patient 〉=initial BMI of 1 BMI unit≤22 〉=26 that body weight reduces
Placebo ?34 ?3/8(38％) 3/13(23％)
10?mg ?30 ?2/9(22％) 2/10(20％)
25?mg ?32 ?2/10(20％) 4/13(30％)
100?mg ?29 ?1/6(17％) 10/14(71％)
D1/D5 antagonist among the present invention or D1/D5 partial agonist can be used for the treatment of the food addiction separately, also can be used in combination with other medicines, behavior therapy for example, the fat-reducing plan, other CNS chemical compound of describing among the present invention, especially the obesity chemical compound comprises beta 3 antagonisies, lipase inhibitor (as orlistat), NPY agonist and antagonist, 5HT 2c receptor stimulating agent, glucagon-like peptide 1, melanocortin peptide, cholecystokinin, corticotropin-releasing factor, leptine sample (leptin-mimicking) chemical compound and blocker, fat absorption blocker and nicotinic agonist.Preferred beta 3 agonist have:
BMS 196085, and its chemical name is [R-(R *, R *)]-[4-[2-[[2-(3-chlorphenyl)-2-ethoxy] amino] propyl group] phenoxy group] methanesulfonic acid; And
SR 58611A, its chemical name are [R-(R *, S *)]-[[7-[[2-(3-chlorphenyl)-2-ethoxy] amino] 5,6,7,8-tetrahydrochysene-2-naphthalene] the oxygen base] the acetic acid ethyl ester.The structure of these chemical compounds as shown in figure 15.
D1/D5 antagonist among the present invention or D1/D5 partial agonist can be used in combination with other medicaments, these medicaments have been proved to be and can have absorbed the serious hope that reaches food intake by erstricted diet, and these medicaments comprise sibutramine (sibtramine), fluoxitine Fenfluramine and analog, amphetamine and analog, phentolamine, diethylproprion and mazindol.
Table 2 proof was measured through many days, and patient crowd's alcohol consumption amount of not absorbing any ethanol reduces.
Table 2
The dosage of SCH39166 (milligram) Abstain patient's percentage rate (%) of at least 1 day of ethanol Abstain patient's percentage rate (%) of at least 3 days of ethanol
0 (placebo) ?35 ?29
?10 ?43 ?23
?25 ?41 ?31
?100 ?59 ?48
D1/D5 antagonist among the present invention or D1/D5 partial agonist can be used for the treatment of the ethanol addiction separately, also can with behavior therapy and (or) other CNS chemical compound described in the present invention (especially ethanol agonist drug) is used in combination.
Table 3 shows that the SCH 39166 of low dosage also is being effective aspect the reduction smoking capacity.
Table 3
The dosage of SCH 39166 (milligram) Apart from patient's percentage rate (%) of at least 1 day of smoking last time Apart from patient's percentage rate (%) of at least 3 days of smoking last time
?0 ?32 ?3
?10 ?57 ?27
?25 ?53 ?19
?100 ?38 ?17
D1/D5 antagonist among the present invention or D1/D5 partial agonist chemical compound can be used for the treatment of nicotine separately and have a liking for addiction, also can be used in combination with behavior therapy, smoking cessation plan, Nicotine replacement therapy (for example fragment (patches) and chewing gum); Be used in combination separately or with other CNS chemical compound, especially buspirone described in the present invention and bupropion (original text is Buproprion, intends should be Bupropion).
Chemical compound among the present invention can be used separately, also can be used in combination with some other specific DNS chemical compound, and these chemical compounds comprise:
A. the obesity chemical compound comprises beta 3 agonist, sibutramine, fat suppression agent (as orlistat, NPY agonist and antagonist), 5HT-2c receptor stimulating agent, glucagon-like peptide 1, melanocortin peptide, cholecystokinin, corticotropin-releasing factor, leptine sample (Leptin-mimicking) chemical compound and blocker, fat absorption blocker and nicotine agonist;
B.5-seretonine receptor 5 agonist, for example buspirone, a gepirone and Yi Sha cutting edge of a knife or a sword (ipsapirone); Or 5-hydroxytryptamine receptor antagonist, for example ritanserin (ritanserin), Ketanserin (ketanserin), ondansetron (ondansetron), Granisetron, sumitriptan, rizatriptan and electriptan;
C. antipsychotic drug (as the fixed alcohol of fluorine piperazine, haloperidol, chlorpromazine) and antianxiety drugs are (as stable, tavor triazolam, alprazolam and buspirone;
D. antidepressant drug is as despiramine, imipramine, amitriptyline, Clomipramine, fluoxetine, fluvoxamine, paroxetine, Sertraline, Bupropion and citalopram;
E. dopaminergic agonist is as bromine angle wheat cyclic peptide, amantadine;
F. anticonvulsant drug and mood stabilizer are as carbamazepine, phenytoin, lithium, valproic acid, vigabatrin, lamotrigine, Tiagabine (tiagabine) and zonisamide;
G. the agonist of cocaine sample is as mazindol, BA4311;
H. the catalytic antibody of cocaine; And
I. ethanol and opiate antagonist are as alleviating alcohol addiction sulfur, acamprosate, naltrexone.
D1/D5 antagonist among the present invention and D1/D5 partial agonist reduce with the using dosage that being used in combination of above-mentioned other CNS chemical compound can make every kind of chemical compound, thereby improve drug effect and reduce side effect.
Preferred D1/D5 agonist compounds is SCH 39166, SCH 23390, NNC-22-0010 and BTS-73-947 among the present invention.Preferred D1/D5 partial agonist chemical compound is (+) SKF38393.
Because the present invention may comprise the compound recipe of two kinds of compositions and use that these compositions can simultaneously or one after the other be used together, perhaps use with single combination drug form in some certain embodiments.When each composition separate administration, the dosage number of times of every kind of composition every day is not necessarily identical, for example, when a kind of active duration of composition than long time, its frequency of using just can reduce.Can take traditional technology, with conventional pharmaceutical purpose excipient and additive preparation compound preparation.
These components can be used by any traditional mode oral or injection, for example capsule, tablet, powder, flat capsule, suspension or solution.When a kind of CNS chemical compound combines with D1/D5 antagonist or D1/D5 partial agonist when using, this CNS chemical compound will be used in its known dosage range usually.Accurate amount of application needs also to depend on drug effect, patient's age, body weight, health and the reaction of institute's administered compound by the clinician's decision that cures mainly.
To these chemical compounds of administration, can provide the concentration that needs of D1/D5 antagonist or D1/D5 partial agonist with various route of administration like this.When this medicine was oral with capsule or tablet form, the dosage range of every day was about 0.1 to about 500mg/kg, more preferably scope be every day about 0.1 to about 150mg/kg, most preferred scope is that every day about 0.1 is to about 10mg/kg.These chemical compounds are preferably used 1-3 time every day.
Although other component may also be fit to, the composition of SCH 39166 tablets is as follows: 5 milligrams of 25 milligrams 100 milligrams sheet heart SCH of composition, 39,166 5.0 25.0 100.0 lactose monohydrate NF, 114.0 94.0 79.4 attritive powder sodium starch hydroxyl second, 6.0 6.0 8.0 hydrochlorate NF polyvinylpyrrolidone 4.0 4.0 10.0USP (K29/32) stearic acid magnesium salts NF, 1.0 1.0 2.0 pure water USP/BP (evaporation) (evaporation) (evaporation) tablet sheet heart weight 130.0mg 130mg 200.0mg
This tablet can pass through standard technology, and the dyestuff that adopts any approval to use wraps quilt.Expect that the prescription of available a kind of lasting release prolongs the time of application of this chemical compound.
Though the present invention may comprise using respectively of two kinds of chemical compounds, the present invention also relate to simultaneously with each independently medicine component be combined into the form of medicine box.This medicine box preferably should comprise the description of using of each independent component.
Because the present invention combines with the above specific embodiment of enumerating to describe, many replacements wherein, modification, change concerning the personnel that grasp ordinary skill, all will be understood.All these replacements, modification, change all belong within essence of the present invention and the scope.
Claims are according to the modification of the 19th of treaty
Statement international office when revising according to " the 19th of Patent Cooperation Treaty " was received in JIUYUE in 1999 on the 8th, increased new claim 13-17, had kept the claim of not changing.
A kind of D1/D5 antagonist, a kind of D1/D5 partial agonist or their mixture at a kind of medicine of preparation, to reduce mammal to food or cause application in the addiction of addiction material.
2. the application described in claim 1, the application dosage scope of this D1/D5 antagonist or D1/D5 partial agonist are that every day about 0.01 is to about 500mg/kg.
3. application as claimed in claim 1 or 2, causing the addiction material has cocaine, amphetamine, nicotine, Opiate, Nicotiana tabacum L. or ethanol.
4. the application described in above claim 1-3, the D1/D5 antagonist has SCH39166, SCH 23390, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 or A69024, and the D1/D5 partial agonist is SKF 38393.
5. as any described application among the above claim 1-4, the D1/D5 antagonist is SCH 39166.
6. D1/D5 antagonist or D1/D5 partial agonist and one or more chemical compounds that are selected from following kind are combined in a kind of medicine of preparation, to reduce mammal to food or cause application in the addiction of addiction material:
A: obesity chemical compound;
B:5-seretonine receptor 5 agonist and antagonist;
C: psychosis/antianxiety drugs;
D: antidepressant;
E: dopaminergic agonist;
F: anticonvulsant drug/amitriptyline;
G: the agonist of cocaine sample;
H: the catalytic antibody of cocaine; And
I: ethanol antagonist pharmaceuticals.
7. the application described in above claim 6, the D1/D5 antagonist is selected from SCH39166, SCH 23390, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 or A-69024.
8. the application described in claim 7, D1/D5 antagonist are SCH 39166.
9.SCH 39166 at a kind of medicine of preparation, to reduce mammal to the application in the addiction of food.
10.SCH 39166 at a kind of medicine of preparation, to reduce mammal to the application in the addiction of nicotine.
11. one kind is used to reduce to food or causes the medicine box of the addiction of addiction material, comprises D1/D5 antagonist or D1/D5 partial agonist, and in conjunction with one or more chemical compounds that are selected from following kind of apoplexy due to endogenous wind:
A: obesity chemical compound;
B:5-seretonine receptor 5 agonist and antagonist;
C: psychosis/antianxiety drugs;
D: antidepressant;
E: dopaminergic agonist;
F: anticonvulsant drug/amitriptyline;
G: the agonist of cocaine sample;
H: the catalytic antibody of cocaine; And
I: ethanol antagonist pharmaceuticals.
12. the medicine box described in claim 10, D1/D5 antagonist wherein is SCH39166.
13.SCH 39166 with the combination of a kind of obesity chemical compound, reduce application in the medicine of mammal food addiction in preparation.
14. the application of claim 13, wherein the obesity chemical compound is selected from beta 3 agonist, sibutramine, lipase inhibitor, NPY agonist and antagonist, 5HT-2c receptor stimulating agent, glucagon-like peptide 1, melanocortin peptide, cholecystokinin, corticotropin-releasing factor, leptine sample chemical compound and blocker, fat absorption blocker and nicotine agonist.
15. the application of claim 14, wherein lipase inhibitor is orlistat.
16. the application of claim 14, obesity chemical compound wherein is a sibutramine.
17. the application of claim 14, obesity chemical compound wherein are beta 3 agonist.

Claims (12)

  1. A kind of D1/D5 antagonist, a kind of D1/D5 partial agonist or their mixture at a kind of medicine of preparation, to reduce mammal to food or cause application in the addiction of addiction material.
  2. 2. the application described in claim 1, the application dosage scope of this D1/D5 antagonist or D1/D5 partial agonist are that every day about 0.01 is to about 500mg/kg.
  3. 3. application as claimed in claim 1 or 2, causing the addiction material has cocaine, amphetamine, nicotine, Opiate, Nicotiana tabacum L. or ethanol.
  4. 4. the application described in above claim 1-3, the D1/D5 antagonist has SCH 39166, SCH 23390, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 or A69024, and the D1/D5 partial agonist is SKF 38393.
  5. 5. as any described application among the above claim 1-4, the D1/D5 antagonist is SCH 39166.
  6. 6. D1/D5 antagonist or D1/D5 partial agonist and one or more chemical compounds that are selected from following kind are combined in a kind of medicine of preparation, to reduce mammal to food or cause application in the addiction of addiction material:
    A: obesity chemical compound;
    B:5-seretonine receptor 5 agonist and antagonist;
    C: psychosis/antianxiety drugs;
    D: antidepressant;
    E: dopaminergic agonist;
    F: anticonvulsant drug/amitriptyline;
    G: the agonist of cocaine sample;
    H: the catalytic antibody of cocaine; And
    I: ethanol antagonist pharmaceuticals.
  7. 7. the application described in above claim 6, the D1/D5 antagonist is selected from SCH 39166, SCH 23390, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 or A-69024.
  8. 8. the application described in claim 7, D1/D5 antagonist are SCH 39166.
  9. 9.SCH 39166 at a kind of medicine of preparation, to reduce mammal to the application in the addiction of food.
  10. 10.SCH 39166 at a kind of medicine of preparation, to reduce mammal to the application in the addiction of nicotine.
  11. 11. one kind is used to reduce to food or causes the medicine box of the addiction of addiction material, comprises D1/D5 antagonist or D1/D5 partial agonist, and in conjunction with one or more chemical compounds that are selected from following kind of apoplexy due to endogenous wind:
    A: obesity chemical compound;
    B:5-seretonine receptor 5 agonist and antagonist;
    C: psychosis/antianxiety drugs;
    D: antidepressant;
    E: dopaminergic agonist;
    F: anticonvulsant drug/amitriptyline;
    G: the agonist of cocaine sample;
    H: the catalytic antibody of cocaine; And
    I: ethanol antagonist pharmaceuticals.
  12. 12. the medicine box described in claim 10, D1/D5 antagonist wherein is SCH39166.
CN98812730A 1997-10-28 1998-10-26 Method of reducing craving in mamals Pending CN1283116A (en)

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CN110327350A (en) * 2019-07-11 2019-10-15 温州医科大学 D1 dopamine receptor antagonist SCH39166 is in the application as preparation treatment eye pathological drug
CN110833621A (en) * 2019-12-06 2020-02-25 中国医科大学 Application of dopamine receptor 1 antagonist in preparation of drug for treating mouse schizophrenia caused by ketamine

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US6890951B2 (en) 1998-08-05 2005-05-10 Brookhaven Science Associates Llc Treatment of addiction and addiction-related behavior
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CN110327350A (en) * 2019-07-11 2019-10-15 温州医科大学 D1 dopamine receptor antagonist SCH39166 is in the application as preparation treatment eye pathological drug
CN110327350B (en) * 2019-07-11 2021-02-23 温州医科大学 Application of dopamine D1 receptor antagonist SCH39166 in preparation of drugs for treating pathological angiogenesis of eyes
CN110833621A (en) * 2019-12-06 2020-02-25 中国医科大学 Application of dopamine receptor 1 antagonist in preparation of drug for treating mouse schizophrenia caused by ketamine

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