TW200848020A - Use of 5-HT6 antagonists to prevent relapse into addiction - Google Patents

Abstract

The invention relates to a novel use of compounds and pharmaceutically acceptable salts thereof, which are 5-HT6 antagonists. These compounds are useful for the preparation of medicaments for preventing relapse into addiction, in particular relapse into addiction to substances of abuse, including opiates, hallucinogens, inhalants, phencyclidine, amphetamines, cocaine, cannabis, nicotine, and alcohol, into relapse to addiction to certain medicines, including sedatives, hypnotics and anxiolytics, and into relapse to certain addictive behaviors, including gambling.

Description

200848020 IX. INSTRUCTIONS: t invention belongs to the technical field; j technical field The present invention relates to a new use of a 5-ΗΤ6 antagonist and a pharmaceutically acceptable salt thereof. These compounds can be used to prepare drugs for preventing relapse of addictive or addictive behavior. L Prior Art 3 Background Art Due to the combination of genetic, drug-induced and environmental factors, it is generally recognized that addiction is a chronic recurrent disease. It will happen multiple times. But - fortunately - not always. "Addiction, physical, and/or psychological dependence can be the result of applying many substances of abuse, such as opiates, hallucinogens, cocaine, marijuana, nicotine, and alcohol (often referred to as "drugs,"). This sometimes disturbs "the real drug: medicine. However, it should be realized that the difference between the "drug," and "drug," is unclear. When used at the proper concentration, opiates, cocaine And marijuana certainly have a clear therapeutic benefit. Mutatis mUtandlS: When used inappropriately, drugs, especially certain sedatives, sleepy and anti-anxiety drugs, are bound to become addictive. For many people, running, It Things, gambling, smoking, and drinking are enjoyable entertainments. However, in particular, for the latter two, they usually cause cancer. In addition to training, there is no definitive therapy to prevent addiction. It is difficult for different drugs to successfully overcome addiction. When it is once cancerous, it is no longer difficult to find drugs, no longer craving for drugs, and it is not subject to withdrawal symptoms. It overcomes addiction and no longer thinks This person is a patient. 5 200848020 This is happening, but - unfortunately - not always. Once the addiction is cleared, at least as far as pharmacological intervention is concerned, the story is over. There is no medicine yet. It has been clinically proven to be useful in preventing recurrence. It is well known that after a long period of withdrawal, the reciprocal immunity is very high. It can be re-exposed to the drug (De Wit, 1996). Re-exposure to drug-related stimuli (Childress, 1992), or by exposure to stressors (Sinha, 1999) can cause recurrence. Alcohol is one of the most widespread and abused addictive drugs in the world. In the so-called "recurrence model", the recurrence of alcohol can be studied in the laboratory animals. In this model, conditions similar to those in the human condition can recur for finding alcohol after a long period of withdrawal (Liu, 2002; L6, 1998). In this relapse model, De Vries et al. observed that the CB! receptor antagonist SR141716A (rimonabant) was able to selectively reduce previous limitations associated with cocaine, heroin, nicotine and alcohol delivery. Sex drugs suggest induced relapse behavior (De Vries, 2001, 2003, 15 2005). This suggests that CB-antagonists may have a therapeutic effect in preventing relapse of substance addiction.

It has been suggested that 5-11 D6 antagonists are valuable in the treatment of drugs and alcohol addiction (alcoholism) and in the withdrawal of therapeutic drugs, especially alcohol, cocaine, nicotine and benzodiazepines (GB 2,341). , 549, US 20 2003/0220325, US 2005/020575, US 2005/020596, US

6 187 805, WO 01/017963, WO 02/041889, WO 02/051832, WO 02/051837, WO 02/060903, WO 2002/089811, WO

2002/098857, WO 2003/013510, WO 2003/053433, WO 2003/066632, WO 2003/072548, WO 2003/072558, WO 200848020

2003/089438, WO 2003/099797, WO 2004/009600, WO 2005/066157 and WO 2006/081332). The absence of a 5-HT6 antagonist is an inspiration for the treatment of potential therapeutic agents for the prevention of addiction relapse. The object of the present invention is to develop a drug for preventing relapse of addiction, which has a mechanism of action different from that of the 5 cannabinoid-CB i receptor. SUMMARY OF THE INVENTION Surprisingly, we have found that 5-HT6 antagonists are active in animal models predicting human relapse behavior: inhibition induced by stimulation in rats 10 Self-administration behavior recurrence (Shaham, 2003). After learning to drink alcohol 12% (v/v) in the two-bottle example, the rats were trained to self-drink alcohol in the operating cage. After the response rate stabilized, the animals were given alcohol for 3 weeks. Subsequently, the effect of the 5-HT6 antagonist on relapse was investigated by exposing the animal to an alcohol-related stimulus. We found that these compounds are able to inhibit the suggestive-induced behavior of finding alcohol 15 . Using a very similar experimental model, we also found that 5-HT6 antagonists can inhibit the suggestive-induced induction of nicotine behavior. Therefore, 5-HT6 antagonists can be used to prepare drugs for preventing relapse of addiction, especially to prevent addiction recurrence of substances abused, among which substances abused include opiates, hallucinogens, 20 inhalers, and benzocycline. Ding, amphetamine, cocaine, marijuana, nicotine and alcohol prevent the recurrence of addiction to certain drugs, including sedatives, sleeping pills and anxiolytics, and prevent certain addictive behaviors, including the recurrence of gambling. In a preferred embodiment, the invention includes the use of the following 5-HT6 antagonists: BGC-20-761, BVT-74316, CNS-10000, 7 200848020 CNS-11010, CNS-25100, diF-BAMPI, E- 6837, FMPD, GSK-215083, JCF-177, KR-055014, KR-055015, LY-483518 (=SGS-518), MS-245, PHA-565272A, PRX-07034, Ro 04-6790, Ro-4368554 , Ro 63-0563, Ro 65, 7199, Ro 5 65-7674, Ro 66-0074, SAM-315, SB-21411, SB-258510, SB-258585, SB-271046, SB-331711, SB-357134, SB-399885, SB-699929, SB-737050A, SB_742457 (=GSK-742457), ST-1938 and WAY-181187 (=SAX-187).

FMPD E-6837 GSK-215083 8 200848020

Ro-65-7199 Ro-65-7674 RO-66-0074

SB-214111 SB-258510 SB-258585 9 200848020

SB-357134 SB-271046 SB-331711

SB-399885 SB-737050A

SB-699929 LY-483518 = SGS-518 10 The invention also relates to the use of the 5-HT6 antagonists described in the following patents and patent applications: EP 0 815 861, DE 10053794, DE 10053795, DE 10053796, DE 10053799, DE 10053813 , GB 2,341,549,

US 2003/220325, US 2003/229069, US 2004/019064, US

2005/124613, US 2005/020575, US 2005/020596, US 15 2006/069094, US 2006/084676, US 5,990,105, US 6,133,287, US 6,187,805, US 6,191,14, US 6, 194,410,

US 6,943,169, WO 1998/027058, WO 1998/027081 'WO 10 200848020 1999/002502, WO 1999/037623, WO 1999/042465 1999/047516, WO 1999/065906, WO 2000/012073 2000/012623, WO 2000 /034242, WO 2000/037452 2000/063203, WO 2001/012629, WO 2001/017963 5 2001/032646, WO 2001/032660, WO 2001/038316 2002/008178, WO 2002/008179, WO 2002/018358 2002/032863 , WO 2002/036115, WO 2002/041889 2002/042293, WO 2001/017963, WO 2002/041889 2002/051832, WO 2002/051837, WO 2002/060871 10 2002/060903, WO 2002/078693, WO 2002/089811 2002/092585, WO 2002/098857, WO 2002/100822 2002/100842, WO 2003/013510, WO 2003/014097 2003/035061, WO 2003/039547, WO 2003/042175 2003/053433, WO 2003/066056, WO 2003 / 066632 15 2003/068220, WO 2003/068732, WO 2003/068740 2003/068752, WO 2003/072198, WO 2003/072548 2003/072558, WO 2003/080580, WO 2003/082877 2003/089438, WO 2003/099792 , WO 2003/099797 2003/101962, WO 2003/101990, WO 2003/104193 20 2004/000828, WO 2004/009548, WO 2004/009600 2004/014895, WO 2004/026830, WO 2004/031181 2004/035047, WO 2004/041781, WO 2004/041792 2004/048328, WO 2004/050085, WO 2004/078176, 2004/080969, WO 2004/098588, WO 2005, vol.

2005/016891, WO 2005/026177, WO 2005/051398, WO 2005/066157, WO 2005/105776, WO 2006/037482, WO 2006/062481, WO 2006/066748, WO 2006/081332, WO

2005/021530, WO 2005/037834, WO 2005/051399, WO 2005/067933, WO 2005/113539, WO 2006/038006, WO 2006/066745, WO 2006/066756, WO 2006/091703, WO

2005/025576, WO 2005/051397, WO 2005/058858, WO 2005/095346, WO 2006/037481, WO 2006/061126, WO 2006/066746, WO 2006/066790, WO 2006/114402 and WO 10 2006/134150. Other embodiments relate to the use of one or more compounds of formula (1):

R° or its tautomers, stereoisomers, N-oxides, isotopes, analogs, or pharmaceutically acceptable salts, hydrates or solvates of any of the above, wherein: -Ri represents hydrogen An unsubstituted alkyl group (CM) or an alkyl group substituted by one or more halogen atoms (Cm) ' _ R 2 and R 3 independently represent hydrogen, an unsubstituted alkyl group (Ci 4) or a 20 or more Halogen-substituted thiol (Ci_4), or

Ri and R2 together with the rear atoms labeled 'a and b form a ring-fired 12 200848020 base ring, or R2 and R3 together with a carbon atom labeled 'b' form a c3 8_cycloalkyl ring, • labeled 'b The dotted line between the carbon atoms of 'and 'c' represents a single or double bond, • IU and I independently represent hydrogen, unsubstituted alkyl (CV4) or alkyl substituted by one or more halogen atoms (C !_4), or, R3 and R4 together with the carbon atoms labeled b and c' form a C3 cycloalkyl ring, or R4 and & together with the carbon atom labeled 'c' form a c3 8-cycloalkyl ring , -R6 and R? independently represent hydrogen, alkyl (Cm), alkyl (Ci-4), (C^) alkoxy, dialkyl (Cl_3) substituted by one or more halogen 1 halogen atoms An amino-alkyl (Cm), optionally substituted aryl, optionally substituted C5-8-cycloalkyl or optionally substituted C5-8-heterocycloalkyl, or R6 and I together with the nitrogen atom to which they are attached Forming an optionally substituted C5-8-heterocyclic alkyl group, 15 〇 "-Rs represents an optionally substituted aryl group, _CR9=CRi()-aryl group, wherein R9 and Han 1() independently represent hydrogen or alkyl -(Cm), or -C tri C-aryl. The invention relates to having a racemate, a mixture of diastereomers and individual stereoisomers of the compound of (1). The invention also relates to the E isomer, the Z isomer and the E/Z mixture of the compound of formula (1). The compounds of formula (1), their synthesis, physicochemical properties, affinity to the 5-HT6 receptor (pKr value) and 5_HT6 are disclosed in PCT/EP2007/059944 filed on September 20, 2007. Functional activity (PA2 value) of an antagonist of a body, the contents of which are incorporated herein by reference. Further embodiments relate to one or more compounds of formula (1) or 13 thereof

ZUU848UZU, N-oxide, an acceptable salt, an isotopically-labeled similar hydrate or solvate tautomer, a stereoisomer, or a pharmaceutical use of any of the above, wherein ~· represents hydrogen or hydrazine 2, 盥 禅 forms a cyclohexyl ring, , ° 4 α and 'b' carbon atoms together -I and R · domain money money for 'b, carbon; soil (Cl-3), or R2 and R3 and The labeled human atoms together form a cyclopentyl or cyclohexyl ring, the dotted line between the carbon atoms of the _ 1 ticketing yarn represents a single or double bond, and R5 independently represents hydrogen, and the alkane is 'b, and 'C, Shishanmei;, soil 1_3), or anti-3 and R4 together with the labeled anaerobic atoms form a C3·8-cycloalkyl ring, and the protons U6 and R7 independently represent money, green (C1_3), quilt or teeth a radical ', a substituted alkyl group (C1.4), a methoxy group, a cyclohexyl group, a benzyl group or a 4_π bottom bite-R8 represents an optionally substituted aryl group, CR9=CIW aryl group, wherein R9 10 independently represents Hydrogen or alkyl (Ci_3), or -CeC_aryl. Green In another embodiment, the invention relates to a compound of formula (1) or an inter', stereoisomer, N-oxide, isotopically-labelled analog, or a pharmaceutically acceptable salt, hydrate of any of the foregoing Or the use of solvates wherein Ri, IU, R5 and R6 represent hydrogen, R2 and r3 independently represent alkane 2 fluorenyl (Cm), or the core and counter 3 together with a carbon atom labeled 'b, form a cyclopentyl group Or a hexyl ring, the dotted line between the carbon atoms labeled 'b, and 'c, represents a single bond, R7 represents an alkyl group (CM), and R8 represents a single- or double-ring substituted by one or more halogen atoms. Aryl. Most preferred is the use of a compound of formula (1), referred to as "Compound 33," 200848020, in PCT/EP2007/059944, having the following structure:

Compound 33 5 Other embodiments of the invention include, but are not limited to: methods for preventing relapse of substances that are abused, addictive to drugs or addictive behaviors; substances that prevent abuse are selected from the group consisting of opiates, hallucinogens, inhalants, Methods for recurrence of phencyclidine, amphetamine, cocaine, marijuana, nicotine and alcohol addiction 10; methods for preventing relapse of alcohol addiction; methods for preventing relapse of nicotine addiction; methods for preventing recurrence of marijuana addiction; A method for recurrence of opiate addiction; 15 methods for preventing recurrence of cocaine addiction; methods for preventing relapse of drug addiction selected from sedatives, hypnotics, and anxiolytics; and methods for preventing relapse of gambling addiction. [Embodiment 3 20 Detailed Description Definitions Throughout the specification, the term "5-HT6 receptor antagonist" means the following active compound, wherein the activity is determined by a clear and generally accepted drug 15 200848020, including Those described in PCT/EP2007/059944 do not exhibit substantial cross-reactivity with other receptors. In one embodiment, a compound of the invention is at least 10 times more potent as a 5-HT6 receptor antagonist than an agonist or antagonist of any other receptor. Preferably, a compound having 100-fold selectivity is selected, and a compound having a selectivity factor of 1000 or higher is most preferred. The general terms used in the description of the compounds have their usual meanings. The term alkyl radical as used herein refers to a monovalent saturated, branched or straight chain hydrocarbon chain. Unless otherwise stated, these chains contain from 1 to 18 carbon atoms, and the representatives of these alkyl groups 10 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, tert-amyl, hexyl, isohexyl, heptyl, octyl, decyl, fluorenyl, undecyl, twelfth, thirteen, fourteen Base, fifteen alkyl, hexadecane, heptadecyl, octadecyl and the like. When defined as "lower", the alkyl group contains from 1 to 6 carbon atoms. For the same amount of carbon, the original term "alkane" and derivative terms such as "alkoxy" are used. The amount of carbon in various hydrocarbon-containing fractions is indicated by a prefix, indicating the minimum and maximum number of carbon atoms in the moiety, ie the prefix (^-(^ means that the number of carbon atoms present includes the integer "X" from the endpoint To the integer "y". For example, "alkyl (C^)" means methyl, ethyl, n-propyl or isopropyl, and "alkyl (<^_4)" 20 means "methyl, ethyl" , n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl. The term "alkenyl" means having one or more carbon-carbon double bonds. a linear or branched hydrocarbon group such as a vinyl group, a propenyl group, a butenyl group or the like, for example, represents a (C2_4) alkenyl group. "Alkynyl group" means a straight or branched chain having one or more carbon-carbon triple bonds. Hydrocarbyl group, such as ethynyl, propynyl, 1-butyne 16 200848020, 2-butynyl, etc., for example, represents (C2.4) alkynyl. Unless otherwise indicated, "dilute" and "alkynyl" The chain may contain from 1 to 18 carbon atoms. The term "mercapto" refers to alkyl (Cl_3) carbonyl, arylcarbonyl or aryl-alkyl (Cm)carbonyl. "Aryl" includes monocyclic or fused bicyclic Aromatic or hetero-aryl ^ 5 base Including, but not limited to, furyl, thienyl, pyrrolyl, furazolidin, 9 thiazolyl, imidazolyl, imidazo[2,1-7][1,3]thiazolyl, pyrazolyl, oxazolyl, iso Thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, /3 $ triazinyl, phenyl, oxazolyl, fluorenyl, pyridazinyl, isodecyl, stupid [b]bit Meryl, 1,2,3,4-tetrahydronaphthyl, tetrahydroisoindolyl, nodal 10, ketone, benzo[b]°secenyl, 2,3-dihydro-1, 4-benzo-Bis 4 (benzodioxin)-5-yl, benzimidazolyl, benzothiazolyl, benzo-u 2 thiadiazyl, fluorenyl, quinolinyl, isoquinolinyl, pyridazine Phtalazinyl, quinazolinyl, quinolinolinyl, 18-naphthyridinyl, pteridine or ureido. "Halo," or "fungel," means chloro, fluoro, bromo or iodo; "Hetero," in the "heteroalkyl, 15-heteroaryl" and the like, refers to one or more of N, oxime or hexamethylene. "Heteroalkyl, including alkyl having a hetero atom at any position," Thus including N_linked, 0-linked or S-linked alkyl. The term "substituted, means having one A specific group or moiety of a plurality of substituents. When any group may have multiple substituents and provide various substituents which are capable of being substituted, the substituents are independently selected and are not necessarily the same. The term "unsubstituted" Refers to a specific group having no substituent. When used in the substituent, the term "independent" means that when more than one substituent may be present, they may be the same or different from each other. "Optionally substituted" means A group may be substituted or unsubstituted by one or more groups selected from the group consisting of Q-8 alkyl, Cm alkenyl, alkynyl, aryl, fluoro, chloro, dimethyl, hydroxy , Cl虞oxy, Cm-alkenyloxy, aryloxy, decyloxy, amino, c18 alkylamino, dialkyl (Ci; square base gas, sulfur, Cl·8 sulfur-sulphur, arylthio , cyano, oxo, 5 schylhydrazyl, decylamino, Cl-8 alkylamino, dialkyl (Cu) amino, carboxyl, or two optional substituents may be attached to the carbon atom to which they are attached Together, a 5- or 6-fluorene aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur is formed. The optional substituent may itself have other optional substituents. Preferred optional substituents include q fluorenyl such as methyl, ethyl ίο and monofluoromethyl, fluoro, chloro, hydrazine, hydroxy, for example methoxy, ethoxy and trifluoromethoxy Base, and amino group.

"Cwichenyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, anthracene or %, octyl, c5_8 hetero-wetyl, meaning a ring containing a hetero atom, including but not limited to Ottomyl, morphinyl, azepanyl, azoprene, 1st generation, linalyl, decyl, sulphate, tetrahydrofuranyl, tetraazinyl; as part of other groups As used herein, the terms "oxygen,", "sulfur" and "carbo", mean an oxygen atom, a sulfur atom, and a few groups (c=〇), respectively, as a link between two groups. a group such as a thiol group, an oxyalkyl group, a thiol group, a ship group, etc. When used alone or as part of another group, the term "amino" refers to either at the end or between two other groups. As the nitrogen atom of the linker 1S, the group may be primary, secondary or tertiary (each two hydrogen atoms are connected to a nitrogen atom, one chlorine atom is connected to a gas atom, and no hydrogen atom is connected to a nitrogen atom). . As part of other groups, the term "Achieve," and "continued," respectively, refers to -SO- or 18 200848020 -S〇2- 〇 for a more lucid description of ' The term "compound" also includes tautomers, stereoisomers, N-oxides, isotopically labeled analogs or pharmaceutically acceptable salts, hydrates or solvates, when not explicitly mentioned. 5 N-oxides of the above compounds are also within the scope of the invention. The tertiary amine may or may not produce an N-oxidized metabolite. The extent to which N-oxidation occurs can vary from trace to near quantitative conversion. N-oxides may be more active or less active than their corresponding tertiary amines. At the same time, the N-oxides can be easily reduced chemically to their corresponding tertiary amines, which can occur in different degrees in the human body at 10 degrees. Some N-oxides are approximately quantitatively reduced to the corresponding tertiary amines, and in other cases the conversion is only a trace reaction, or even not at all (Bickel, 1969). Any compound that is metabolized in vivo to produce a bioactive agent (i.e., a compound of formula (1)) is a prodrug within the scope and spirit of the present application. The prodrug is a treatment of 15 doses which are not active by themselves but are converted into one or more active metabolites. Thus, in the methods of treatment of the present invention, the term "administering," or "using in therapy" will include the use of a specifically disclosed compound or with a compound that is not specifically disclosed but which can be converted to the particular compound in vivo after administration to a patient. The compounds are useful in the treatment of a variety of such diseases. Prodrugs are bioreversible derivatives of drug molecules that overcome some of the barriers to the application of parent drug molecules, including, but not limited to, solubility, permeability, stability, Pre-systematic metabolism and targeting limitations (Bundgaard, 1985; King, 1994; Stella, 2004;

Ettmayer, 2004; J. Rvinen, 2005). Prodrugs, i.e., compounds which are metabolized to a compound of formula (1) when administered to a human or mammal by any known route, are also within the scope of the invention. In particular, this relates to compounds having primary or secondary amino groups or via groups. These compounds can be reacted with an organic acid to give a hydration compound of the formula (1) in which other groups which are easily removed after administration, such as gynecamine, succinyl-methylene derivatives, 〇_( A derivative of a oxy-methylene-5-aminocarbamic acid derivative, a methionine, a ketone, or an aryl ketone, an oral biliary, an oral biliary, or a non-stoichiometric solvent. In general, some of the compounds have a tendency to introduce a fixed molar ratio of solvent molecules in the solid state during the crystallization process, and thus the form of the granules. When 汝 丨Β, 丨Β .......... 晶 10 15 20 焖 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 洛 ij ij ij ij ij ij ij ij ij ij When the solvent is water, a "hydrate" can be formed. The compound of the formula (1) and its orally acceptable salt may be present in the form of a hydrate or a solvate. These hydrates and solvates are also included in the present invention. Examples thereof are coffee hydrate, dihydrogen dihydrate, and the like. "Amorphous, the form has an amorphous material in the order of 1 row, and generally does not give a characteristic

Private X-rays are derived from jj/Q graphics. The sun shape has been described in Bym (1995) and Martin (1995). In order to make a more concise description, some quantitative expressions given in this paper do not use the term "about" to limit the number of ^, and the animal understands that whether or not it is explicitly used: t J3 each given in this paper The values are the values actually given by the values, and also the approximate values of the values, which can be reasonably inferred based on the ordinary techniques in the art, and the packets are obtained from the test and/or measurement conditions without giving values. Approximate values. The terms "select,, and" select b ^, select 扣 扣 对 对 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 特定 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 The compound of the present invention, for example, can exhibit reactivity to the 5-ΗΤ6 receptor, and does not exhibit substantial parental reactivity to other 5-quinone receptors. The towel of the present invention has a selectivity of at least about 1 对于 for the 5-HT6 style and at least about 50 times selectivity for the 5 HT receptor.

Rather, the 5-HT6 receptor has a selectivity of at least about 1 fold, a selectivity of at least about 250-fold for 5-HT6 by the month + J liter, or at least about 5 times for the desired target. The selectivity. Variations of the word in the specification and the description of the present application, such as "including," and "comprising", "comprising," and "containing" are not intended to exclude other additions. The compounds of the formula (1) are administered as a raw material chemical, but they are preferably present as "pharmaceutical compositions. According to a further aspect, the present invention provides a pharmaceutical composition comprising at least one compound of the formula (1), at least one pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the above 15 substances, with one or more pharmaceutics An acceptable carrier, and optionally one or more additional therapeutic ingredients. The carriers must be "acceptable" they must be compatible with the other ingredients of the formulation and are not toxic to the recipient. The term "composition" as used herein includes a product comprising a predetermined amount or fraction of a particular ingredient, as well as any product that produces 20 directly or indirectly from a particular amount of a particular combination of ingredients. In connection with a pharmaceutical composition, the term includes a product comprising one or more active ingredients and an optional carrier comprising an inert ingredient, and by any combination of two or more ingredients, mixed or aggregated, or dissociated from one or more ingredients. Any product that is produced directly or indirectly by other forms of reaction or interaction of one or more ingredients. Generally, 21 200848020 prepares a pharmaceutical composition comprising mixing the active ingredient homogeneously and directly with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product to produce the desired formulation. The pharmaceutical composition includes sufficient active target compound to produce the desired effect on the development or condition of the disease. As a result, the pharmaceutical composition of the present invention includes any composition prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and is not toxic to the recipient. dose. The 10 affinity of the compounds of the invention for the 5-HT6 receptor was determined as described below. From the measured binding affinities of a given compound of formula (1), we can estimate the theoretical minimum effective dose. When the concentration of the compound is equal to twice the measured Kr value, the compound can occupy almost 100% of the 5-HT6 receptor. When the ideal bioavailability is assumed, the theoretically lowest effective dose is obtained by converting the concentration to the number of mg of compound per kg of patient body weight. 15 Pharmacokinetics, Pharmacodynamics, and other considerations may adjust the amount of the agent actually administered to a higher or lower value. The typical dose per dose of active agent can vary over a wide range depending on a number of factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, as determined by the physician. Generally, the total daily dose administered to a patient in a single or individual dose may be, for example, from 0.001 to 10 mg/kg body weight per day, more usually from 0.01 to 1,000 mg/day total active ingredient. These doses can be administered from one to three times a day to the patient in need of treatment, or a dose of efficacy each time, and administered for at least 2 months, more typically at least 6 months or long term. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent that treats a condition treatable by administering the composition of the present invention. The amount is an amount sufficient to display a detectable therapeutic or ameliorating response in a tissue system, animal or human. Effects can include, for example, treating the diseases listed herein. The precise and effective amount of the patient will depend on the size and health of the patient, the nature and extent of the condition being treated, the recommendation of the treating physician (researcher, veterinarian, doctor or other clinician), and the therapeutic agent selected for administration or A combination of therapeutic agents. Therefore, it is not necessary to specify an accurate effective defect in advance. The term "learnably acceptable salt" refers to those salts within the scope of sound medical judgment that are suitable for contact with tissues of humans and lower animals without abnormal toxicity, irritation, allergic response, etc. 10 A reasonable benefit/risk ratio is proportional. Pharmaceutically acceptable salts are well known in the art. When the compounds of the present invention are finally isolated and purified, or by reacting them with a pharmaceutically acceptable non-toxic acid or salt, including inorganic or organic salts and inorganic or organic acids, respectively, a pharmaceutically acceptable salt can be prepared in situ. , 1977). It can be regenerated into "free salty, form by contacting the salt with salt or acid and separating the parent compound in a conventional manner. The parent form of the compound and the degree of resolution of the various salt forms in certain physical properties such as polar solvents. The aspect is different, but for the purposes of the present invention, the salt and the parent of the compound are equivalent. "Complex" means a compound of the present invention, for example, a complex of the formula (1): a complex complexed with a metal ion, wherein At least one metal atom is chelated. The complex can be prepared by methods well known in the art (Dwyer, 1964). The term "treatment," as used herein, refers to any treatment of a mammal, such as a human disease or condition, comprising: (1) inhibiting a disease or condition, ie, preventing its occurrence, and (2) ameliorating a disease 35 or a condition, ie, causing the disease to regress. , or (3) stop ^ 23 200848020

Therapeutic and/or prophylactic administration. 5 A prophylactic, diagnostic, and therapeutic regimen implemented in vivo or in vitro of a human or other mammal. "Mammals, including economically important animals such as cattle and sheep and pigs, especially those that produce meat, as well as livestock, exercise improvement and slowing, stopping or reversing development, severe, if appropriate, the method includes medicine The term "medical treatment, which is intended to encompass animals, zoo animals and humans" is preferred herein. The term "patient" as used herein has become an animal, preferably a mammal, and most preferably a human, which is the subject of treatment, observation or experiment. EXAMPLES Stimulation-induced elimination of alcohol self-administered relapse Animals: 64 male Wistar atmospheres (Harlan, the Netherlands) weighing 280-300 g were purchased for test compound 33. Place these moving objects individually in a controlled room with temperature _ (T = 22 ± 2 °C) and humidity (rel% = 60 ± 5 %) in a reverse 12-hour light-dark cycle (in the morning) 7 · 00 turn off the lights) 'Bianbian thinking drinking water. Animal food is 1 $ σΑ of food per animal per day. The test was started 1 week after the adaptation to the environment and lasted for 12-14 weeks. Self-administration of the drug: All cultures and experiments were performed in 16 operating chambers (3 24.1 x 29.2 cm) surrounded by a sound attenuating ventilation chamber (Med Associates, Georgia, VT). The room is fitted with grid doors, red darker interior lights and smart panels facing the interior lights. In the Wisdom Board, there are two nose-poke holes (0 2.5 cm) at 5.5 cm on the net door.

16 cm apart. The red dim stimulus is located on the two nose puncture holes U 24 200848020 cm. Between the rain nose puncture holes is a container for delivering alcohol. Above the container is a solid tone generator voice module. One nose puncture hole is used as the active hole and the other is used as the inactive hole. The puncture holes created in the active wells resulted in the delivery of wine drops (0.19 ml; 12%) in the container. The wine drops were delivered in 4.2 seconds using an infusion pump (PHM-100, MedAssociates, 5 Georgia, VT). During the alcohol delivery, the active nose puncture hole is illuminated and a 2 second sound (± 65 dB) is produced by the sonalert speech module. Turn off the stimulating light for 5 seconds (the difference signal). In the 15-second pause, the result was no nose stamp. At all times, the response in the inactive wells was detected, but no results were obtained. 10 Acquisition and withdrawal: Animals were trained for 10 days according to a fixed scale 1 schedule (FR1-曰表) (reward for each active response; 6 minutes per day). Subsequently, animals were cultured through the FR2-schedule up to the FR4-schedule (reward once every 2nd and f activity responses; 6 minutes per day). If the alcohol dose (FR4-schedule) is above the drug effective dose 〇·3 g/kg/hr (Lin Seman, 1987) as described in the literature, the animal is selected for further testing. After Ik, when the response to the FR4-schedule was stabilized, it was placed in a cage for 3 weeks. 20 Relapsed trials: After the withdrawal period, each animal was tested for signal-induced recurrence twice, in the step-by-step elimination training and interval (W-between 1 week. Will be mobilized with the forest _ test Μ, And never accept the same / oral therapy for two people on the 4th day of 'the animal is placed in the operating cage without alcohol and alcohol-related stimulation (discontinuous and differentiated signals) for 3 or 4 hours (test 曰 1: 仏On the test day 2:3 hd; the response was removed (4). At the end of the elimination period, 1 hour, the animals were removed from the control material and treated with the antagonist 25 200848020. After the drug was administered, the animals were returned to the operation room. And continue the elimination period. When the last hour has elapsed, the signal-induced relapse test period (continued: 45 minutes) is started. During the test, the experimental conditions are similar to those during the training according to the service schedule, except that At the beginning of the period, U used 12 〇·20 ml of 12% wine drop (tester delivered to the container at the beginning of the test period) and 2) after each 4th response, there was only a signal (no alcohol was delivered). The test was performed and saved by the MED-PCIV program (Tatham, 1989) The drug: alcohol 12% (v/v) is made from 96% alcohol and diluted with tap water. Compound 33 is suspended in 5% Tween 80, 0.25% methyl fiber 1 〇, 5% PEG40 (^ H2OHPLC (65% of final volume). Ethanol was added and evaporated under Νπ gas. The pH was adjusted to 5.8. Compounds in the range of 〇, 3, 10 and 30 mg/kg were administered intraperitoneally 15 minutes before the test. The injection volume was 2 ml/kg. The analysis of the ##-induced recurrence data was performed, and the total number of nasal punctures (responses) in the active 15 and inactive wells was analyzed by one-way ANOVA, followed by Fisher's. The LSD multiple comparison test used different doses of 5_Ht6 antagonist as an intermediate factor. Since each animal had two signal-induced recurrences and the signal-reactivity was generally low during the second trial, the test day could be Used as a covariate. 2 〇 stimuli-induced elimination of nicotine self-administered recurrent animals: 32 male rats (Harlan, the Netherlands) weighing 280-300 g were purchased for the test compound. Placed separately at temperature - (T = 22 ± 2 C) and humidity (rel% = 6〇 ± 5 %) in a controlled room, placed in a reverse 12-hour light-dark cycle (in the morning 26 200848020 7 · 00 turn off the lights) 'arbitrary water and food. The environment began to be tested after the week and lasted for 12-14 weeks. Surgery: After 1 week of adaptation to the environment, as detailed above (De Vries, 1999), the venous fistula rubber catheter was implanted to the right under isoflurane anesthesia. The neck is quiet 5 veins. Self-administration of drugs: all training and testing in attenuated ventilation by sound

The chamber (Med Associates, Georgia, VT) was carried out in 16 operating chambers (30.5 X 24·1 X 29.2 cm). The room is fitted with grid doors, red darker interior lights and smart panels facing the interior lights. In the Wisdom Board, there are two nose stamp holes (0 2.5 cm) at 10 5.5 cm on the grid door, which are 16 cm apart. The red dim stimulus is located 12 cm above the two nose puncture holes. A voice module is placed on top of the center of the smartboard. During self-administration, animals were connected to an infusion pump (PHM-100, Med Associates, Georgia, V.T.) via a shaft to receive intravenous infusion of nicotine (40 pg/kg/inf). One nose puncture hole is used as the active 15 hole and the other is used as the inactive hole. The puncture holes created in the active wells resulted in the delivery of the nicotine infusion for a total of 2 seconds. During this infusion, the active nose puncture hole (yellow light) is illuminated and there is a sound stimulus (2900 Hz and 65 dB sound for 2 seconds) (discontinuous signal). At the time of nicotine delivery, turn off the stimulating light for 15 seconds (the difference signal). During the timeout period, there was no nasal puncture hole result. The response in the inactive wells was detected at all 20 times, but no results were obtained. Obtain, Withdraw and Relapse: Conduct behavioral training 5-7 days after surgery. Animals were cultured for 10 days according to a fixed ratio 1 schedule (FR1-schedule) (each active nose mark resulted in nicotine infusion and related signals; 60 minutes per day). Animals were then trained for 3 days via the FR2-schedule and then moved to the FR3-Schedule 27 200848020 training animals (respectively every 2n% yd active nose pokes resulted in rewards and related signals; 60 minutes per day). After the response behavior is stabilized, if at least 5 rewards are obtained during the last three time periods of the FR3 schedule and the prizes obtained are evenly distributed over that time, the animal is selected for further testing. Subsequent responses to nicotine were eliminated. During this elimination period (11 days, 6 days per day), the animals were placed in operation 'but no nicotine and nicotine-related stimuli (discontinuous and differentiated signals) were used. Finally, the animal's signal-induced relapse test was performed. During the test period (lasting 3 〇 minutes), the experimental conditions were similar to those during the FR3-schedule training, except that nicotine was not used and 10 animals were not connected to the shaft. The signal-induced relapse test was performed twice; between the two test days, there was one week of further elimination training (intermittent). During the nickname-induced relapse, the effect of the 5·ΗΤ6 antagonist was studied in the loss of the scar. Drugs - Self-administered nicotine: (i) Nicotine tartrate (Sigma, 15 St Loins, MO) was dissolved in sterile saline. The dose from the week of the solution to 7.4 nicotine of the solution is expressed by the weight of the free salt. The compound was suspended in TWeen 8〇, which is 5% of the final volume. Add ethanol and under N2 gas... seven 3 minutes. Subsequently, PEG 400, which accounts for 5% of the final volume, accounts for 1% of the most sulfhydryl cellulose, which is 25% of the genus Spear, and accounts for 55% of the final volume of the HPLC 20 HPLC, which produces a uniform mixing of J ρ Η 3.76 Suspension. After adjusting the pH to 5.9, a 112 〇 HPLC was added to the final volume of 10%. Compounds 33 in the range of 〇, 3, 10 and 30 mg/kg were administered intraperitoneally 15 minutes before the test. The injection volume was 2 ml/kg. ,,Charge. Ten analysis • Analysis of signal-induced recurrence data, the total number of nasal punctures (responses) in activity 28 200848020 and inactive wells was double-tuned, one-way ANOVA analysis, and then Fisher's LSD multiple comparison imaging test Different doses of 5-HT6 antagonist were used as intermediate factors. Since each animal is subjected to two signal-induced relapses and the signal_reactivity is generally low during the second test, the test day can be used as a covariation. Pharmacological test results Recurrence of cerebral palsy in rats (4): Compounds In the operating cage, all animals are prone to alcohol self-administration and consume their reward. They produce a clear difference in H) between active and inactive wells. The average amount of alcohol intake is 〇 5〇 g/kg/hr. The response in the aforementioned active wells of all animals was eliminated during the elimination period of the test day.

The post-signal rhinoceros treatment group of Compound 33 from the total & 4 alcoholic drinkers total _ 0 mg / kg of compound 33 22.1 ± 4.7 1.2 ± 0.6 3 mg / kg of compound 33 27.0 ± 6.1 1.1 ± 0.2 10 mg / Kg of compound 3 3 —^3.5 ± 4.2 2.2 ± 1.5 30 mg/kg of compound 33 卜 1.8* ± 0.9 0.8 ± 0.1 Fisher's LSD multiple comparison test after one-way ANOVA showed that during the signal-induced test for alcohol The amount of active nasal puncture of animals treated with 3 mg/kg Compound 33 was significantly lower than that treated with placebo. (*p 29 200848020 < 0.005). There was no significant difference between the placebo and the reagent amount of Compound 33 in the inactive nose. Signal-induced Finding Alcohol Recurrence in Rats: SB-271046 In animals, all animals are prone to alcohol self-administration, 5 and they are rewarded for their reward. They produce a clear difference between active and inactive wells. The average amount of alcohol intake is 0.50 g/kg/hr. During the elimination phase of the test ,, the response in the aforementioned active wells of all animals was eliminated.

• HCI 10 SB-271046 Nasal postmark after alcohol-induced signal ^::;::::||:_ The total number of alcoholics in the previous round of alcoholics 0 mg/kg SB-271046 17.7 ± 3.3 1.5 ± 0.6 3 mg/kg SB-271046 11.9 ± 5.4 1.1 ± 0.5 10 mg/kg SB-271046 6.0* ± 2.7 0.9 ± 0.5 20 mg/kg SB-271046 1.2** ± 0.7 2.7 ± 1.9 Fisher's LSD after one-way ANOVA Multiple comparison tests showed that animals treated with 10 mg/kg SB-271046 had significantly lower active nasal punctures than those treated with placebo during the signal-induced alcohol-seeking trial. (*p 15 < 0.05). For SB-271046 at a dose of 20 mg/kg, the amount of active nasal puncture was significantly lower than placebo, **ρ < 0.005. There was no significant difference in the inactive nasal puncture between placebo and the amount of the agent 30 200848020 SB-271046. Signal-induced Finding of Nicotine Recurrence in Rats In the operating cage, 27 out of 32 rats met the criteria for nicotine self-administration and were selected for further testing. The selected animals were prone to produce nicotine self-administration behavior, showing a clear bias for the active nasal puncture. During the elimination period, the response in the aforementioned active wells of all animals was eliminated. η...................................... ^ ___L*疋古丁诿精棺棺 _ Alcoholics treatment group~—- 0 mg/kg of compound 33 24.50 ± 4.25 3.14 + 0.64 3 mg/kg of compound 33 24.83 Soil 3^^' 4.58 ± 1.17 10 mg /kg of compound 33 28.50 ± 7.40 3.00 + 1.04 30 mg/kg of compound 33 7.92* ± 4.44 1.75 ± 0.74 Fisher's LSD multiple comparison test after one-way ANOVA showed that during the letter 10 induction of nicotine-inducing trials, Animals treated with 30 mg/kg Compound 33 had significantly lower active nasal punctures than those treated with placebo. (*p < 0.05). There was no significant difference in the inactive nasal puncture of placebo and the amount of compound 33 administered. Pharmaceutical Formulations 15 For clinical use, 5-HT6 antagonists are formulated into pharmaceutical compositions, which are important and novel embodiments of the invention as they comprise compounds, more particularly the specific compounds disclosed herein. Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and 20 disclosed herein. Other types, or other types apparent to those skilled in the art from the description and general knowledge of the field of this document 2008 200848020. For example, the active ingredients may also be in the form of inclusion complexes in cyclodextrins, their ethers or their esters. The composition is for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, gastrointestinal, rectal, parenteral or other routes of administration. 5 The pharmaceutical preparation comprises a mixture of at least one 5 - Η T 6 antagonist and a pharmaceutically acceptable adjuvant, diluent and/or carrier. A suitable range of the total amount of active ingredients is from about 1% (w/w) to about 95% (w/w) of the formulation, suitably from 0.5% to 50% (w/w), preferably 1% to 25% (w/w). Compound 33 10 microcrystalline cellulose 200 fuming ceria 10 stearic acid 10 5-HT6 antagonist may be in a form suitable for administration, including by a usual 10 method, with auxiliary substances such as liquid or solid, powdery ingredients, For example, liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavoring agents, colorants and/or buffering substances which are commonly used in pharmacy. Commonly used auxiliary substances include acid-breaking town, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, milk protein, gelatin, starch, branched starch, cellulose and their derivatives. , animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol, and disintegrating and lubricating agents such as magnesium stearate, calcium stearate, hard Sodium decyl fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. Tablets were prepared with the following ingredients: 20 Ingredients_amount (mg/tablet) 25 Total 230 32 200848020 These ingredients were mixed and compressed into tablets, each weighing 230 mg. The active ingredient (4) may be premixed with other inactive ingredients in a mixed form (4). The active ingredients may also be mixed with one another prior to mixing with the inactive ingredients to form a formulation. 5 软 A soft capsule is prepared by using a capsule comprising a mixture of the active ingredient of the present invention, vegetable oil, fat or other carrier suitable for soft capsules. Hard capsules may contain granules of the active ingredient. The hard capsules may also contain the active ingredient together with solid powdery ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn powder, branched powder, cellulose derivatives or gelatin. 10 剂量 The dosage unit for rectal administration is prepared in the form of (1) a suppository comprising a mixture of the active substance and a neutral fat base; (8) a form of gelatin rectal capsule comprising the active substance and vegetable oil, liquid paraffin or other suitable gelatin a mixture of carriers of rectal capsules; (iii) a microenema form; or (iv) a dry micro-enema form, which requires 15 build-up in a solvent. The limbs are prepared as syrups, elixirs, concentrates or suspensions, such as solutions or suspensions, which comprise the active ingredient and the remainder, the remainder of which includes, for example, sugars or sugar alcohols and alcohols, water, glycerol, propylene glycol and poly This compound of ethylene di 20 alcohol. If necessary, 'these liquid preparations may contain coloring agents, flavoring agents, preservatives, sucrose and sputum methylcellulose or other thickening preparations can also be prepared into too much / you can use 适当 in the appropriate solvent Rebuilt the form of the dry # end. Parenteral administration & / : The sputum used in the preparation of the invention can be prepared in a pharmaceutically acceptable solution. These solutions may also contain ingredients, preservatives and/or buffers. Solutions for parenteral administration can also be prepared 33 200848020 into a dry formulation that is reconstituted with a suitable solvent prior to use. Also provided in accordance with the invention are formulations and "kits of parts," comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention for medical treatment. Attached to these containers are various written materials, such as instructions for use or notifications in the form prescribed by government agencies, which are used to regulate the manufacture, use or sale of pharmaceuticals, and the notifications reflect the manufacture and use of human or veterinary applications. Or the approval of the sales organization. The use of a formulation of the invention in the manufacture of a medicament for preventing relapse of addiction, a method of medical treatment or comprising administering to a patient a therapeutically effective amount of at least one 10 5-HT6 antagonist, or a 5-HT6 antagonist or prodrug In the case of application. For example, without limitation, several pharmaceutical compositions may be provided, including preferred active compounds for systemic or topical use. Other compounds of the invention or compositions thereof may be used in place of the compound (or otherwise administered). The concentration of active ingredients can vary within the broad scope discussed herein. The amounts and types of ingredients that may be included are well known in the art. 34 200848020 References Since the following references are useful to those skilled in the art or are useful for a more complete description of the invention, they are incorporated herein by reference. However, any reference to any of the literature or references cited herein, and 5 to any reference, is not an admission that they are prior art documents or citations.

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Cues on Reinstatement of Ethanol Seeking 'Exacerbation by History of Dependence and Role of Concurrent Activation of Corticotropin-Releasing Factor and Opioid Mechanisms”, J. of Neuroscience (2002) ; 22(18) : 7856-7861 20 Martin, EW· (Editor ), "Remington : The Science and

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Claims (1)

200848020 X. Patent application scope: 1. The use of a 5-11 butyl 6 antagonist for the preparation of a pharmaceutical composition for preventing relapse of addiction. 2. The use of the first aspect of the patent application, wherein the 5_ht6 antagonist is selected from the group consisting of: BGC-20-76hBVT-74316, CNS-10000, CNS-11010, CNS-25100, diF-BAMPI, E-6837, FMPD , GSK-215083, JCF-177, KR-055014, KR-055015, LY-483518, MS-245, PHA-565272A, PRX-07034, Ro 04-6790, R0-4368554, Ro 63-0563, Ro 65- 7199, Ro 65-7674, R〇66-0074, SAM-315, SB-214111, SB-258510, SB_258585, SB-271046, SB-331711, SB-357134, SB-399885, SB-699929, SB-737050A , SB-742457, ST-1938 and WAY-181187, or their tautomers, stereoisomers, N-oxides, isotopically labeled analogues, or pharmacologically acceptable salts, hydrates of any of the foregoing Or solvate. 3. The use of claim 1, wherein the 5_Ητ6 antagonist is a compound of formula (1): R1 °2 〇 = S=〇 R7 R8 A labeled analog, or a pharmacological salt, hydrate or a solvate of any of the above, wherein: -I represents hydrogen, unsubstituted alkyl (Ci 4) or alkyl substituted by one or more halogen atoms , -R2 and & independently represent hydrogen, unsubstituted alkane or alkyl (Cm) substituted by one or more dentate atoms, or ruthenium and osmium together with carbon atoms labeled v and 'b, form C58 - a ring-based ring, or R2 and R3 together with a carbon atom labeled 'b' form a C3 8-cycloalkyl ring, - the dotted line between the carbon atoms of b and 'c' represents a single or double a bond, -R4 and R5 independently represent hydrogen, an unsubstituted alkyl group (Ci 4) or an alkyl group substituted with one or more halogen atoms (Ci 4), or, & and I are labeled with 'b, and The carbon atoms of 'c, together form a C3 "cycloalkyl ring, or R4 and Rs together with the carbon atom labeled 'C' form a C3_8_cycloalkyl ring, -R6 and R7 independently represent hydrogen, alkyl (Ci_4 An alkyl (Cl-4), (Cl-3) alkoxy group, a dialkyl (C!_3) amino-alkyl group (Cl-3) substituted with one or more halogen atoms, optionally substituted And optionally substituted C5 8-cycloalkyl or optionally substituted C5_8-heterocycloalkyl, or R6 and R7 together with the nitrogen atom to which they are attached form an optionally substituted Cw heterocycloalkyl group, -R8 represents Optionally substituted aryl, _CR9=CRl〇-aryl, wherein 40 200848020 R9 and R1() independently represent hydrogen or alkyl-(Ci 3), or <triaryl. 4. The use according to claim 3, wherein the 5_ΗΤ6 antagonist is a compound of the formula (1): wherein: R1, r4, hydride and hydrazine represent hydrogen, and r2 and R3 independently represent a burnt group (Ci 3), or hydrazine and together with the carbon atom labeled as ..., form a cyclopentyl or cyclohexyl ring, the dotted line between the carbon atoms labeled 'b, and 'c, represents a single bond, and the heart represents an alkyl group ( Cm), Rs represents a mono- or bicyclic aryl group substituted by one or more iS atom. • The use of claim 3, wherein the 5_ΗΤό antagonist is a compound: 6. The use of any of the W items of the patent application scope, wherein the addiction is directed against abuse (4) substances, drugs or addictive behaviors. 7. The use of claim 6 wherein the substance of abuse is selected from the group consisting of opiates, hallucinogens, inhalants, benzocycline, amphetamine, cocaine marijuana, nicotine and alcohol. 8 The use of the sixth application of the patent scope, wherein the substance abused is alcohol. 9. The use of claim 6 wherein the drug is selected from the group consisting of a sedative, a hypnotic, and an anxiolytic. 1〇t application for the sixth rhyme use, its emotional behavior is bet 41 200848020 VII, designated representative map: (a) The representative representative of the case is: () map. (none) (two) representative map A brief description of the component symbols: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: