MX2008008095A - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction - Google Patents

Abstract

The present invention is a method for the treatment of alcohol abuse and / or addiction comprising administering to a subject in need thereof a therapeutically effective amount of one or more novel benzo-fused heterocycle sulfamide derivatives of formula (I) and / or formula (II) as herein defined.

Description

USE OF BENZO-FUSED HETEROCICLIC SULFAMIDE DERIVATIVES FOR THE TREATMENT OF ABUSE AND ADDICTION OF SUBSTANCES CROSS REFERENCE WITH RELATED REQUESTS This application claims the benefit of the Provisional Application of E.U.A. 60/751, 679, filed on December 19, 2005, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to the use of benzo-fused heterocyclic sulfamide derivatives for the treatment of substance abuse and addiction.

BACKGROUND OF THE INVENTION Alcohol abuse, usually characterized as an inappropriate pattern of alcohol use, leading to significant impairment or difficulty clinically, is a serious medical or social problem. It has been suggested that the agents that produce a selective decrease in drinking alcohol 10 in animals, without producing a parallel decrease in water or food intake, they are likely to be clinically effective in the treatment of human alcoholism (Myers 1994). Daidzin, the active ingredient of the Chinese herb radix pureariea (RP), used as a traditional treatment for "alcohol addiction" in China, fits the profile: it decreases the alcohol intake in the golden hamster, without producing a decrease in the intake of water or food 15 (Keung and Valle3 1993). In contrast, many drugs, including specific serotonergic agonist (eg, sertraline) and opiate antagonists (eg, naloxone and naltrexone), which have been shown to inhibit alcohol consumption in animals have a deteriorated consumption of water and food at the same time. time (Myers 1994). However, although atypical antipsychotic has been proposed as possible treatments for substance abuse, the medication may undergo substantial hepatic metabolism in patients with substance abuse. The population of patients with hepatic impairment is very high. Consequently it may be convenient to treat patients with substance abuse with an atypical anti-psychotic, which is not metabolized significantly in the liver. There remains a need to provide effective treatment for substance abuse and / or addiction, plus abuse of and / or addiction to particularly alcohol, cocaine, heroin, methamphetamine, ketamine, ecstasy, nicotine, oxycodone / oxycodone, codeine, morphine, and the similar.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a method for the treatment of substance abuse and / or addition comprising the administration to a subject in need thereof of a therapeutically effective amount of a compound of formula (I) wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; / i P I is selected from the group consisting of where b is an integer from 0 to 4, and where c is an integer from 0 to 2, each R5 is independently selected from the group consisting of then a is 1, or a pharmaceutically acceptable salt thereof The present invention further relates to a method for the treatment of substance abuse and / or addiction comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof An example of the invention is a method for the treatment of abuse and / or addiction of alcohol comprising the administration to a subject in need thereof of a therapeutically effective amount of any of the compounds or pharmaceutical compositions described Here A further example of the invention is a method for the treatment of abuse and / or addiction of a substance of abuse selected from the group consisting of alcohol, cocaine, heroin, methamphetamine, ketamine, ecstasy, nicotine, oxycodone / oxycodone., codema, morphine, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described herein. The present invention also relates to methods for the treatment of abuse and / or addiction of substances that comprises administration to a subject in need thereof of co-therapy with a therapeutically effective amount with at least one anti-addiction agent and a compound of formula (I) or formula (II) as described herein DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for the treatment of substance abuse and / or addiction comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein (i, a, R1, R2 and R4 are as defined herein The present invention also relates to methods for the treatment of substance abuse and / or addiction comprising co-therapy with a therapeutically effective amount with at least one agent anti-addiction and a compound of formula (I) or formula (II) as described herein As used herein, unless otherwise indicated the term "substance" when referring to substances of abuse and / or addiction include any legal or illegal substance to which a subject or patient may develop an addiction. Classes of drugs that may be abused include, but are not limited to, stimulants, hallucinogens, barbiturates, natural and synthetic opioids, and benzodiazepines. Suitable examples include, without limitation, alcohol, cocaine, heroin, methamphetamine, ketamine, ecstasy, nicotine, oxycodone / oxycodone, codeine, morphine, and the like As used herein, unless otherwise indicated, the term "anti-addiction agent" means any pharmaceutical agent useful for the treatment of abuse and / or substance addiction More particularly, "anti-addiction agents" include substitution drugs, drugs that block or mitigate withdrawal symptoms, drugs that block pleasurable sensations and rewards of substance abuse, and the like. Suitable examples include, but are not limited to, naltrexone (including vivtrex), nalmefene, antabuse, acamprosate, palipendone and the like. Preferably, wherein the substance of addiction is alcohol, the anti-addiction agent used in the co-therapy methods of the present invention is naltrexone The term "subject" as used herein, refers to an animal, preferably a mammal, more preferably a human, which has been the subject of treatment, observation or experiment. The term "therapeutically effective amount" as used here, it means the amount of active compound or pharmaceutical agent that produces the biological or medicinal response in a tissue, animal or human system that is sought by a researcher, veterinarian, doctor or other clinician, which includes the alleviation of the symptoms of the disease or disorder being treated When the present invention is directed to co-therapy or therapy of combination, comprising the administration of one or more compounds of formula (I) or formula (II) and one or more anti-adipation agents, "therapeutically effective amount" refers to the amount of the combination of agents taken together in a that the combined effect produces the desired biological or medicinal response. For example, the therapeutically effective amount of the co-therapy comprising administration of a compound of formula (I) or formula (II) and at least one anti-addiction agent may be the amount of the compound of formula (I) or formula (II) and the amount of the anti-addiction agent that when taken together or consecutively have a combined effect that is therapeutically effective. In addition, it will be recognized by a person skilled in the art that in the case of co-therapy with a therapeutically effective amount, as in the previous example, the amount of the compound of formula (I) or formula (II) and / or the amount of the anti-addiction agent individually may or may not be therapeutically effective. As used herein, the terms "co-therapy" and "combination therapy" refer to the treatment of a subject in need thereof by administering one or more compounds of formula (I) or formula (II) in combination with one or more anti-addiction agents, wherein the compound (s) of formula (I) or formula (II) and the anti-addiction agent (s) are administered by any suitable means, simultaneously, consecutively, separately or in a simple pharmaceutical formulation. When the compound (s) of formula (I) or formula (II) and the Anti-addiction agents are administered in separate dosage forms, the number of dosages administered per day for each compound can be the same or different. The compound (s) of formula (I) or formula (II) and the anti-adipic agent (s) can be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (se), transdermal and rectal. The compounds may also be administered directly to the nervous system including, but not limited to, the intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intra-spinal and / or peri-spinal routes of administration by delivery by intracranial or intravertebral needles and / or catheters with or without pumping devices. The compound (s) of formula (I) or formula (II) and the anti-adipic agent (s) can be administered according to simultaneous and alternating regimens, at the same time or at different times during the course of therapy, concurrently in divided or individually. In one embodiment of the present invention R1 is selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention R2 is selected from the group consisting of hydrogen and methyl. In still another embodiment of the present invention R1 and R2 are each hydrogen or R1 and R2 are each methyl. In one embodiment of the present invention - (CH2) a- is selected from the group consisting of -CH2- and -CH2-CH2-. In another form of the present invention - (CH2) a- is -CH2-. In one embodiment of the present R4 is selected from the group consisting of hydrogen and methyl, preferably, R4 is hydrogen. In one embodiment of the present invention a is 1. In one embodiment of the present invention b is an integer from 0 to 2. In another embodiment of the present invention c is an integer from 0 to 2. In another embodiment of the present invention b is an integer from 0 to 1. In another embodiment of the present invention c is an integer from 0 to 1. In yet another embodiment of the present invention the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1. Still in another embodiment of the present invention b is an integer from 0 to 2 and c is 0. In one embodiment of the present invention, select from the group consisting of entity invention, is selected from the group consisting of In one embodiment of the present invention, , 'i F i' _ _ is selected from the group consisting of 2- (2,3-d? h? drobenzo [1,4] d? ox? n? lo), 2- (benzo [1, 3jd? Oxol), 3- (3,4-d? H? Drobenzo [1,4] d? Oxep? N? Lo), 2- (6-chloro-2,3-d? H? dro-benzo [1,4] d? ox? n? lo), 2- (6-fluoro-2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2 - (chromanol), 2- (5-fluoro-2,3-d? h? drobenzo [1,4] d? ox? n? lo), 2- (7-chloro-2,3- d? h? dro-benzo [1,4] d? ox? n? lo), 2- (6-chlorobenzo [1,3] d? oxol), 2- (7-n? tro- 2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (7-met? L-2,3-d? H? Dro-benzo [1, 4] d? ox? n? lo), 2- (5-chloro-2,3-d? hydro? benzo [1,4] dioxon), 2- (6- bromo-2,3- d? h? dro-benzo [1, 4] d? ox? n? lo), 2- (6,7-d? chlor-2,3-d? h? drobenzo [1,4] d? ox? n? lo), 2- (8-chloro-2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2- (2,3-dih? naphtho [2,3-b] [1,4] d? ox? n? lo) and 2- (4-met? l-benzo [1,3] d? oxol? lo) In another embodiment of the present invention , it is selected from the group consisting of 2- (benzo [1,3] d? oxol? lo), 2- (2,3-d? h? dro-benzo [1,4] d? ox? n? lo) , 2- (6-chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (7-chloro-2,3-d? Hydro? benzo [1, 4] d? ox? n? lo), 2- (7-met? l-2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2 - (6-bromo-2,3-d? H? Dro-benzo [1, 4] d? Ox? N? Lo) and 2- (6,7-dichloro-2,3-d? benzo [1,4] d? ox? n? lo) In another embodiment of the present invention, / 1 P \ \ '^ - ^ _ < is selected from the group consisting of 2- (2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2- (7-met? l-2,3-d? h-dro-benzo [1,4] d? ox? n? lo) and 2- (6-bromo-2,3-d? h? dro-benzo [1,4] d? ox? n? lo) In one embodiment of the present invention R5 is selected from the group consisting of halogen and lower alkyl. In another embodiment of the present invention R5 is selected from chlorine., fluoro, bromo and methyl In one embodiment of the present invention, the stereo-center in the compound of formula (I) is in the S configuration. In another embodiment of the present invention, the stereo-center in the compound of formula (I ) is in the R configuration. In one embodiment of the present invention, the compound of formula (I) is present as an enantiomerically enriched mixture, wherein the% enantiomer enrichment (% ee) is greater than about 75%, preferably greater than about 90%, more preferably greater than about 95%, still more preferably greater than about 98% Additional embodiments of the present invention, include those wherein the substituents selected from one or more vapables defined herein (ie, R1, R2, R3, R4, XY and A) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined Here representative compounds of the present invention are listed in Table 1 below. Additional compounds of the present invention are listed in Table 3. In the following tables 1 and 2, the column having the title "stereo" defines the stereo-configuration in the carbon atom of the heterocycle linked in the asterisk When there is no designation in the list, the compound is prepared as a mixture of stereo-configurations When a designation "R" and "S" is listed, the stereo-configuration is based on enantiomepcamente enriched start material TABLE 1 Representative compounds of formula (I) TABLE 2 Additional compounds of the present invention As used here, unless otherwise indicated, "Halogen" means chlorine, bromine, fluorine and iodine. As used herein, unless otherwise noted, the term "alkyl" whether used alone or as part of a substituent group, includes straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise indicated, "lower" when used with alkyl means a carbon chain composition of 1-4 carbon atoms. As used herein, unless otherwise indicated, "alkoxy" denotes an oxygen ether radical of the straight or branched chain alkyl groups described above. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. As used here, the notation "*" denotes the presence of a stereogenic center. When a particular group is "substituted" (eg, alkyl, aryl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, more preferably from one to two. substituents, independently selected from the list of substituents.

With reference to substituents, the term "independently" means that when more than one of said substituents is possible, said substituents may be the same or different from each other. Under the standard nomenclature used throughout this description, the terminal portion of the designated side chain is described first, followed by functionality adjacent to the point of attachment. Thus, for example, a substituent "phenyl-alkyl-amino-carbonyl-alkyl" refers to a group of the formula (I rent) Abbreviations used in the specification, particularly the schemes and examples, are as follows DCC Dicyclohexyl Carbodnmide DCE Dichloroethane DCM Dichloromethane DIPEA or DIEA Diisopropylethylamine DMF N, N-D? Met? Lformam? DMSO Dimethyl sulfoxide EDC Ethylcarbodnmide Et3N or TEA Tetylamine Et2O Diethyl ether EA or EtOAc Ethyl acetate EtOH Ethanol IPA 2-propanol Hept Heptane HOBT 1 -Hydroxybenzotriazole HPLC High pressure liquid chromatography LAH Lithium aluminum hydride M or MeOH Metanol NMR Nuclear Magnetic Resonance Pd-C Palladium catalyst in carbon HPLC RP High pressure reverse phase liquid chromatography RT or rt Ambient temperature TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography When the compounds according to this invention have at least one chiral center, they can accordingly exist as enantiomers. When the compounds possess two or more chiral centers, they may optionally exist as diastereomers. It must be understood that all isomers and mixtures thereof are included within the scope of the present invention. In addition, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention., some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and it is also intended that said solvates be included within the scope of this invention. For use in medicine, the salts of the compounds of this invention are they refer to non-toxic "pharmaceutically acceptable salts". Other salts, however, may be useful in the preparation of compounds according to this invention or their pharmaceutically acceptable salts Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid Further, when the compounds of the invention carry an acidic radical, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example, sodium or potassium salts, alkaline metal salts, for example, calcium or magnesium salts, and salts formed with suitable organic gandos, for example, quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include following acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisilate, estolate, esilate, fumarate, gluceptate, gluconate, glutamate, ghcolilarsanilate , hexylresormate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsilate, nitrate, ammonium salt N-methyglucamine, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, sa cilate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, tpetiodide and valerate. Representative acids and bases that can be used in the preparation of pharmaceutically acceptable salts include the following acids include acetic acid, 2,2-d-chloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid , benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) - camphor acid, camphorsulfonic acid, (+) - (1 S) -canfor-10-sulfonamide, cappuc acid, caproic acid, caprylic acid , cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1, 2-d-sulfonic acid, ethanesulfonic acid, 2-hydroxetane-sulphonic acid, formic acid, fumapco acid, galactanic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutapco acid, coenzyme acid, hippoid acid, hydrobromic acid, hydroclone, (+) - L-lactic acid, acid (±) -DL-lactide, lactobionic acid, malic acid, (-) - L-malic acid, malonic acid, acid (±) -DL - Nondrug, methanesulfonic acid, naphthalene-2-sulphonic acid, naphthalene-1, 5-d-sulfonyl acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, oratic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, sahcic acid, 4-aminoclassic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid , tannic acid, (+) - L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid, and the bases include ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (d? ethylamido) -ethanol, ethanolamine, ethylenediamma, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydrox? et? l) -morpholine, piperazine, hydroxide potassium, 1- (2-hydroxyethanol) -pyrrolidone, secondary amine, sodium hydroxide, tnetanolamine, tromethamine and zinc hydroxide The compounds of formula (I) can be prepared in accordance to the procedure briefly described in scheme 1 SCHEME 1 Accordingly, an appropriately substituted compound of formula (X), a known compound or compound prepared by means of known methods, reacts with sulfamide, a known compound, preferably wherein the sulfonamide is present in an amount in the range of about 2 to about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, preferably at an elevated temperature in the range of about 50 ° C to about 100 ° C, more preferably at about the reflux temperature, to produce the compound corresponding to formula (la). Alternatively, a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, reacts with a suitably substituted compound of formula (XI), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pipdin, and the like, in a organic solvent such as DMF, DMSO, and the like, to produce the corresponding compound of formula (I) / v \ i P i) The compounds of formula (X) wherein \ _ is It can be prepared according to procedure briefly described in scheme 2 SCHEME 2 (Xa) Accordingly, a suitably substituted compound of formula (XII), a known compound or compound prepared by a known method (for example as described in scheme 3 above) Reacts with NH 4 OH, a known compound, optionally in a solvent organic such as acetonitoplo, and the like, to produce the compound corresponding to formula (XIII) The compound of formula (XIII) reacts with a suitably selected reducing agent, such as LAH, and the like, in an organic solvent such as THF, diethyl ether, and the like, to produce the corresponding compound of formula (Xa) " ~~ - ~ N, i 'R The compounds of formula (X) where is selected from You can prepare according to the procedure briefly described in scheme 3 SCHEME 3 OR "H- ?: \ (CH2 n 1 MH, 'P h. M (; ^ -H? U-? H, - i) Accordingly, a suitably substituted compound of formula (XIV), a known compound or compound prepared by known methods, reacts with NH 4 OH in the presence of a coupling agent such as DCC, and the like, optionally in a solvent organic such as acetonitop, and the like, to produce the corresponding compound of formula (XV) The compound of formula (XV) reacts with a suitably selected reducing agent, such as LAH, and the like, in an organic solvent such as THF , diethyl ether and the like, to produce the corresponding compound of formula (Xb) The compounds of formula (X) wherein select from where a is 2, it can be prepared from according to the procedure briefly described in scheme 4 SCHEME 5 u (i \ Accordingly, a suitably substituted compound of formula (XVI) wherein J1 is a suitable leaving group such as Br, Cl, I, tosyl, mesyl, tpflyl, and the like, a known compound or compound prepared by known methods (for example, by activating the corresponding compound wherein J1 is OH), reacts with a cyanide such as potassium cyanide, sodium cyanide, and the like, in an organic solvent such as DMSO, DMF, THF, and the like, to produce the corresponding compound of formula (XVII) The compound of formula (XVII) is reduced according to known methods, for example by reacting with a suitable reducing agent such as LAH, borane, and the like, to produce the corresponding compound of formula (Xc) The compounds of formula (X) wherein select from where a is 1, it can be prepared according to the procedure briefly described in scheme 5 SCHEME 5 ? / i? n l / \ < \ i (Xd) Accordingly, a suitably substituted compound of formula (XVIII), a known compound or compound prepared by known methods is activated, according to a known method, to produce the corresponding compound of formula (XIX), wherein J2 is a leaving group suitable, such as tosylate, Cl, Br, I, mesylate, triflate and the like The compound of formula (XIX) reacts with a phthalimide salt such as potassium philimide, sodium phthalimide, and the like, in an organic solvent such as DMF, DMSO, acetonitrile, and the like, preferably, at an elevated temperature in the range of 50 ° C to about 200 ° C, more preferably, at about the reflux temperature, to produce the corresponding compound of formula (XX). The compound of formula (XX) reacts with N2H4, a known compound, in an organic solvent such as ethanol, methanol, and the like, preferably, at an elevated temperature in the range of about 50 ° C to about 100 ° C, more preferably, a approximately reflux temperature, and the like, to produce the corresponding compound of formula (Xd) A person skilled in the art will recognize that the F F 1 1 compounds of formula (X) wherein _ 'is selected from (R)? they can be prepared similarly according to known methods or for example, according to the procedures briefly described in schemes 2-5 above, by selecting and replacing the corresponding naphthyl-fused compounds for the benzo-fused starting materials. experience in the art will also recognize that when a single enantiomer (or a mixture of enantiomers in which one enantiomer is enriched) of a compound of formula (X) is desired, the above procedures as described in schemes 1 to 5 can be applied by replacing the corresponding single enantiomer (or mixture of enantiomers in which one enantiomer is enriched) for the appropriate starting material. A person skilled in the art will recognize that when a reaction step of the present invention can be carried out in a variety of solvents or solvent systems, said reaction step can be carried out in a mixture of suitable solvents or solvent systems. solvents. When the processes for the preparation of the compounds according to the invention result in a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form, or individual enantiomers can be prepared by means of enantiospecific synthesis or by means of resolution. The compounds can, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by means of salt formation with an optically active acid, such as (-) - di-p-toluyl- D-tartaric and / or (+) - di-p-toluyl-L-tartaric followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of esters or diastereomeric amides, followed by chromatographic separation and chiral auxiliary removal. Alternatively, the compounds can be resolved using a chiral HPLC column. During any of the procedures for the preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups. or reagents in any of the target molecules This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed JFW McOmie, Plenum Press, 1973, and TW Greene & P G M Wuts, Protective Groups in Qrqanic Synthesis, John Wiley & Sons, 1991 Protecting groups can be removed at a convenient later stage using methods known in the art. The present invention further comprises pharmaceutical compositions containing one or more compounds of formulas (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or More of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the route desired administration (eg, oral, parenteral) Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, ghcoles, oils, alcohols, Savory agents, preservatives, stabilizers, coloring agents and the like, for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and similar The solid oral preparations can also be coated with substances such as sugars or enteric coating to modulate the higher absorption site for parenteral administration, the carrier will normally consist of sterile water and other ingredients may be added to increase solubility or preservation. Suspensions or injectable solutions may be prepared using aqueous carriers together with appropriate additives. To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient are intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, wherein the carrier can take a wide variety of forms depending on the desired preparation form for administration, for example, oral or parenteral such as In the preparation of the compositions in the oral dosage form, any of the usual pharmaceutical media can be used in this way, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, sabotagers, preservatives, coloring agents and the like, to Solid oral preparations such as, for example, powders, capsules, caplets, gel capsules and tablets, carriers and suitable additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like Due to their easy administration, the tablets and capsules represent the most convenient oral dosage unit form, in which case the solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated with sugar or enteric by standard techniques. For parenterals, the carrier will usually comprise steplad water, through other ingredients, for example, for purposes such as solubility facilitation or for preservation, may also be included. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be prepared. employ pharmaceutical compositions here They will contain, per dosage unit, for example, tablet, capsule, powder, injection, spoon and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per dosage unit, per example, tablet, capsule, powder, injection, suppository, spoon and the like, of about 0-1-1000 mg and can be provided in a dosage of about 0 01 -150 0 mg / kg / day, preferably about 0 1 to 100 mg / kg / day, more preferably from about 0 5-50 mg / kg / day, more preferably from approximately 1 0-25.0 mg / kg / day, or any interval in these Dosages, however, can be waived depending on the requirement of the patients, the severity of the condition to be treated and the compound to be used. Target administration or post-pepodic dosage can be employed. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, self-injector devices or suppositories, for oral, parenteral administration, intranasal, sublingual or rectal, or for administration by inhalation or insufflation Alternatively, the composition may be present in a form suitable for administration once weekly or once a month, for example, an insoluble salt of the active compound, such as decanoate salt , can be adapted to provide a depot preparation for intramuscular injection. For the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tablet-forming ingredients such as corn starch, lactose. , sucrose, sor bitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, for example water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or its salt pharmaceutically acceptable When we We refer to these pre-formulating compositions as homogeneous, it means that the active ingredient is equally dispersed throughout the composition so that the composition can be easily subdivided into effective dosage forms equally such as tablets, pills and capsules. This pre-formulation composition solid is then subdivided into unit dosage forms of the type described above containing from 0 1 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise formed into compound to provide a dosage form that produces the long-acting advantage. For example, the tablet or pill may comprise an internal dosage and an external dosage component, the latter being in the form of a cover on the former The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or to have a delayed release. of material can be used for said enteric layers or coatings, said materials including a number of polymethic acids with said materials such as lacquer, cetyl alcohol and cellulose acetate The liquid forms in which the novel compositions of the present invention can be incorporated for administration orally or by injection include, aqueous solutions, syrups with suitable flavor, aqueous or oily suspensions, and flavored emulsions with Edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles Dispersion or suspension agents suitable for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrro donut or gelatin The method of treatment of abuse and / or alcohol addiction described in the present invention can also be carried out using a pharmaceutical composition comprising any of the compounds as is defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably about 50 to 500 mg, of the compound, and may be constituted in any form suitable for the selected mode of administration Carriers include excipients pharmaceutical inert and necessary s, including, but not limited to, binders, suspending agents, lubricants, sabotards, sweeteners, preservatives, inks, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including formulations) immediate release, synchronized release and sustained release), granules, and powders, and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions Useful forms for parenteral administration include sterile solutions, emulsions and suspensions Conveniently, compounds of the present invention can be administered in a single target dose, or the total target dosage can be administered in divided doses of two, three or four times daily. In addition, the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in the art to be administered in the form of a delivery system transdermal, dosing administration will, of course, continue more than intermittent throughout the dosing regimen. For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a non-toxic, oral pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water and the like. Additionally, when desired or If necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, sodium tragacanth or oleate, sodium stearate, magnesium stearate, sodium benzoate. , sodium acetate, sodium chloride and the like Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like Liquid forms in suspending or dispersing agents with suitable flavor such as synthetic gums and natural, by example, tragacanth, acacia, methyl cellulose and the like For parenteral administration, suspensions and sterile solutions are desired. Isotonic preparations which generally contain suitable preservatives are used when intravenous administration is desired. Compounds of this invention can be administered in any of the above compositions and according to the dosage regimens established in the art each time the treatment of abuse and / or alcohol addiction is required. The daily dosage of the products can be varied over a wide range of 0 to 150 mg / kg per human adult. per day For oral administration, the compositions are preferably provided in the form of tablets containing 0 01, 0 05, 0 1, 0 5, 1 0, 2 5, 5 0, 10 0, 15 0, 25 0, 50 0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage The patient to be treated An effective amount of the drug is ordinarily supplied at a dosage level of about 0.01 mg / kg to about 1500 mg / kg of body weight per day. Preferably, the range is from about 0-1 to about 100. mg / kg body weight per day, more preferably, from about 0 5 mg / kg to about 50 mg / kg, more preferably, from about 10 to about 25 mg / kg of body weight per day The compounds are They can be administered in a regimen of 1 to 4 times per day. Optimal dosages to be administered can be easily determined by those of skill in the art, and will vary with the particular compound used, the manner of administration, the concentration of the preparation, the manner of administration, and the progress of the disease condition. In addition, the factors associated with the patient Particular to be treated, including age, weight, diet and time of administration to the patient, will result in the need to adjust dosages. A person skilled in the art will recognize that, both in vivo tests in vitro using suitably, cellular and / or animal models known and generally accepted serve as a prognostic of the ability of a test compound to treat or prevent a given disorder. A person skilled in the art will additionally recognize that human clinical trials including efficacy and variable dose assays, first in humans, in healthy patients and / or those who suffer from a given disorder, can be mplete according to well known methods in clinical and medical techniques The following examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims that they follow later EXAMPLE 1 ((3,4-dihydro-2H-benzo [b1f1, 41dioxepin-3-yl) methyl) sulfamide (compound # 3) Catechol (5 09 g, 46 2 mmol) and potassium carbonate are combined in acetonitop and heated at reflux for one hour. 2-Chloromethyl-3-chloro-1-pre (5.78 g, 46.2 mmol) is added and the reaction is carried out. Continue to reflux for 24 hours. The solution is cooled to room temperature and filtered. The filtrate is evaporated and the residue is diluted with water and extracted with diethyl ether (3x). The combined organic solution is dried over MgSO4 and concentrated. Chromatography (2% ethyl ether in hexane) produces 3-methylene-3,4-dihydro-2H-benzo [b] [1,4] dioxepin as a colorless oil. MS (ESI): 163.2 (M + H +) 1 H NMR (300 MHz, CDCl 3), d: 6.94 (m, 4 H), 5.07 (s, 2 H), 4.76 (s, 4 H). Dissolve 3-methylene-3,4-d? -hydro-2H-benzo [b] [1,4] dioxepine (5.00 g, 30.8 mmol) in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL) is added at 0 ° C. The reaction is stirred at room temperature for 5 hours. Aminosulfonic acid (6.97 g, 61.6 mmol) is added. The reaction is refluxed overnight The reaction is cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 ml) is added The solution is extracted with ethyl acetate (3 x 100 ml). The combined organic solution is dried over MgSO4. The solution is concentrated under vacuum and purified by chromatography (2% to 8% methanol in dichloromethane) to yield ((3,4-dihydro-2H-benzo [b] [1,4] dioxepin-3-yl) methyl. ) amine as a colorless oil. MS (ESI): 180.1 (M + H +) 1 H NMR (300 MHz, DMSO) d: 6.92 (m, 4 H), 4.21 (m, 2 H), 4.07 (m, 2 H), 3.33 (broad, 2 H), 3.16. (d, J = 4 Hz, 1 H), 2.72 (d, J = 4 Hz, 1 H), 2.30 (m, 1 H). Combine ((3,4-dihydro-2H-benzo [b] [1,4] dioxepin-3-yl) methyl) amine (2.90 g, 16.2 mmol) and sulfamide (3.11 g, 32.4 mmol) in dry dioxane ( 60 mi) and heated to reflux overnight. Chloroform is added and the precipitate is removed by filtration. The filtrate is concentrated under vacuum and purified by chromatography (acetone from 2% to 8% in dichloromethane) to yield the title compound as an off-white solid. 258.8 (M + H +) 1 H NMR (300 MHz, DMSO) d: 6.92 (m, 4 H), 6.71 (broad, 1 H), 6.59 (broad, 2 H), 4.19 (m, 2 H), 4.04 (m, 2 H) ), 3.00 (m, 2H), 2.39 (m, 1 H).

EXAMPLE 2 N- (2,3-D-Hydro-benzo [1,4-dioxin-2-ylmethyl) -sulfamide (compound # 1) 2,3-d-Hydro-1,4-benzd? Ox? N-2-? Lmet? Lam? Na racemic (4 4 g, 26 mmol) and sulfonamide (5 1 g, 53 mmol) are combined in 1,4-d-oxane (100 ml) and refluxed for 2 h. The reaction is cooled to room temperature and a small amount of solid is filtered and discarded. The filtrate is evaporated in vacuo and the residue is purified using chromatography. of flash column (DCM methanol-10: 1) to yield a white solid. The solid is recrystallized from DCM to yield the title compound as a white solid. P f 97.5 -98 ° C Elemental analysis: Calculated analysis: C, 44 25 , H, 4 95, N, 1 1 47, S, 13 13 Analysis found C, 44 28, H, 4 66, N, 1 1 21, S, 13.15. H1 NMR (DMSO d6) d 6.85 (m, 4H), 668 (bd s, 3H, NH), 4 28 (m, 2H), 3 97 (dd, J = 6 9, 1 1 .4 Hz, 1 H), 3 20 (m, 1 H), 3 10 (m, 1 H) EXAMPLE 3 (Benzo [1,13-dioxol-2-ylmethyl) sulfonamide (compound # 2) Catechol (10.26 g, 93.2 mmol), sodium methoxide (25% by weight in methanol, 40.3 g, 186 mmol), and methyl dichloroacetate (13.3 g, 93.2 mmol) in dry methanol (100 g) were combined. mi) The solution is heated to reflux overnight The reaction is cooled to room temperature, acidified by the addition of concentrated hydrochloric acid and then reduced in volume under vacuum to about 50 ml Water is added and the mixture is extracted with diethylether (3 x 100 mL) The combined organic solution is dried with MgSO 4, concentrated to a brown solid, and chromatographed (2% ethyl acetate in hexane) to produce benzoic acid methyl ester [1, 3]. d? oxol-2-carboxylic acid as a colorless oil MS (ESI) 195 10 (M + H +) 1 H NMR (300 MHz, CDCl 3), d 6 89 (broad, 4H), 6 29 (s, 1 H), 4 34 (q, J = 7 Hz, 2H), 1 33 (t, J = 7 Hz, 3H) is added to benzo [1, 3] d? Oxol-2-carboxy acid methyl ester ( 7 21 g, 40 0 mmol), ammonium hydroxide (29% in water, 10 ml) and sufficient acetonitoplo to make the mixture homogeneous (~ 5 ml) The solution is stirred for two hours at room temperature and then distilled water is added. Amide of benzo [1,3] d? oxol-2-carboxylic acid is collected. precipitated as a white solid by filtration and used without further purification MS (ESI) 160 00 (M + H +) 1 H NMR (300 MHz, DMSO), d 7 99 (s, broad, 1 H), 7 72 (s, broad, 1 H), 6 94 (m, 2H) 6 86 (m, 2H), 6 30 (s, 1 H) Amide of benzo [1,3] d? oxol-2-carboxylic acid is dissolved? co (5.4 g, 32.9 mmol) in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1M in THF 39.5 mL, 39.5 mmol) is added slowly to the solution at room temperature. The reaction is stirred at room temperature for 24 hours Distilled water is added to destroy excess LAH Aqueous sodium hydroxide (3.0 M, 100 mL) is added and the solution is extracted with ethyl acetate (3 x 100 mL) The combined organic solution is wash with water and dry over MgSO.sub.3 The solvent is evaporated to yield C-benzo [1,3] d? oxol-2-? l-met? lam? na as a colorless oil MS (ESI) 152 1 (M + H + ) 1 H NMR (300 MHz, CDCl 3), d 6 87 (m, 4 H), 6 09 (t, J = 4 Hz, 1 H), 3 13 (d, J = 4 Hz, 2 H) C-benzo is combined [1 , 3] d? Oxol-2-? L-met? Lam? Na (2 94 g, 19 4 mmol) and sulfamide (3 74 g 38 9 mmol) in dry dioxane (50 ml) and the solution was refluxed at all overnight The reaction is concentrated and the residue is chromatographed (2% to 10% acetone in dichloromethane) to yield the title compound as a white solid EM (ESI) 230 0 (M + H +) 1 H NMR (300 MHz, CDCl 3), d 6 87 (m, 4 H), 6 25 (t, J = 4 Hz, 1 H), 4 79 (broad, 1 H), 4 62 (broad, 1 H), 3 64 (d, = 4 Hz, 2H) EXAMPLE 4 (2S) - (-) - N- (2,3-dihydro-benzo [1,4-dioxo-2-ylmethyl) -sulfamide (compound # 4) Catechol (13 2 g, 0 12 mol) and potassium carbonate (16 6 g, 0 12 mol) in DMF (250 ml) are stirred and (2R) -gl? Cylide tosylate (22 8) is added. g, 0-10 mol) and the reaction is stirred at 60 ° C for 24 hours. The reaction is cooled to room temperature and diluted with ice water (11) and extracted with diethylether (4 times). The combined organic solution is washed three times. times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to give a white solid which is purified by flash column chromatography (DCM methanol-50 1) to produce ((2S) - 2,3-d? H? Dro-benzo [1,4] d? Ox? N-2-? L) methanol as a solid The solid is dissolved (13.3 g, 68 mmol) in cooled pipdma (85 ml) at 0 ° C, p-toluenesulfonyl chloride (13.0 g, 68 mmol) is added and the reaction mixture is stirred at room temperature for 20 h. The reaction is diluted with diethyl ether (1 l) and 1 N HCl (l2). I) The organic layer is separated and washed twice with 1 N HCl (500 ml), 4 v You drink with water (150 ml), once with Brine, dry (MgSO) and evaporate in vacuo to yield a white solid which is purified by flash column chromatography (Hept EA-2 1) to produce ester (2S) -2, 3-d? H? Dro-benzo [1,4] d? Ox? N-2-ylmethiol of toluene-4-sulfone? Co acid as a white solid White solid is combined with potassium phthalimide (14.4 g , 78 mmol) in DMF (250 ml) and refluxed for 1 hour, cooled to room temperature and poured into water with vigorous stirring (15 I) and stirred for 30 minutes. The white solid and the solid is washed several times with water, 2% NaOH, and water again and allowed to air dry to yield a (2S) -2- (2,3-d? h? dro-benzo [1,4] d? ox? n-2-? lmet? l) -? soldol-1, 3-dione as a white solid powder White solid powder is combined with hydrazine (2 75 g, 86 mmol) in EtOH (225 ml ) and refluxed for 2 hours, cooled to room temperature and 1N HCl was added at pH 10 and stirred for 15 minutes. The white solid was filtered and washed with fresh EtOH (discarded solid) and the filtrate was filtered off. evaporate in vacuo to a solid, which is divided between diethyl ether and dilute aqueous NaOH. ethylether (Na2SO4) and evaporated in vacuo to yield a light yellow oil The oil is purified by flash column chromatography (DCM MeOH -10 1) to yield an oil A portion of the oil (4.82 g, 29 mmol) in 2- propanol (250 mL) is treated with 1N HCl (30 mL) and heated in a bath until homogenous and then allowed to cool to room temperature. After 3 hours, the mixture is cooled with ice for 2 hours. A puffed solid White (the corresponding HCl salt of (2S) -C- (2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine) is filtered and then recrystallized again from 2-propanol to produce a white solid. [α] D = -69.6 (c = 1.06, EtOH) The white solid is partitioned between DCM and dilute NaOH, and the DCM is dried (NaS04) and evaporated in vacuo to yield (2S) -C- (2.3 -dihydro-benzo [1,4] dioxin-2-yl) -methylamine as an oil. [α] D = -57.8 (c = 1.40, CHCl3) The oil (2.1 g, 12.7 mmol) and sulfonamide (2.44 g, 25.4 mmol) is heated to reflux in dioxane (75 ml) for 2 hours and the crude product is heated. purify by flash column chromatography (DCM: MeOH 10: 1) to yield a white solid, which is recrystallized from DCM to yield the title compound as a white crystalline solid. P.f .: 102-103 ° C [a] D = -45.1 ° (c = 1.05, M); H NMR (DMSOdd) d 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1 H), 3.20 (dd, J = 5.5, 13.7 Hz, 1 H), 3.10 (dd, J = 6.9, 13.7 Hz, 1 H). Elemental Analysis: Calculated Analysis: C, 44.25; H, 4.95; N, 1 1.47; S, 13.13 Analysis found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.

EXAMPLE 5 N- (2,3-dihydro-benzori, 41-dioxin-2-ylmethyl) -N ', N'-dimethylsulfamide (compound # 6) Racemic 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine (8.25 g, 5.0 mmol) and tritylamine (1.52 g, 15 mmol) in DMF (10 mL) are combined and cooled in an ice bath as described. add dimethisulfamoyl chloride (1.44 g, 10 mmol). The reaction mixture is then stirred for 3 hours with continuous cooling. The reaction mixture is partitioned between ethyl acetate and water, and the ethyl acetate solution is washed with brine, dried (MgSO4) and evaporated in vacuo to yield an oil. The oil is purified using flash column chromatography (ethyl acetate: heptane-1: 1) to yield a white solid, which is recrystallized (ethyl acetate / hexane) to yield the title compound as a white floc solid. P.f .: 76-78 ° C EM 273 (MH +) Elemental analysis: Calculated analysis: C, 48.52; H, 5.92; N, 10.29; S, 1 1.78 Analysis found: C, 48.63; H, 5.62; N, 10.20; S, 11.90 1 H NMR (CDCl 3) d 6.87 (m, 4 H), 4.59 (bd m, 1 H, NH), 4.35 (m, 1 H), 4 27 (dd, J = 2 3, 1 1 4 Hz, 1 H), 4 04 (dd, J = 7 0, 1 1 4, 1 H), 3 36 (m, 2 H), 82 (s, 6H) EXAMPLE 6 N- (2,3-d.hydro-benzo [1,41-dioxan-2-ylmethyl] -N-methylsulfonamide (compound # 7) 2,3-d-Hydro-1,4-benzd? Ox? N-2-? Lmet? Lam? Na racemic (825 mg, 5 mmol) is dissolved in ethyl formate (15 ml), heated reflux for 30 minutes and evaporate in vacuo to yield N- (2,3-d? h? dro-benzo [1,4] d? ox? n-2-? lmet? l) -formamide as a Oil The diethylether oil (25 mL) is treated with 1 M LAH in THF (9.0 mL, 9.0 mmol) at 0 ° C and stirred for 5 hours at room temperature. The reaction is cooled in an ice bath and annealed with water (0 50 ml), followed by 3N NaOH (0 50 ml) and water (0 50 ml) The mixture is then stirred at room temperature for 1 h. The solid is filtered and the filtrate is evaporated in vacuo to yield a residue. which is divided between 1 N HCl and diethyl ether. The aqueous phase is basified with 1 N NaOH and extracted with diethyl ether. The organic phase is dried (MgSO.sub.4) and evaporated m vacuo to yield (2,3-d? H? Dro-benzo [1,4] d? Ox? N-2-? Lmet? L) -met? L- am? na like an oil MS 180 (MH +) 1 H NMR (CDCl 3) d 6.85 (m, 4 H), 4.30 (m, 2 H), 4.02 (dd, J = 7.9, 11.6 Hz, 1 H), 2.85 (m, 2 H), 2.50 (s) , 3H). The oil (380 mg, 2.1 mmol) and sulfamide (820 mg, 8.5 mmol) are combined in dioxane (15 mL), heated to reflux for 1.5 hours and evaporated in vacuo to yield a crude residue. The residue is purified via column chromatography (ethyl acetate / heptane 1: 1) and the resulting solid is recrystallized from ethyl acetate / hexane to yield the title compound as a white solid. Mp: 97-98 ° C EM 257 (M "1) Elemental analysis: Calculated analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41 Analysis found: C, 46.48; H, 5.65; N, 10.90; S, 12.07 1 H NMR (CDCl 3) d 6.86 (m, 4 H), 4.52 (bs, 2 H), 4.46 (m, 1 H), 4.29 (dd, J = 2.3, 1 1.5 Hz, 1 H), 4.05 (dd, J = 6.5, 1 1.5 Hz, 1 H), 3.51 (dd, J = 6.7, 14.9 Hz, 1 H), 3.40 (dd, J = 5.9, 14.9 Hz, 1 H), 2.99 (s, 3H).

EXAMPLE 7 (2S) - (-) - N- (6-chloro-213-dihydro-benzofl, 4-dioxin-2-ylmethyl) -sulfamide (compound # 8) Following the procedure outlined in example 4 above, 4-chlorocatechol is reacted to produce a mixture of (2S) -C- (7-chloro-2,3-d? H? Dro-benzo [1,4] d? ox? n-2-? l) -met? lam? na and (2S) -C- (6-chloro-2,3-d? h? dro-benzo [1,4] d? ox? n-2 -? l) -met? lam? na (ca ratio 3 1 isomers 6-chloro 7-chloro by RP HPLC) The mixture is dissolved in 2-propanol (100 ml) and 1 N HCl in diethylether is added until a pH = 1 0 is reached The hydrochloride salt that precipitates is filtered (2 65 g) and re-cpstalized from methanol / IPA to produce white crystals The white crystals are divided between DCM and diluted NaOH The DCM is dried and evaporated in vacuo to yield (2S) -C- (6-chloro-2,3-d? h? dro-benzo [1,4] d? ox? n-2-? l) -met? lam? na purified as an oil [a] D = -67 8 (c = 1 51, CHCl3) The oil (775 mmol) and sulfonamide (150 g, 15.5 mmol) are combined in dioxane (50 ml) and heated at reflux for 2 hours, they are cooled to room temperature and evaporated in vacuo to produce a solid. to be purified via flash column using DCM / methanol 1 to yield the title compound as a white solid EM 277 (M "1) [a] D = -59 9o (c = 1 1 1, M) 1 H NMR (CDCl 3) d 6 90 (d, J = 2 2 Hz, 1 H), 6 81 (m, 2 H), 4 76 (m, 1 H), 4 55 (s, 2 H), 4 40 (m, 1 H), 4 29 (dd, J = 2 4 , 1 1 5 Hz, 1 H), 4 05 (dd, J = 7 1, 1 1 5 Hz, 1 H), 3 45 (m, 2H) Elemental analysis Calculated analysis C, 38 78, H, 3 98, N, 10 05 Analysis found C, 38 80, H, 3 67, N, 9 99 The filtrates of crystallized hydrochloride salt of (2S) -C- (6-chloro-2,3-d? H? Dro-benzo [ 1, 4] d? Ox? N-2-? L) -methalamine prepared above are recovered (ca 1 1 of 6-chloro 7-chloro isomers) and evaporated in vacuo to produce a solid, which is partition between DCM (200 ml) and dilute NaOH (0 5 M, 50 ml) The DCM solution is washed once with brine, dried (Na 2 SO 4) and evaporated in vacuo to yield an oil, which is purified via HPLC of reverse phase (10-50% ACN with 0-16% TFA in water with 0 20% TFA) to produce (2S) -C- (7-chloro-2,3-d? h? dro-benzo [ 1, 4] d? Ox? N-2-? L) The residue is combined with sulfonamide (090 g, 9.4 mmol) in dioxane (25 ml) and heated to reflux for 2 5 hours, cooled to room temperature and evaporated in vacuo. to produce an oil The oil is purified by flash column chromatography using DCM / methanol - 10 1 to produce (2S) - (-) - N- (7-chloro-2,3-d? benzo [1,4] dioxin-2-ylmethyl) -sulfamide as a white solid. MS 277 (M "1) H NMR (CDCl 3 / CD 3 OD) d 6.88 (d, J = 0.7 Hz, 1 H), 6.81 (m, 2H), 4. 37 (m, 1 H), 4.30 (dd, J = 2.3, 1 1.6 Hz, 1 H), 4.04 (dd, J = 7.0, 11.6 Hz, 1 H), 3. 38 (m, 2H).

EXAMPLE 8 Chroman-2-ylmethylsulfamide (compound # 10) Combine chroman-2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol) in DCM (40 mL) and DMF (10 mL). Dimethylaminopropyl ethylcarbodiimide (EDC, 4.84 g, 25 mmol) is added at room temperature and the reaction mixture is stirred for 30 minutes. Ammonium hydroxide (2.26 ml, 33.4 mmol) is added and the reaction mixture is stirred for 16 hours. The reaction mixture is diluted with DCM (50 ml) and water (50 ml) and the pH of the mixture is adjusted to approximately pH = 3.0 with 1 N HCl. The DCM is separated and the aqueous phase is extracted twice with DCM. . The combined DCM phase is dried (Na2SO4) and evaporated in vacuo to yield an oil, which is purified by flash column chromatography (ethyl acetate) to yield an oil.

The oil (5.35 g, 30 mmol) in THF (90 ml) is stirred as 1 M LAH in THF (36 ml, 36 mmol) is added and the reaction mixture is then stirred at room temperature for 20 hours. The reaction is quenched with water, stirred for 2 hours, the solution decanted, dried (Na2SO4) and evaporated in vacuo to yield C-chroman-2-yl-methylamine as an oily amine. The oily amine (1.63 g, 10 mmol) and sulfamide (1.92 g, 20 mmol) are combined in dioxane (50 ml) and heated at reflux for 2 hours. The solution is cooled and evaporated in vacuo to yield an oil, which is purified via column chromatography (DCM: 10: 1 methanol) to yield a white solid. The solid is recrystallized from ethyl acetate / hexane to yield chroman-2-ylmethylsulfamide as a white solid. P.f .: 100-101 ° C EM 241 (M "1) Elemental analysis: Calculated analysis: C, 49.57; H, 5.82; N, 1.56; S, 13.23 Analysis found: C, 49.57; H, 5.80; N, 11.75; S, 13.33.

EXAMPLE 9 2- (2,3-Dihydro-benzo [1,4] dioxin-2-yl) -ethylsulfamide (compound # 16) Potassium cyanide (2 05 g, 31.5 mmol) is added to 2-bromomet? L- (2,3-d? H? Drobenzo [1,4] d? Ox? Na (6 87 g, 30 mmol) in DMSO (90 ml) and stirred at room temperature for 20 hours. The reaction mixture is then diluted with water (250 ml) and extracted twice with diethyl ether. The diethyl ether is washed with water, then washed twice with brine, dry (Na2SO4) and evaporate in vacuo to yield 2-c? anomet? l- (2,3-d? h? drobenzo [1,4] d? ox? na) as a white solid 1H NMR (CDCl3) d 6 89 (m, 4H), 4 50 (m, 1 H), 4 31 (dd, J = 2 3, 11 5 Hz, 1 H), 4 08 (dd, J = 6 2, 1 1 6 Hz, 1 H), 2 78 (d, J = 6 1, Hz, 2H) Dissolve 2-c? Anomet? L- (2,3-d? H? Drobenzo [1,4] d? Ox? Na) in THF (50 ml) and BH3 1 M in THF (80 ml, 80 mmol) is added and the reaction mixture is refluxed for 5 hours, then stirred at room temperature for 16 hours. With ice bath cooling, it is added 2N HCl until a pH = 10 is reached The reaction mixture is then stirred for 1 h at room temperature and evaporated in vacuo to yield an oil. The oil is partitioned between 3N NaOH and diethylether, and the diethylether solution is washed with Brine, dry (Na2SO4) and evaporate m vacuo to yield crude 2- (2,3-d? h? drobenzo [1,4] d? ox? n-2-? l) et? lam? na MS (M + H) + 180. Crude 2- (2,3-dihydrobenzo [1,4] dioxin-2-yl) ethylamine is combined in dioxane (100 ml) with sulfonamide (3.0 g, 31 mmol) and it is heated to reflux for 2 hours. The solution is cooled and evaporated in vacuo to yield an orange solid, which is purified by column chromatography (DCM: MeOH-10: 1) to yield a white solid. The solid is re-crystallized from DCM to yield the title compound as a solid. MS (M-1) 257 M.p.: 101-103 ° C (corr) 1 H NMR (CDCl 3): d 6.86 (m, 4H), 4.70 (m, 1 H), 4.52 (s, 2H), 4.30. (m, 2H), 3.94 (dd, J = 7.4, 11.3 Hz, 1 H), 3.43 (dd, J = 6.4, 12.9 Hz, 2H), 1.94 (dd, J = 6.5, 12.9, 2H). Elemental Analysis: Measured: C, 46.48; H, 5.60; N, 10.81; S, 12.41 Calculated: C, 46.50; H, 5.46; N, 10.85; S, 12.41.

EXAMPLE 10 (2S) - (-) - N- (6,7-Dichloro-2,3-dihydro-benzo [1,4-dioxin-2-ylmethyl) -sulfamide (compound # 29) 4.5-d.chloroatecol (8.6 g, 48 mmol) and potassium carbonate (64.6 g, 48 mmol) in DMF (200 mL) are added. (2R) -gl? Cylide tosylate is added. (9 12 g, 40 mmol) and the reaction mixture is stirred at 60 ° C for 24 hours. The reaction mixture is cooled to room temperature and then diluted with ice water (600 ml) and extracted with diethylether (4 times ) The combined organic solution is washed three times with 10% potassium carbonate, twice with brine, dried (MgSO 4) and evaporated in vacuo to yield a viscous oil of (2S) -2- (6,7-d). chloro-2 3-d? h? dro-benzo [1,4] d? ox? na) methanol Dissolves (2S) -2- (6,7-d? chloro-2,3-d? hydro-benzo [1,4] d? oxane) methanol (6 4 g, 27 mmol) in pipdine (50 ml) cooled to 0 ° C. Then p-toluenesulfonyl chloride (5 2 g, 27 g) was added. mmol) and the reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is diluted with diethyl ether and 1 N HCl (750 ml) and the organic layer is separated and washed twice with 1 N HCl (2 ml). 50 ml), once with water (150 ml), twice with brine, dried (MgSO 4) and evaporated in vacuo to give light yellow solid of (2S) -6,7-d-chloro-2,3-ester. -d? h? dro-benzo [1, 4] d? ox? n-2-? lmet? l? co of the toluene-4-sulfon? 1 H NMR (CDCl 3) d 7 79 (d, J = 8 3 Hz, 2 H), 7 36 (d, J = 8 O Hz, 2 H), 6 94 (s, 1 H), 6 83 (s, 1 H ), 4 37 (m, 1 H), 4 2 (m, 3H), 4 03 (dd, J = 6 3, 11 7 Hz, 1 H), 2 47 (s, 3H) Ester (2S) is combined -6,7-d-chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N-2-ylmethyl of toluene-4-sulfon? Co acid (8 g, 20 5 mmol) with potassium phthalimide (6 1 g, 33 mmol) in DMF (75 ml) and refluxed for 1 hour, cooled to room temperature and poured into water with vigorous stirring (0 5 I) and then stir 30 minutes The white solid is filtered and the solid is washed several times with water, 2% NaOH, and water again and then allowed to air dry to yield (2S) -2- (6,7-d? Chloro-2,3-d? H? Dro-benzo [1,4] dtox ? n-2-? lmet? l) -? so? ndol-1, 3-d? ona (6 0 g, 80%) as a white powdery solid The white powdery solid is combined with hydrazine (1 06 g , 33 mmol) in EtOH (80 ml) and refluxed for 2 hours, then cooled to room temperature. 1 N HCl is added to adjust the pH of the reaction mixture to pH 10 and the reaction mixture is then added to the reaction mixture. stir for 15 minutes The white solid is filtered and washed with fresh EtOH (discarded solid) and the filtrate is evaporated in vacuo to a solid, which is divided between diethylether and dilute aqueous NaOH. The diethylether solution is dried (Na2SO4) and evaporate in vacuo to yield a viscous oil of (2S) -2-amomethyl-6,7-d? chloro-2,3-d? h? dro-benzo [1, 4] d? ox Na) 1 H NMR (CDCl 3) d 6 98 (s, 1 H), 6 96 (s, 1 H), 4 25 (dd, J = 2 0, 11 2 Hz, 1 H), 4 15 (m, 1 H), 4 0 (m, 1 H), 2 97 (d, J = 5 5 Hz, 2 H) A portion of the oil (3.8 g, 16 mmol) and sulfamide (3.1 g, 32.4 mmol) are heated under reflux in dioxane (100 ml) for 2 hours and the crude product is purified by flash column chromatography (DCM: MeOH 20: 1) to produce the title compound as a white solid, which is recrystallized from ethyl acetate / hexane to yield the title compound as a white crystalline solid. MS [MH] - 31 1 .0 Pf: 1 19-121 ° C [a] D = -53.4 ° (c = 1 .17, M) 1 H NMR (DMSOdd): d 7.22 (s, 1 H), 7.20 (s, 1 H), 6.91 (bd s, 1 H), 6. 68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 1 1.5 Hz, 1 H), 3.1 5 (m, 2H) Elemental Analysis: Measured: C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24 Calculated: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.

EXAMPLE 11 (2S) - (-) - N- (7-amino-2,3-dihydro-benzof1, 4-dioxin-2-methylmethyl) -sulfamide (compound # 36) H Prepare (2S) - (-) - N- (2,3-dihydro-7-nitro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (1.2 g, 4.15 mmol), from 4- nitrocatechol according to the procedure outlined in Example 4. The (2S) - (-) - N- (2,3-dihydro-7-nitro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide, then it is combined with 10% Pd / C in methanol (120 ml) and shaken under a hydrogen atmosphere (2.65 atm) at room temperature for 3 hours. The solids are filtered and washed with % M in DCM and the filtrate is evaporated in vacuo to provide the crude product. The crude product is dissolved in 0.2 N HCl (25 ml), frozen and lyophilized to yield the title compound as a white puff solid, as the corresponding hydrochloride salt. MS (M + H) + 260 1 H NMR (DMSO d 6): d 10.2 (bd s, 3 H), 6.86 (m, 1 H), 6.85 (s, 1 H), 6.74 (dd, J = 2.5, 8.4 Hz , 1 H), 4.22 (m, 2H), 3.88 (dd, J = 6.7, 1 1 .4 Hz, 1 H), 3.04 (m, 2H).

EXAMPLE 12 (2SH -) - N- (7-methy1-2,3-dihydro-benzop? 41-dioxin-2-ylmethyl) -sulfamide (compound # 19) The title compound is prepared according to the procedure described in example 4 above, starting with 4-methaltolcatechol, to produce a white solid, which is recrystallized from ethyl acetate / hexane to yield the title compound as a solid white MS [MH] 257 1 H NMR (CDCl 3) d 676 (m, 1H), 666 (m, 2H), 480 (m, 1H), 457 (bd s, 1H), 440 (m, 1H), 428 (m 1 H), 403 (dd, J = 69, 114 Hz, 1H), 345 (m, 2H), 225 (s, 3H) Elemental Analysis Calculated C, 46 50, H, 5 46, N, 10 85 , S, 12 41 Found C, 46 65, H, 5 60, N, 10 84, S, 12 61 EXAMPLE 13 In vivo model of rats that prefer alcohol Rats that prefer alcohol selectively aged male adults (which are known in the art to be useful for the study of the effect of test compounds or voluntary alcohol consumption) are grouped into three groups; vehicle and compound # 8 (50 and 100 mg / kg, po). The rats are housed individually in wire mesh cages under a constant ambient temperature of 22 ± 1 ° C and light-dark cycle 12:12 (8: 00-20: 00, dark). The animals are fed with Agway Prolab rat / mouse / Hamster formula 3000 and water at pleasure. The consumption of alcohol is determined using the method of choosing two standard bottles. The animals are first given free access to water in a graduated Richter tube for 2 days. They are then given access to only a 10% (v / v) ethanol solution for 3 consecutive days. During this period the animals become acclimated to drink from Richter tubes and the taste and pharmacological effects of alcohol. Therefore, free access to both water and 10% alcohol solution is given for at least 4 consecutive weeks and throughout the study period. Rats have free access to food. The consumption of water and alcohol is recorded in 4, 6, and 24 hours after treatment, while the consumption of food is measured in 24 hours. The body weight of the animal is measured every day.

After establishment of a stable baseline for consumption of alcohol, food and water, the rats are administered with vehicle or compound # 8 via oral gavage administration using a randomized cross-over design to have the ability to compare the efficacy of these compounds in alcohol consumption with an FDA-enhanced drug set? , naltrexone, is included as a positive control Some rats are provided with an oral dose of naltrexone (20 mg / kg) The interval between treatment is at least 3 days The consumption of alcohol and water is recorded 4, 6 and 24 hours after administration of the drug and the consumption of food is recorded in 24 hours A total of 8-10 animals per group is used The results are presented as means ± SEM The consumption of alcohol (g / kg) is calculated by multiplying the volume of alcohol consumed in ml by 10% and 0 7893 (ethanol density) / body weight in kg The alcohol preference, expressed as a percentage, is calculated as follows (volume of alcohol consumed in ml / total fluid consumption in ml) x 100 (Rezvaní and Grady, 1994; Rezvam et al, 1997) Statistical differences between control and drug-treated groups are determined using ANOVA and Turkey Student's t-test for multiple comparison. As shown in Table 4 below, compound # 8 decreases alcohol consumption in rats that prefer alcohol in 6 h (@ 50 and dose of 100 mg / kg) post-dosing TABLE 4 Test results of rats that prefer alcohol EXAMPLE 14 As a specific embodiment of an oral composition, 100 mg of compound # 8 is prepared as in example 7, formulated with enough finely divided lactose to provide a total amount of 580 to 590 mg to fill a hard gel capsule of size O Although the above specification shows the principles of the present invention, with examples provided for the purpose of illustration, it is understood that the practice of the invention includes all customary variations, adaptations and / or modifiers as come within the scope of the following claims and its equivalents

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of formula (I) wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; whole from 0 to 4; and where c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; with the condition that when then a is 1; or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment of substance abuse or addition.

2. The use as claimed in claim 1, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; / 1 R Ii '\ is selected from the group consisting of J ; where b is an integer from 0 to 2; and where c is an integer from 0 to 1; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; with I the condi- tion A that when Ado is then a is 1; or a pharmaceutically acceptable salt thereof.

3. The use as claimed in claim 2, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; where b is an integer from 0 to 2; and where c is 0; each R5 is independently selected from the group consisting of halogen, alkyl lower and nitro; with the proviso that when (i P i is then a is 1, or a pharmaceutically acceptable salt thereof. 4 - . 4 - The use as claimed in claim 3, in where R1 and R2 are each independently selected from the group consists of hydrogen and lower alkyl, R4 is selected from the group consisting of hydrogen and methyl; a is an integer from 1 to 2; /, FM, • ^ _ • is selected from the group consisting of 2- (2,3-dih? Drobenzo [1,4] d? Ox? N? Lo), 2- (benzo [1, 3] dioxolyl), 2- (3,4-dihydro-2H-benzo [1,4] d? oxepinyl), 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-chloro- 2,3- dihydro-benzo [1,4] dioxinyl), 2- (6-fluoro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (chromanyl), 2- (5- fluoro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-chloro-2,3-dihydrobenzo [1,4] d? oxanyl), 2- (6-chloro- benzo [1,3] dioxolyl), 2- (7-nitro-2,3-dihydrobenzo [1,4] dioxinyl), 2- (7-methyl-2,3-d? hydro-benzo [1, 4] dioxonyl), 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-bromo-2,3-dihydro-benzo [1,4] d? oxinyl), 2- (6,7-dichloro-2,3-d? hydro-benzo [1,4] d? oxanyl), 2- (8-chloro-2,3-dihydrobenzo [1], 4] d? Ox? N? Lo), 2- (2,3-dihydro-naphtho [2,3-b] [1,4] dioxinyl) and 2- (4-methyl-benzo [1, 3] d? oxol? lo); - "- with the condition that when _ is 2- (3,4-d? hydro-2H- benzo [1,4] d? oxep? n? lo), then a is 1, or a pharmaceutically acceptable salt thereof 5 - The use as claimed in claim 4, wherein R and R2 are each independently selected from the group consisting of hydrogen and methyl, R 4 is selected from the group consisting of hydrogen and methyl, a is an integer from 1 to 2, it is selected from the group consisting of 2- (benzo [1, 3] d? oxole), 2- (2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2- (2,3-d) H-dro-benzo [1,4] d? ox? n? lo), 2- (6-chloro-2,3-d? h? dro-benzo [1,4] d? ox? n? lo? ), 2- (7-chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (7-met? L-2,3-d? H) ? dro-benzo [1, 4] d? ox? n? lo), 2- (6-bromo-2,3-d? h? dro-benzo [1,4] d? ox? n? lo) and 2- (6,7-d? Chlor-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), or a pharmaceutically acceptable salt thereof 6 - The use as the one is claimed in claim 1, wherein the compound of formula (I) is selected from the group consisting of (2S) - (-) - N- (6-chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N-2-? Lmet? L) -suffam? Da, and pharmaceutically acceptable salts thereof 7 - The use as claimed in claim 1, wherein the substance of abuse or addiction is selected from the group consisting of alcohol, cocaine, heroin, methamphetamine, ketamine, ecstasy, nicotine, oxycodone / oxycodone, codeine and morphine 8 - The use as claimed in claim 1, wherein the substance of abuse or addiction is selected from the group consisting of alcohol, cocaine, heroin, methamphetamine and nicotine. 9. Use as claimed in claim 1, wherein the substance of abuse or addiction is alcohol or nicotine. 10. The use as claimed in claim 1, wherein the substance of abuse or addiction is alcohol. 1 1 .- The use of a compound selected from the group consisting of (2S) - (-) - N- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide; and pharmaceutically acceptable salts thereof, for the preparation of a medicament useful for the treatment of substance abuse or addition. 12. The use as claimed in claim 1, wherein the substance of abuse or addition is selected from the group consisting of alcohol, cocaine, heroin, methamphetamine, ketamine, ecstasy, nicotine, oxycodone / oxycodone, codeine and morphine. 13. Use as claimed in claim 1, wherein the substance of abuse or addiction is selected from the group consisting of alcohol, cocaine, heroin, methamphetamine and nicotine. 1

4. Use as claimed in claim 1, wherein the substance of abuse or addition is alcohol or nicotine.

5. The use as claimed in claim 11, wherein the substance of abuse or addition is alcohol. 1

6. The use of a compound of formula (II) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment of alcohol abuse or addiction. 1

7. Use as claimed in claim 16, wherein the substance of abuse or addiction is selected from the group consisting of alcohol, cocaine, heroin, methamphetamine, ketamine, ecstasy, nicotine, oxycodone / oxycodone, codeine and morphine. 1

8. Use as claimed in claim 16, wherein the substance of abuse or addiction is selected from the group consisting of alcohol, cocaine, heroin, methamphetamine and nicotine. 1

9. Use as claimed in claim 16, wherein the substance of abuse or addiction is alcohol or nicotine. 20. Use as claimed in claim 16, wherein the substance of abuse or addiction is alcohol.