TWI408129B - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction - Google Patents

Abstract

The present invention is a use of one or more novel benzo-fused heterocycle sulfamide derivatives of formula (I) and /or formula (II) as herein defined for the manufacture of a medicament for the treatment of alcohol abuse and / or addiction.

Description

Use of benzo-fused heterocyclic sulfonamide derivatives for the treatment of substance abuse and addiction Cross-reference related application

The present application claims the benefit of U.S. Provisional Application Serial No. 60/751,679, filed on Dec.

The present invention is directed to the use of a benzo-fused heterocyclic sulfonamide derivative for the treatment of substance abuse and addiction.

Alcohol abuse, typically characterized by maladaptive patterns of alcohol use, leads to clinically significant damage or disaster, a serious medical and social problem; it has been suggested that a choice for alcoholic beverages in animals is a An agent that reduces sex and does not reduce the absorption of water or food in parallel is a clinically effective treatment for human alcoholism (Myers 1994); daidzin (an isoflavone in soybean), a Chinese herb Radix pureariea One of the active ingredients in (RP) , in China, is used in the traditional treatment of "alcohol addiction", which is consistent with the image that it reduces alcohol in gold hamsters and does not reduce water or food absorption. 15 (Keung And Vallee3 1993), in contrast, many drugs, including specific adrenergic stimulants (eg, sertraline) and opioid antagonists (eg, naloxone and naltrexone) Naltrexone)), which have been shown to be used to inhibit alcohol consumption in animals, have reduced water or food consumption at the same time (Myers 1994); however, although SARS Types of antipsychotic drugs have been proposed as potential therapeutic aspects for substance abuse, which may result in substantial liver metabolic reactions in substance abuse patients, and the population of patients with liver damage is quite high Therefore, it is advantageous to use atypical antipsychotics that are not significantly metabolized in the liver for the treatment of substance abuse.

There is still a need to provide an effective treatment for substance abuse and/or addiction, especially for alcohol, cocaine, heroin, methamphetamine, ketamine, ecstasy Substance abuse and/or addiction to (Ecstacy), nicotine, oxycontin/oxycodone, codeine, morphine, and the like.

Brief Description of the Invention

The invention is directed to the use of a compound of formula (I) Wherein R ¹ and R ² 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; For selection from the following base Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro; for or In the case of a, a is 1; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the abuse and/or addiction of a therapeutic substance.

The invention also relates to the use of a compound of formula (II)

Or their pharmaceutically acceptable salts for the manufacture of a medicament for the abuse and/or addiction of therapeutic substances.

An exemplary embodiment of the invention is a method of treating alcohol abuse and/or addiction comprising administering to a patient in need thereof a therapeutically effective amount of any of the compounds or pharmaceutically acceptable compositions described herein.

Another example of the invention is a treatment comprising, including, for alcohol, cocaine, heroin, methamphetamine, ketamine, Ecstacy, nicotine , oxycodone, oxycodone, codeine, morphine, and other methods of abuse and/or addiction, including the administration of a therapeutically effective treatment to patients in need thereof Any of the compounds or pharmaceutically acceptable compositions described herein.

The invention is also directed to a method for the abuse and/or addiction of a therapeutic substance comprising administering to a patient in need thereof a therapeutically effective amount of at least one anti-addict agent and formula (I) or formula (II) as described herein. The compound is co-therapy.

Detailed description of the invention

The invention is directed to the use of a compound of formula (I)

Or a pharmaceutically acceptable salt thereof, wherein , a, R ¹ , R ² and R ⁴ are defined herein for the manufacture of a medicament for the abuse and/or addiction of therapeutic substances.

The present invention is also directed to the use of a compound of formula (I) or formula (II) as described, in a therapeutically effective amount, in combination with at least one anti-addict agent for the manufacture of a substance for abuse and/or addiction The use of pharmaceuticals.

As described herein, except as otherwise stated when referring to abuse and / or addiction substance of the "substance", including the Department of objects may cause or any lawful or unlawful material development of addiction patients; possible Drugs that cause abuse include, but are not limited to, stim ulants, hallucinogens, barbiturates, natural and synthetic opioid opiods, and benzo Suitable examples of benzodiazepines include, but are not limited to, alcohol, cocaine, heroin, methamphetamine, K-tart, ecstasy, nicotine, oxycontin/oxycodone (oxycodone), codeine, morphine, and so on.

As used herein, unless otherwise stated, " anti-addiction agent " means any pharmaceutical agent that is used to treat substance abuse and/or addiction, and more specifically, "anti-addiction agent" includes Substitute drugs, replacement drugs (for example, heroin replaced by methadone), block craving drugs, block or alleviate drug withdrawal symptoms, and block the pleasure of substance abuse Apparent and rewarding drugs, and the like, suitable examples include, but are not limited to, naltrexone (including vivtrex), nalmephene, antabuse, acamsetate ), paliperidone; when the addictive substance is alcohol, preferably, the anti-addictant used in the synergistic-therapy of the present invention is naltrexone.

The term " object " as used herein refers to an animal, preferably a mammal, preferably a human, which is the subject of treatment, observation or experimentation.

As used herein, " therapeutically effective amount " means the amount of active compound or formulation that can be derived from a tissue system, animal or human being, as explored by a researcher, veterinarian, doctor or other clinician. Responders to medicine, including symptoms of remission or discomfort in treatment.

When the present invention is directed to synergistic-therapeutic or combination therapy, it comprises administering one or more compounds of formula (I) or formula (II) and one or more anti-addictants, "therapeutic effective amount". The total amount of the drug to be used in combination may be combined to induce a desired biological or pharmaceutical response effect, for example, a therapeutically effective amount of synergistic-therapy includes administering a compound of formula (I) or formula (II) and In the case of at least one anti-addict agent, the amount of the compound of the formula (I) or the formula (II) and the anti-addict agent, which are administered together or sequentially, have a therapeutically effective combined effect, and The skilled hands of the Bank can understand the amount of the compound of formula (I) or formula (II) and/or anti-addiction agent, as exemplified in the above examples, in the amount of therapeutic effect in synergistic therapy. The amount, which is administered separately, may be non-therapeutic.

As used herein, " synergistic-therapeutic " and " combination therapy " refers to the administration of one or more compounds of formula (I) or formula (II) to a subject in need thereof, in combination with one or more Anti-addicts (classes), wherein the compound of formula (I) or formula (II) and the anti-addict agent (class) can be used simultaneously, simultaneously, separately or in a single manner using any suitable method. a pharmaceutically acceptable formulation; when a compound of formula (I) or formula (II) is administered in a separate dosage form with an anti-addiction agent, the dosage of each compound administered per day The number of versions may be the same or different; the compound of formula (I) or formula (II) and the anti-addict agent may be administered via the same or different routes, including, but not limited to, oral administration. Intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, and rectal; compounds can also be administered directly to the nervous system, including, but not limited to, intracerebral (intracerebral), intraventricular, intraventricular (intracerebroventricular), intrathecal (intrathec) Al), intracisternal, intraspinal and/or peri-spinal pathways, by intracranial or intracerebral needles and/or catheters, attached Administration with or without a pump device; compounds of formula (I) or formula (II) and anti-addicts (classes) may be the same or different at different times or under different courses of treatment At the time point, the coexistence is administered in a component or individual form.

In a specific embodiment of the invention, R ¹ is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and methyl, in another embodiment of the invention. R ¹ and R ^{2 are} each hydrogen or R ¹ and R ^{2 are} each a methyl group.

In a specific embodiment of the invention, -(CH ₂ ) _a - is selected from the group consisting of -CH ₂ - and -CH ₂ -CH ₂ -. In one embodiment of the invention, -(CH ₂ ) _a - is -CH ₂ -.

In a particular embodiment of the invention, R ⁴ is selected from the group consisting of hydrogen and methyl, preferably R ⁴ is hydrogen.

In a specific embodiment of the invention, a is one.

In a specific 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 self. An integer from 0 to 1, in another embodiment of the present invention, c is an integer from 0 to 1. In still another embodiment of the present invention, the sum of b and c is an integer from 0 to 2, preferably. The ground is an integer from 0 to 1. In another embodiment of the invention, b is an integer from 0 to 2 and c is zero.

In a specific embodiment of the invention, Selection from the following

In another embodiment of the invention, , selected from the following bases:

In a specific embodiment of the invention, The selection is based on the following base: 2-(2,3-dihydro-benzo[1,4] dioxins Dioxinyl, 2-(benzo[1,3]dioxolyl), 3-(3,4-dihydro-benzo[1,4]dioxepinyl), 2-(6-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] dioxins Base), 2-(chromo-based), 2-(5-fluoro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-chloro-benzo[1,3]dioxanyl), 2-(7-nitro-2,3-dihydro-benzo[1,4]dioxin Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] dioxins Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(8-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(2,3-dihydro-naphtho[2,3-b][1,4] dioxins Base) and 2-(4-methyl-benzo[1,3]dioxanyl).

In another embodiment of the invention, The selection is based on the following groups: 2-(benzo[1,3]dioxyl), 2-(2,3-dihydro-benzo[1,4]dioxin Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] dioxins And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] dioxins base).

In another embodiment of the invention, The selection is based on the following base: 2-(2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] dioxins And 2-(6-bromo-2,3-dihydro-benzo[1,4] dioxins base).

In one embodiment of the invention, the R ⁵ is selected from the group consisting of halogen and lower alkyl. In another embodiment of the invention, the R ⁵ is selected from the group consisting of chlorine, fluorine, bromine and methyl.

In a specific embodiment of the invention, the stereo-centered S-configuration on the compound of formula (I), in another embodiment of the invention, the stereo-centered R- on the compound of formula (I) configuration.

In a particular embodiment of the invention, the compound of formula (I) is present in a mixture of mirror images, wherein % mirroring richness (% enantimeric enrichment, % ee) is above about 75%, preferably It is more than about 90%, more preferably more than about 95%, and most preferably more than about 98%.

Another embodiment of the invention includes those wherein the substituent is selected from one or more variables defined herein (ie, R ¹ , R ² , R ³ , R ⁴ , X-Y, and A) and Individually selected as any individual substituent or a substituent selected from any of the defined complete forms.

Compounds of the invention having a representative for the treatment of alcohol abuse and addiction are listed in Table 1 below, and other compounds of the invention for use in the treatment of alcohol abuse and addiction are listed in Table 2 below. In the following Tables 1 and 2, the column entitled "Stereo" indicates the stereo-configuration of the carbon atoms of the heterocycle attached to the bond indicated by the asterisk, the label is not listed, and the compound is The stereo-configured mixture is prepared and, when labeled with an "R" or "S" configuration, this stereo-configuration is labeled based on the starting material with more mirror images.

As used herein, unless otherwise stated, " halogen " means chloro, bromo, fluoro and iodo.

As used herein, unless otherwise indicated, the term " alkyl ", whether alone or as part of a substituent, includes straight-chain and branched-chain groups, for example, alkyl includes methyl, ethyl, propyl. , isopropyl, butyl, isobutyl, second-butyl, tert-butyl, pentyl, etc., unless otherwise noted, when used in conjunction with alkyl, the word " lower " means A carbon chain composed of 1 to 4 carbon atoms.

As used herein, unless otherwise stated, " alkoxy " refers to an oxygen ether group of a straight or branched alkyl group as described above, for example, methoxy, ethoxy, n-propoxy, Di-butoxy, tert-butoxy, n-hexyloxy and the like.

As used herein, the symbol " ^* " refers to the location where the stereogenic center is present.

When a particular group is " substituted " (eg, alkyl, aryl, etc.), it is meant that the group may have one or more substituents, preferably from 1 to 5 substituents, more Preferably, from 1 to 3 substituents, most preferably from 1 to 2 substituents, are independently selected from the listed substituents.

When referring to a substituent, "independently" means that when more than one such substituent may be present, such substituents may be the same or different from each other.

In the standard nomenclature used in this specification, the terminal portion of the indicated side chain is described first, followed by the adjacent functional groups pointing to the attachment point, thus, for example, "phenyl-alkyl-amino-carbonyl" -alkyl "substituent" means a substituent having the formula

The abbreviations used in the specification, especially in the figures and examples, are as follows: DCC = dicyclohexylcarbodiimide DCE = dichloroethane DCM = dichloromethane DIPEA or DIEA = diisopropylethyl Amine DMF = N, N-dimethylformamide DMSO = dimethyl hydrazine EDC = ethyl carbodiamine Et ₃ N or TEA = triethylamine Et ₂ O = 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=methanol NMR=nuclear magnetic resonance Pd-C=palladium/ Carbon catalyst RP HPLC = reversed phase high pressure liquid chromatography RT or rt = room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography

When the compounds according to the invention have at least one center of the palm, they may be present as mirror images. When the compound has two or more pairs of palm centers, they may still be non-mirrored, as can be understood, all of this Isomers and mixtures thereof are encompassed within the scope of the invention; in addition, the crystalline forms of some of the compounds may exist as polymorphs and these are also included in the present invention; in addition, some compounds may form solvates with water ( That is, the hydrate), or a solvate with a general organic solvent, such solvates are also included in the scope of the present invention.

For pharmaceutical use, the salts of the compounds of the invention are non-toxic " pharmaceutically acceptable salts ", however, other salts are also useful in the preparation of the compounds according to the invention or their pharmaceutically acceptable Salts; suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, an example of which is 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 compound of the present invention carries an acidic moiety, it is suitable The pharmaceutically acceptable salts may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic ligands, for example, four Grade ammonium salts, and thus, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, hydrogencarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide Calcium edetate Campylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, Ito Estolate, esylate, fumarate, gluceptate, gluconate, glutarate, (glycdollylarsanilate), hexyl benzene diphenolate ( Hexylresorcinate), hydrabamine salt, hydrobromide, hydrochloric acid, hydroxynaphthoate, iodide, hydroxyethyl sulfate, lactate, lactobionate, laurate, malate, cis Butenedioate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methyl Glycosyl ammonium salt, oleate, pamoate, palmitate, pantothenate, phosphate/hydrogen phosphate, polygalacturate, salicylate, night fat , sulphate, alkaline acetate, succinate, tannin, tartrate, teoclate, tosylate, three Iodide (triethiodide) and valerate (valerate).

Representative acids and bases which may be employed in the preparation of pharmaceutically acceptable salts include: acetic acid, acetic acid, 2,2-dichloroacetic acid, acetylated amino acids, adipic acid, alginic acid, ascorbic acid , L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1s)- Camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- Ethyl sulfonic acid, formic acid, fumaric acid, galactose diacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid (L-glutamic acid), α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, cis Butenedioic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1- Hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, milk Acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-high glutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, Tannin, (+)-L-tartaric acid, thiocyanate, p-toluenesulfonic acid and undecylenic acid; and alkalis including ammonia, L-arginine, benethamine, Benzin (benzathine), calcium hydroxide, choline, dimethylaminoethanol (deanol), diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl - glucosamine, hydrabamine, 1H-imidazole, L-isoamine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, hexahydropyridyl , potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

The compound of formula (I) can be prepared according to the process described in Scheme 1.

Thus, a suitably substituted compound of the formula (X) which is a known compound or a compound obtainable by a known method, is reacted with a known sulfonamide compound, preferably wherein The sulfonamide is present in an amount ranging from about 2 to about 5 equivalents, preferably in an organic solvent (e.g., THF, dioxane, etc.), preferably at a temperature of from about 50 ° C to about 100 ° C, more preferably at Heating is carried out at reflux temperature to produce the related compound of formula (Ia).

Alternatively, a suitably substituted compound of the formula (X) which is a compound known or obtainable by known methods, and a suitably substituted compound of the formula (XI), which is a The reaction of a compound or a compound which can be prepared by a known method is carried out in the presence of a base (for example, TEA, DIPEA, pyridine, etc.) in an organic solvent (for example, DMF, DMSO, etc.) to prepare a correlation. a compound of formula (I).

a compound of formula (X) wherein for Prepared according to the method outlined in Figure 2.

Alternatively, a suitably substituted compound of formula (XII), which is a compound known or which can be prepared by known methods (such as those described in the above Scheme 3), with NH ₄ OH (which is a The known compound) is optionally reacted in an organic solvent (e.g., acetonitrile, etc.) to produce the related compound of formula (XIII).

The compound of formula (XIII) is reacted with an appropriately selected reducing agent, for example, LAH, etc., in an organic solvent (e.g., THF, diethyl ether, etc.) to give the related compound of formula (Xa).

a compound of formula (X) wherein for Prepared according to the method outlined in Figure 3.

Thus, a suitably substituted compound of formula (XIV) which is a known compound or a compound which can be prepared by known methods, is reacted with NH ₄ OH, in a coupling agent (for example, DCC or the like). The compound of formula (XV) is prepared in the presence of an organic solvent (e.g., acetonitrile, etc.).

The compound of the formula (XV) is reacted with an appropriately selected reducing agent (for example, LAH, etc.) in an organic solvent (for example, THF, diethyl ether, etc.) to obtain a related formula (Xb). Compound.

a compound of formula (X) wherein For picking And wherein a is 2, it can be prepared according to the method outlined in Figure 4.

Thus, a suitably substituted compound of the formula (XVI) wherein J ¹ is a suitable cleavage group such as Br, Cl, I, toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, etc. Etc., which is a known compound or a compound which can be prepared by a known method (for example, by activating a related compound in which J ¹ is OH), and is cyanide (for example, potassium cyanide, sodium cyanide, Etc., reacting in an organic solvent (e.g., DMSO, DMF, THF, etc.) to produce a related compound of formula (XVII).

The compound of the formula (XVII) is reduced according to a known method, for example, by reacting it with a suitable reducing agent (for example, LAH, borane, etc.) to obtain a related compound of the formula (Xc).

a compound of formula (X) wherein For picking And wherein a is one, it can be prepared according to the method outlined in Table 5.

Thus, a suitably substituted compound of the formula (XVIII) which is a known compound or a compound obtainable by a known method, is activated according to a known method to obtain a related compound of the formula (XIX), Wherein J ² is a suitable cleavage group, for example, toluenesulfonyl, Cl, Br, I, methanesulfonyl, trifluoromethanesulfonyl, and the like.

The compound of the formula (XIX) is reacted with a ruthenium salt (for example, potassium hydrazide, sodium hydrazide, etc.) in an organic solvent (for example, DMF, DMSO, acetonitrile, etc.). Preferably, the compound of formula (XX) is prepared by heating the reaction at a temperature of from about 50 ° C to about 200 ° C, more preferably at a temperature of about reflux.

The compound of the formula (XX) is reacted with N ₂ H ₄ , a known compound, in an organic solvent (for example, ethanol, methanol, etc.), preferably at a temperature of from 50 ° C to about 100 ° C. More preferably, heating is carried out at a temperature of about reflux to obtain a related compound of the formula (Xd).

Experts of the art can recognize compounds of formula X), of which For selection from: , , , , or Alternatively, it can be prepared according to known methods, or prepared according to, for example, the method outlined in the above Tables 2 to 5, by changing the benzo-fused starting material to selected and substituted. Related naphthyl-fused compounds.

It is also recognized by those skilled in the art that when a single mirror image of a compound of formula (X) is desired (or one of the mirror images is a mixture), the methods described in the above Tables 1 through 5 will be appropriate. The starting material is replaced by an associated single mirror image (or one of the mirror images is a mixture).

In the art of the art, the reaction steps of the present invention can be carried out in a wide variety of solvent or solvent systems, and the reaction steps can be carried out in a suitable solvent or mixture of solvent systems.

The process for the preparation of the compounds according to the invention increases the mixture of stereoisomers which can be separated by conventional techniques (for example preparative chromatography) and the compounds can be separated into racemic isomers. The form, or individual mirror image, can be prepared by mirror-specific synthesis or by resolution, and the compound can be resolved into a mirror image of its constituents, for example, with its optically active acid, for example, (-)-di-pair- Reaction with tolyl-D-tartaric acid and/or (+)-di-p-tolyl-yl-L-tartaric acid to form a non-mirrored counterpart, followed by fractional crystallization, followed by the formation of a free base, the compound can be borrowed The esters or guanamines are formed, separated by chromatography and removed, and the compounds can be separated using a HPLC column.

During any of the methods for preparing the compounds of the invention, it may be necessary and/or necessary to protect sensitive or reactive groups on the molecules involved, which may be achieved by conventional protecting groups, for example, those disclosed In Protective Groups in Organic Chemistry , ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991, this protecting group can be used in the subsequent appropriate stages of the literature. Method removed.

The present invention also encompasses a pharmaceutical composition comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier, a pharmaceutical composition comprising one or more of the compounds of the invention as active ingredients. The compound or compound can be prepared by intimately mixing the compound or compound with a pharmaceutical carrier, which can be used depending on the desired route of administration (eg, oral, non-digestive). Various types, therefore, in the case of liquid oral preparations, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavors, preservatives , stabilizer colorants, etc.; in the case of solid oral formulations, for example, powders, capsules and lozenges, suitable carriers and additives include starch, sugar, diluent, granules, lubricants, binders Solid disintegrating agents, etc., solid oral formulations may also be coated with a substance, such as a sugar or enteric film, to adjust the main site of absorption; for non-digestive administration, the carrier typically includes sterile water. ,also possible Other substances to increase solubility or preservation, injectable suspensions or solutions may also be formulated with a suitable additive an aqueous carrier.

To prepare the pharmaceutical composition of the present invention, one or more of the compounds of the present invention as an active ingredient are intimately mixed with a pharmaceutical carrier according to a conventional pharmaceutical compounding technique, wherein the type of the carrier can be regarded as being administered. Formulations (eg, oral or parenteral, eg, intramuscular) with a wide variety of choices, modes of administration; in the preparation of oral dosage forms, any conventional pharmacy may be employed Medium, thus, in the case of liquid oral preparations, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavors, preservatives, colorants Etc.; for solid oral formulations, such as powders, capsules, sachets, caps and tablets, suitable carriers and additives include starch, sugar, thinner, granules, lubricants, sticks Additives, disintegrating agents, etc.; for the convenience of administration, tablets and capsules represent the most advantageous oral dosage form, wherein it is apparent to use a solid pharmaceutical carrier, if necessary, The agent may be coated with a sugar coating or an enteric film using standard techniques; in the case of non-digestive administration, the carrier usually contains sterile water, and may also include other ingredients, for example, ingredients for dissolution or preservation; or may be prepared. Injectable suspension or solution, wherein a suitable liquid carrier, suspending agent or the like can be employed; the pharmaceutically acceptable composition is in each dosage unit (for example, tablets, capsules, powders, injections, teaspoons, etc.) The active ingredient contained in an amount effective to deliver an effective amount as described above; the pharmaceutically acceptable composition in each dosage unit (eg, tablets, capsules, powders, injections, suppositories, teaspoons, etc.) It will contain from about 0.1 to 1000 mg and from about 0.01 to 150.0 mg/kg/day, preferably from about 0.1 to 100 mg/kg/day, more preferably from about 0.5 to 50 mg/kg/day. More preferably, it is from about 1.0-25.0 mg/kg/day or any range between doses depending on the needs of the patient, the severity of the condition being treated and the compound used, and may be used for daily administration or Post-cycled.

Preferably, these compositions are in the form of dosage units, for example, tablets, pellets, capsules, powders, granules, sterile non-digestive solutions or suspensions, metered gas solutions or liquid sprays. , drops, ampoules, automatic injection design or suppository, for oral, non-digestive, intranasal, sublingual, or rectal administration, or for inhalation or insufflation, or, The formulation may be presented as a dosage form suitable for administration once a week or once a month, for example, an insoluble salt of the active compound, such as a decanoate, may be suitable as a storage formulation for intramuscular injection; for preparation like In the case of a solid composition of tablets, the active ingredient is mixed with a pharmaceutically acceptable carrier, for example, a conventional tablet component, for example, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, phosphoric acid Dicalcium or colloid, as well as other pharmaceutically acceptable diluents, for example, water, for forming a solid pre-formulated composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, homogeneously The so-called pre-formulations are homogeneous, meaning that the active ingredients are dispersed evenly within the composition such that the composition can be easily re-divided into equally effective dosage forms, such as tablets, pills and Capsules, this solid preformulation is further divided into unit dosage forms containing from 0.1 to about 1000 mg of the active ingredient of the invention as described above, the tablets or pellets of the novel composition being coated or compounded To provide a prolonged dosage form, for example, the tablet or pellet may comprise a dosage form of the inner layer and a dosage form component of the outer layer, the latter being the envelope of the former, the two components being separable by the enteric layer, the intestine The film is used to resist the disintegration of the composition in the stomach and allows the components of the inner layer to pass intact into the duodenum or to be delayed; a variety of materials can be used as such enteric films or coatings. It includes many polymeric acids such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms containing the novel compositions of the present invention for oral administration or for injection to the user include, aqueous solutions, suitably flavored thick slurries, aqueous or oily suspending agents, and edible fats and oils (eg, cottonseed oil, sesame oil, coconut oil or Peanut oil), as well as emulsions seasoned with elixirs and similar pharmaceutically acceptable carriers; suitable dispersing or suspending agents for use in aqueous suspensions include synthetic and natural gums, for example, Tragacons gum ( Tragacanth), acacia, algin, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or animal glue.

The method of treating alcohol abuse and/or addiction in the present invention may also be carried out using a pharmaceutically acceptable composition comprising any one of the defined compounds and a pharmaceutically acceptable carrier, and the pharmaceutically acceptable composition may contain A compound of between about 0.1 mg and 1000 mg, preferably between about 50 and 500 mg, and which can be formulated into any dosage form suitable for the mode of administration selected, the carrier comprising the necessary and inert pharmaceutical form Agents, including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweeteners, preservatives, dyes, and coatings, compositions suitable for oral administration include solid dosage forms, for example, Pills, tablets, sachets, capsules (each containing immediate release, timed release and sustained release formulations), granules, and powders, as well as liquid dosage forms, for example, solutions, slurries, elixirs, lotions, and Suspensions, which are used in the form of non-digestive tracts, include sterile solutions, emulsions and suspensions.

Advantageously, the compounds of the invention may be administered in a single daily dose, or the total daily dose may be divided into two, three or four administrations. Further, the compounds of the invention may be administered with appropriate nasal use. The agent is applied topically via the intranasal dosage form, or via a transdermal patch that has been well known to the practitioner, and when used in a transdermal delivery system format, the dosage form is of course continuously discontinuous. The way is the best.

For example, in the form of a tablet or capsule for oral administration, the active drug component can be used in combination with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycol, water, and the like. Suitable or necessary binders, lubricants, disintegrating agents and coloring agents may also be added to the mixture. Suitable binders include, without limitation, starch, animal glue, natural sugars such as glucose or beta. - lactose, corn sweeteners, natural and synthetic gums, for example, acacia (accacia), tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate , sodium acetate, sodium chloride, etc., disintegrating agents include, but are not limited to, starch, methyl cellulose, acacia, bentonite, xanthan gum, and the like.

The liquid dosage form is in a suitably seasoned suspension or dispersant, for example, synthetic and natural gums, for example, Tragacons gum, locust gum, methyl cellulose, etc.; In the meantime, sterile suspensions and solutions are required, and when intravenous administration is desired, the isotonic formulation usually contains a suitable preservative.

The compounds of the present invention can be administered in any of the above compositions and used in the treatment of alcohol abuse and/or addiction according to the dosage form established in the literature.

The daily dose of the product can be used in an adult, varying widely from 0.01 to 150 mg per kilogram of body weight, and when administered orally, depending on the condition of the patient being treated, the composition preferably contains The dosage form of the following active ingredient provides treatment: 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 mg, effective amount of the drug Typically, the dosage value to be supplied is from about 0.01 mg/kg to about 1500 mg/kg body weight/day, preferably from about 0.1 mg/kg to about 100.0 mg/kg body weight/day, and more preferably, From about 0.5 mg/kg to about 50 mg/kg, and more preferably from about 1.0 to about 25.0 mg/kg body weight/day, the utility of this compound can be divided into 1 to 4 times per day.

The most appropriate dosage to be administered can be readily determined by the expert and will depend on the particular compound employed, mode of administration, strength of the formulation, mode of administration, and progression of the condition, and, in addition, The patient's factors, such as the patient's age, weight, diet, and time of administration, will result in the need to adjust the dose.

Applicants understand that both in vivo and in vitro tests using appropriate, known and generally accepted cell and/or animal models predict the ability of a test compound to be used to treat or prevent a given condition.

Experts also understand that human clinical trials include first-in-human, dose-range and efficacy trials in healthy patients and/or those suffering from certain such diseases, which are clinically relevant and A fully known method of medical skill is accomplished.

The following examples are provided to aid in the understanding of the invention and are not intended to be inferred in any way.

Example 1

((3,4-Dihydro-2H-benzo[b][1,4]dioxin-3-yl)methyl)sulfonamide (Compound #3)

Place catechol (5.09 g, 46.2 mmol) and potassium carbonate in acetonitrile, and heat to reflux for one hour, then add 2-chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol). The mixture was refluxed for 24 hours, the solution was cooled to room temperature, filtered, and concentrated. EtOAc EtOAc m. 2-Methyl-3,4-dihydro-2H-benzo[b][1,4]dioxin in the form of a colorless oil.

MS (ESI): 163.2 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.94 (m, 4H), 5.07 (s, 2H), 4.76 (s, 4H).

After dissolving 3-methylene-3,4-dihydro-2H-benzo[b][1,4]dioxin (5.00 g, 30.8 mmol) in dry THF (100 mL), Add borane-THF (1.0 M in THF, 10.3 ml) at 0 ° C, stir at room temperature for 5 hours, add aminosulfonic acid (6.97 g, 61.6 mmol), and heat to reflux overnight to cool the reaction solution. To the room temperature, aq. EtOAc (3 mL, EtOAc) To (8% methanol/dichloromethane), ((3,4-dihydro-2H-benzo[b][1,4]dioxin-3-yl)methyl)amine is obtained as a colorless oily substance .

MS (ESI): 180.1 (M+H ⁺ )

¹ H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 4.21 (m, 2H), 4.07 (m, 2H), 3.33 (width, 2H), 3.16 (d, J = 4 Hz, 1H) ), 2.72 (d, J = 4 Hz, 1H), 2.30 (m, 1H).

((3,4-Dihydro-2H-benzo[b][1,4]dioxin-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g) </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; The title compound was obtained as an off-white solid.

258.8(M+H ⁺ )

¹ H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 6.71 (width, 1H), 6.59 (width, 2H), 4.19 (m, 2H), 4.04 (m, 2H), 3.00 (m) , 2H), 2.39 (m, 1H).

Example 2

N-(2,3-dihydro-benzo[1,4] dioxins -2-ylmethyl)-sulfonamide (Compound #1)

Racemic 2,3-dihydro-1,4-benzodioxin 2-ylmethylamine (4.4 g, 26 mmol) and sulfonamide (5.1 g, 53 mmol) were placed in 1,4-dioxane (100 mL) and heated to reflux for 2 h. After cooling to room temperature, a small amount of solid was removed by filtration, and the filtrate was concentrated in vacuo, and the residue was purified using flash column chromatography (DCM:methanol - 10:1) to give a white solid. Crystallization gave the title compound as a white solid.

Melting point: 97.5-98.5 °C

Elemental analysis: calculated: C, 44.25; H, 4.95; N, 11.47; S, 13.13 found: C, 44.28; H, 4.66; N, 11.21; S, 13.15

¹ H NMR (DMSO d6) δ 6.85 (m, 4H). 6.68 (bds, 3H, NH), 4.28 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (m, 1H) ), 3.10 (m, 1H).

Example 3

(Benzo[1,3]diox-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) , and placed in dry methanol (100 ml), heated to reflux overnight, cooled to room temperature, acidified with concentrated hydrochloric acid, then concentrated to about 50 ml under reduced pressure, water was added and extracted with diethyl ether (3×100 ml). The combined organic layers were dried with EtOAc EtOAc EtOAc. The base ester is a colorless oily substance.

MS (ESI): 195.10 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.89 (width, 4H), 6.29 (s, 1H), 4.34 (q, J = 7 Hz, 2H), 1.33 (t, J = 7 Hz, 3H) .

To benzo[1,3]dioxole-2-carboxylic acid methyl ester (7.21 g, 40.0 mmol), add ammonium hydroxide (29% in water, 10 ml) and a sufficient amount of acetonitrile (~5 ml) The mixture was made homogeneous, stirred at room temperature for 2 hours, and distilled water was added thereto, and a white benzo[1,3]dioxan-2-carboxylic acid decylamine precipitate was collected by filtration and used without purification.

MS (ESI): 160.00 (M+H ⁺ )

¹ H NMR (300 MHz, DMSO), δ: 7.99 (s, s, 1H), 7.72 (s, s, 1H), 6.94 (m, 2H) 6.86 (m, 2H), 6.30 (s, 1H).

The benzo[1,3]dioxan-2-carboxylic acid decylamine (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 ml), and lithium aluminum hydride was slowly added at room temperature ( LAH, 1 M, a solution in THF, 39.5 mL, 39.5 mmoles, stirring at room temperature for 24 hours, adding water to remove excess LAH, and adding aqueous sodium hydroxide (3.0 M, 100 mL) to acetic acid Ester extraction (3x100 ml), the organic layer was combined, washed with water, dried over magnesium sulfate, and evaporated to remove solvent to give C-benzo[1,3]diox-2-yl-methylamine as a colorless oil. Quality.

MS (ESI): 152.1 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.87 (m, 4H), 6.09 (t, J = 4 Hz, 1H), 3.13 (d, J = 4 Hz, 2H)

C-benzo[1,3]diox-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3.74 g, 38.9 mmol) were combined in dry dioxins The title compound was obtained as a white solid.

MS (ESI): 230.0 (M+H ⁺ )

¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.87 (m, 4H), 6.25 (t, J = 4 Hz, 1H), 4.79 (width, 1H), 4.62 (width, 1H), 3.64 (d, J=4 Hz, 2H).

Example 4

(2S)-(-)-N-(2,3-dihydro-benzo[1,4] dioxins -2-ylmethyl)-sulfonamide (Compound #4)

Add catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) in DMF (250 ml) and add (2R)-anhydroglyceryl tosylate (22.8 g, Stirred at 60 ° C for 24 hours, cooled to room temperature, diluted with ice water (1 L), extracted with diethyl ether (4 times), and the combined organic layers were washed 3 times with 10% potassium carbonate. After washing with water for 1 time, washing with brine for 1 time, and concentrating under vacuum to obtain a white solid, which was purified by flash column chromatography (DCM:methanol - 50:1) (2S) -2,3-dihydro-benzo[1,4] dioxins -2-yl)-methanol, as a solid.

This solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL), cooled to 0 ° C, p-toluenesulfonyl chloride (13.0 g, 68 mmol) was added and stirred at room temperature for 20 hours Diluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layer was separated, washed twice with 1 N EtOAc (500 mL), washed with water 4 times (150 ml), washed with brine and dried (Magnesium sulfate), concentrated under vacuum to give a white solid, purified by flash column chromatography (heptane: EA-2:1) to yield toluene-4-sulfonic acid (2S)-2,3- Hydrogen-benzo[1,4] dioxins -2-ylmethyl ester as a white solid.

This white solid was mixed with potassium phthalamide (14.4 g, 78 mmol) in DMF (250 ml), heated to reflux for 1 hour, cooled to room temperature and poured into water (1.5 liters) with vigorous stirring. Stir for 30 minutes, filter off the resulting solid, wash it several times with water, 2% NaOH, and water, and air dry to obtain (2S)-2-(2,3-dihydro-benzo[1,4] evil -2-ylmethyl)-isoindole-1,3-dione as a white powdery solid.

The white powdery solid was mixed with hydrazine (2.75 g, 86 mmol) in EtOH (225 mL), heated to reflux for 2 hr, cooled to room temperature, pH 1 was added with 1 N HCl, stirred for 15 min, filtered white precipitate with fresh EtOH (solid discarded), and the filtrate was concentrated in vacuo to a solid, which was placed in diethyl ether and dilute aqueous NaOH. the ether layer was dried (Na ₂ SO _4), concentrated in vacuo , a bright yellow oily substance was obtained, which was purified by flash column chromatography (DCM: MeOH-10:1) to obtain an oily substance, and a part thereof (4.82 g, 29 mmol) was dissolved in 2 -propanol (250 ml), 1N HCl (30 ml) was added, then heated on a steam bath until homogeneous, and then cooled to room temperature. After 3 hours, the mixture was cooled in an ice bath for 2 s. (Related (2S)-C-(2,3-dihydro-benzo[1,4] dioxins The hydrochloride salt of 2-yl)-methylamine was crystallized from 2-propanol to give a white solid.

[α] _D =-69.6 (c=1.06, EtOH)

The white solid was partitioned between DCM and dilute NaOH solution. The DCM layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield (2S)-C-(2,3-dihydro-benzo[1] , 4] dioxins -2-yl)-methylamine, an oily substance.

[α] D = -57.8 (c = 1.40, CHCl ₃ )

This oleaginous material (2.1 g, 12.7 mmol) was placed in dioxane (75 ml) with sulfonamide (2.44 g, 25.4 mmol) and heated to reflux for 2 hours. Purification (DCM: MeOH 10:1)

Melting point: 102-103 ° C

[α] _D = -45.1° (c = 1.05, M); ¹ H NMR (DMSOd6) δ 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd , J=6.9, 11.4 Hz, 1H), 3.20 (dd, J=5.5, 13.7 Hz, 1H), 3.10 (dd, J=6.9, 13.7 Hz, 1H)

Elemental analysis: calculated: C, 44.25; H, 4.95; N, 11.47; S, 13.13 found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.

Example 5

N-(2,3-dihydro-benzo[1,4] dioxins -2-ylmethyl)-N',N'-dimethylsulfonamide (Compound #6)

Racemic 2,3-dihydro-1,4-benzodioxin 2-methylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL). Aminosulfonyl chloride (1.44 g, 10 mmol), and the reaction mixture was stirred for 3 hours while continuing to cool. The reaction mixture was partitioned between ethyl acetate and water. , dried (MgSO _4), and concentrated in vacuo to obtain oily substance, using flash column chromatography purification of this oily product (ethyl acetate: heptane-1: 1) to give a white solid which was recrystallized (Ethyl acetate / hexanes) to give the title compound as a white powdery solid.

Melting point: 76-78 ° C

MS 273 (MH ⁺ )

Elemental analysis: calculated: C, 48.52; H, 5.92; N, 10.29; S, 11.78 found: C, 48.63; H, 5.62; N, 10.20; S, 11.90

¹ H NMR (CDCl ₃ ) δ 6.87 (m, 4H), 4.59 (bd m, 1H, NH), 4.35 (m, 1H), 4.27 (dd, J = 2.3, 11.4 Hz, 1H), 4.04 (dd, J=7.0, 11.4, 1H), 3.36 (m, 2H), 2.82 (s, 6H).

Example 6

N-(2,3-dihydro-benzo[1,4] dioxins -2-ylmethyl)-N-methylsulfonamide (Compound #7)

Racemic 2,3-dihydro-1,4-benzodioxin 2-Methylmethylamine (825 mg, 5 mmol) was dissolved in ethyl formate (15 mL), then heated to reflux for 30 min and concentrated in vacuo to give N-(2,3-dihydro-benzene. And [1,4] dioxins -2-ylmethyl)-carbenamide, an oily substance.

After dissolving this oleagin in diethyl ether (25 ml), 1 M LAH (9.0 mL, 9.0 mmol) dissolved in THF was added at 0 ° C, and stirred at room temperature for 5 hr. The reaction was quenched with water (0.50 mL). EtOAc (EtOAc) (EtOAc) between 1N HCl and diethyl ether to assign, after the aqueous layer was basified with 1N NaOH, extracted with diethyl ether, and the organic layer was dried (MgSO _4), concentrated in vacuo to afford (2,3-dihydro - benzo [ 1,4] dioxins -2-ylmethyl)-methyl-amine is an oily substance.

MS 180 (MH ⁺ )

¹ H NMR (CDCl ₃ ) δ 6.85 (m, 4H), 4.30 (m, 2H), 4.02 (dd, J = 7.9, 11.6 Hz, 1H), 2.85 (m, 2H), 2.50 (s, 3H)

The oleaginous material (380 mg, 2.1 mmol) and sulfonamide (820 mg, 8.5 mmol) were combined in dioxane (15 mL) and refluxed for 1.5 hr. The product was purified by EtOAc EtOAc EtOAcjHHHHH

Melting point: 97-98 ° C

MS 257 (M ^-1 )

Elemental analysis: calculated: C, 46.50; H, 5.46; N, 10.85; S, 12.41 found: C, 46.48; H, 5.65; N, 10.90; S, 12.07

¹ H NMR (CDCl ₃ ) δ 6.86 (m, 4H), 4.52 (bs, 2H), 4.46 (m, 1H), 4.29 (dd, J = 2.3, 11.5 Hz, 1H), 4.05 (dd, J = 6.5 , 11.5 Hz, 1H), 3.51 (dd, J = 6.7, 14.9 Hz, 1H), 3.40 (dd, J = 5.9, 14.9 Hz, 1H), 2.99 (s, 3H).

Example 7

(2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] dioxins -2-ylmethyl)-sulfonamide (Compound #8)

According to the method in Example 4 above, 4-chlorocatechol was reacted to produce (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] dioxins. -2-yl)-methylamine and (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] dioxins A mixture of 2-yl)-methylamine (approximately 3:1 6-chloro:7-chloro isomer, analyzed according to RP HPLC).

This mixture was dissolved in 2-propanol (100 ml), then 1N HCl dissolved in diethyl ether was added until pH = 1.0, and the precipitated hydrochloride (2.65 g) was filtered. White crystals were obtained. The white crystals were partitioned between DCM and dilute NaOH. DCM was dried and concentrated in vacuo to yield pure (2S)-C-(6-chloro-2,3-dihydro-benzene. And [1,4] dioxins -2-yl)-methylamine, an oily substance.

[α] _D = -67.8 (c = 1.51, CHCl ₃ )

This oil (7.75 mmol) was combined with sulfonamide (1.50 g, 15.5 mmol) in dioxane (50 mL), heated to reflux for 2.0 hr, cooled to room temperature and concentrated in vacuo. The title compound was obtained as a white solid.

MS 277 (M ^-1 )

[α] _D =-59.9° (c=1.11, M)

¹ H NMR (CDCl ₃ ) δ 6.90 (d, J = 2.2 Hz, 1H), 6.81 (m, 2H), 4.76 (m, 1H), 4.55 (s, 2H), 4.40 (m, 1H), 4.29 ( Dd, J = 2.4, 11.5 Hz, 1H), 4.05 (dd, J = 7.1, 11.5 Hz, 1H), 3.45 (m, 2H).

Elemental analysis: calculated: C, 38.78; H, 3.98; N, 10.05 found: C, 38.80; H, 3.67; N, 9.99.

The above crystallized (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] dioxins The filtrate of the hydrochloride salt of 2-yl)-methylamine was recovered (about 1:1 6-chloro: 7-chloroisomer), concentrated in vacuo to give a solid, which was taken in DCM (200 mL) and dilute NaOH (0.5 M, 50 ml) and partitioned between, DCM solution was washed once with brine, dried (Na ₂ SO _4), and concentrated in vacuo to obtain oily substance, was purified via reverse phase HPLC (10-50% ACN, containing 0.16% TFA in water containing 0.20% TFA) to produce (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] dioxins Residue of 2-yl)-methylamine.

This residue was combined with sulfonamide (0.90 g, 9.4 mmol) in dioxane (25 ml), heated to reflux for 2.5 hours, cooled to room temperature and concentrated under vacuum to give an oily product. Flash column chromatography was carried out using a 10:1 DCM/methanol eluting to afford (2S)-(-)-N-(7-chloro-2,3-dihydro-benzo[ 1,4] dioxins -2-ylmethyl)-sulfonamide.

MS 277 (M ^-1 )

¹ H NMR (CDCl ₃ /CD ₃ OD) δ 6.88 (d, J = 0.7 Hz, 1H), 6.81 (m, 2H), 4.37 (m, 1H), 4.30 (dd, J = 2.3, 11.6 Hz, 1H) ), 4.04 (dd, J = 7.0, 11.6 Hz, 1H), 3.38 (m, 2H).

Example 8

Chroma-2-ylmethylsulfonamide (Compound #10)

Chromatin-2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol) were combined in DCM (40 mL) and DMF (10 mL). Dimethylaminopropyl ethylcarbodiamine (EDC, 4.84 g, 25 mmol), the reaction mixture was stirred for 30 min, ammonium hydroxide (2.26 mL, 33.4 mmol) was added and stirred for 16 hr. Dilute with DCM (50 ml) and water (50 ml). The mixture was adjusted to pH = 3.0 with 1N HCl. The DCM layer was separated and the aqueous layer was extracted twice by DCM. The combined DCM layer was dried (Na ₂ SO ₄ ), concentrated under vacuum to give an oily material which was purified by flash column chromatography (ethyl acetate) to give an oil.

After dissolving this oleaginous material (5.35 g, 30 mmol) in THF (90 ml), 1M LAH (36 ml, 36 m. terminate the reaction stirred for 2 hours, the solution decanted, dried (Na ₂ SO _4), and concentrated in vacuo to afford C- chromen-2-yl - methylamine as an oily amine.

The oleoamine (1.63 g, 10 mmol) and sulfonamide (1.92 g, 20 mmol) were combined and placed in dioxane (50 mL) and heated to reflux for 2 hr. Concentrate to obtain an oily substance, which was purified by flash column chromatography (DCM: methanol: 10:1) to give a white solid which was recrystallized from ethyl acetate/hexane to yield - Methylsulfonamide as a white solid.

Melting point: 100-101 ° C

MS 241 (M ^-1 )

Elemental analysis: calculated: C, 49.57; H, 5.82; N, 11.56; S, 13.23 found: C, 49.57; H, 5.80; N, 11.75; S, 13.33.

Example 9

2-(2,3-dihydro-benzo[1,4] dioxins -2-yl)ethylsulfonamide (Compound #16)

Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3-dihydrobenzo[1,4] dioxins dissolved in DMSO (90 mL) (6.87 g, 30 mmol), stirred at room temperature for 20 hours, diluted with water (250 ml), extracted twice with diethyl ether, washed with diethyl ether, washed twice with brine, and dried ( Na ₂ SO ₄ ), concentrated under vacuum to give 2-cyanomethyl-(2,3-dihydrobenzo[1,4] dioxins ), as a white solid.

¹ H NMR (CDCl ₃ ) δ 6.89 (m, 4H), 4.50 (m, 1H), 4.31 (dd, J = 2.3, 11.5 Hz, 1H), 4.08 (dd, J = 6.2, 11.6 Hz, 1H), 2.78 (d, J = 6.1, Hz, 2H).

This 2-cyanomethyl-(2,3-dihydrobenzo[1,4] dioxame Dissolved in THF (50 ml), then added 1 M BH ₃ (80 ml, 80 mmol) dissolved in THF, heated to reflux for 5 hours, then stirred at room temperature for 16 hours, cooled in an ice bath, and added. 2N HCl, until pH=1.0, and the reaction mixture was stirred at room temperature for 1 hour, and concentrated under vacuum to obtain an oily substance which was partitioned between 3N NaOH and diethyl ether to separate diethyl ether layer. Washed with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo to give crude 2-(2,3-dihydrobenzo[1,4] diox. -2-yl)ethylamine.

MS (M+H) ⁺ 180.

This crude 2-(2,3-dihydrobenzo[1,4] dioxole 2-yl)ethylamine, which was mixed with sulfonamide (3.0 g, 31 mmol) in dioxane (100 ml), heated to reflux for 2 h, cooled and concentrated in vacuo. An orange solid was purified by column chromatography (EtOAc EtOAc:EtOAc:

MS(M-1)257

Melting point: 101-103 ° C (corr)

¹ H NMR (CDCl ₃ ): δ 6.86 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 4.30 (m, 2H), 3.94 (dd, J = 7.4, 11.3 Hz, 1H) , 3.43 (dd, J = 6.4, 12.9 Hz, 2H), 1.94 (dd, J = 6.5, 12.9, 2H).

Elemental analysis: found: 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] dioxins -2-ylmethyl)-sulfonamide (Compound #29)

After stirring 4,5-dichlorocatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) in DMF (200 mL), (2R)-glycidyl was added. Toluenesulfonate (9.12 g, 40 mmol), the reaction mixture was stirred at 60 ° C for 24 hours, cooled to room temperature, diluted with ice water (600 mL), extracted with diethyl ether (4 times), combined The organic layer was washed 3 times with 10% potassium carbonate, washed twice with brine, dried (MgSO ₄ ) and concentrated in vacuo to yield viscous oil: (2S)-2-(6,7- Chloro-2,3-dihydro-benzo[1,4] dioxins ) Methanol.

This (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4] dioxole ) Methanol oily product (6.4 g, 27 mmol) was dissolved in pyridine after (50 mL), cooled to 0 deg.] C, followed by the addition of - toluenesulfonic acyl chloride (5.2 g, 27 mmol), at room temperature After stirring for 20 hours, the reaction mixture was diluted with EtOAc EtOAc EtOAc EtOAc. , dried (MgSO _4), concentrated in vacuo, toluene was obtained as a pale yellow solid of 4- sulfonic acid (2S) -6,7- dichloro-2,3-dihydro - benzo [1,4] evil -2-ylmethyl ester.

¹ H NMR (CDCl ₃ ): δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.83 (s, 1H), 4.37 (m) , 1H), 4.2 (m, 3H), 4.03 (dd, J = 6.3, 11.7 Hz, 1H), 2.47 (s, 3H).

Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] dioxins Benzyl-methyl ester (8.0 g, 20.5 mmol) was combined with potassium nabendamide (6.1 g, 33 mmol) in DMF (75 mL). Pour into water (0.5 liters) with vigorous stirring, stir for another 30 minutes, filter off the white solid, wash the solid several times with water, 2% NaOH, and water, then air dry to obtain (2S)-2 -(6,7-dichloro-2,3-dihydro-benzo[1,4] dioxins -2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid.

The white powdery solid was combined with hydrazine (1.06 g, 33 mmol) in EtOH (80 mL), heated to reflux for 2 hrs, then cooled to room temperature, and 1N HCl was added to adjust the pH of the reaction mixture to The mixture was stirred for 15 minutes, the white solid was filtered, washed with fresh EtOH (the solid was discarded), and the filtrate was concentrated to a solid under vacuum, which was partitioned between diethyl ether and dilute aqueous NaOH. the ether layer was dried (Na ₂ SO _4), concentrated in vacuo, to obtain a viscous oily of (2S) -2- aminomethyl - (6,7-dichloro-2,3-dihydro -benzo[1,4] dioxins ).

¹ H NMR (CDCl ₃ ): δ 6.98 (s, 1H), 6.96 (s, 1 H), 4.25 (dd, J = 2.0, 11.2 Hz, 1H), 4.15 (m, 1H), 4.0 (m, 1H) ), 2.97 (d, J = 5.5 Hz, 2H).

A portion of the oleaginous material (3.8 g, 16 mmol) and sulfonamide (3.1 g, 32.4 mmol) were placed in dioxane (100 mL) and heated to reflux for 2 hr. The title compound was obtained as a white crystals.

MS[M-H] ^- 311.0

Melting point: 119-121 ° C

[α] _D = -53.4° (c = 1.17, M)

¹ H NMR (DMSOd6): δ 7.22 (s, 1H), 7.20 (s, 1H), 6.91 (bd s, 1H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.15 (m, 2H).

Elemental analysis: found: 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-benzo[1,4] dioxins -2-ylmethyl)-sulfonamide (compound #36)

(2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] dioxins -2-ylmethyl)-sulfonamide (1.2 g, 4.15 mmol) was prepared from 4-nitrocatecate according to the method described in Example 4, then this (2S)-(- )-N-(2,3-dihydro-7-nitro-benzo[1,4] dioxins -2-ylmethyl)-sulfonamide, shaken with 10% Pd/C (120 ml) in methanol, under hydrogen pressure (39 psi) at room temperature for 3 hours, and filtered to solid The title compound was obtained as a white flaky solid, which was obtained as a white solid. The hydrochloride salt of the compound.

MS(M+H) ⁺ 260

¹ H NMR (DMSO d6): δ 10.2 (bds, 3H), 6.86 (m, 1H), 6.85 (s, 1H), 6.74 (dd, J = 2.5, 8.4 Hz, 1H), 4.22 (m, 2H) , 3.88 (dd, J = 6.7, 11.4 Hz, 1H), 3.04 (m, 2H).

Example 12

(2S)-(-)-N-(7-methyl-2,3-dihydro-benzo[1,4] dioxins -2-ylmethyl)-sulfonamide (Compound #19)

The title compound was prepared according to the method described in the above Example 4, starting from 4-methyl catechol to give a white solid, which was then crystallised from ethyl acetate/hexane to afford white solid. The title compound.

MS[M-H] ^- 257

¹ H NMR (CDCl ₃ ): δ 6.76 (m, 1H), 6.66 (m, 2H), 4.80 (m, 1H), 4.57 (bd s, 1H), 4.40 (m, 1H), 4.28 (m, 1H) ), 4.03 (dd, J = 6.9, 11.4 Hz, 1H), 3.45 (m, 2H), 2.25 (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

The Alcohol Preferring Rats In Vivo Model is a selective-breeding adult adult rat (which is known in the literature for use in researching test compounds for voluntary alcohol absorption). Divided into three groups: vehicle and compound #8 (50 and 100 mg / kg, orally), rats were individually placed in a metal mesh cage, placed in a light-dark cycle with a temperature fixed at 22 ± 1 ° C and 12:12 In the room (8:00-20:00, dark), the animals were fed an Agway Prolab Rat/Mouse/Hamster 3000 formulation with free access to drinking water.

Alcohol absorption was measured using the standard two-bottle choice method. Animals were given free drinking water in a graduated Richter tube. After 2 days, they were given close to only 10% (v/). v) Alcohol solution for 3 consecutive days, during which time the animal becomes accustomed to drinking from the Richter tube and is accustomed to the taste and pharmacy of the alcohol, after which they are allowed to freely access both the drinking water and the 10% alcohol solution. Rats were given free access for at least 4 consecutive weeks to the entire study period. At 4, 6 and 24 hours after treatment, the amount of water and alcohol consumed was recorded, and food intake was performed at 24 hours. Animals were measured daily. Weight.

For alcohol, food, and water intake, after establishing a stable baseline, rats were administered vehicle or compound #8 via oral feeding, using a randomized staggered design to compare the effects of these compounds on alcohol absorption. Also, an established FDA-approved drug, naltrexone, was used as a positive control group. The same mice were given an oral dose of naltrexone (20 mg/kg) at a treatment interval of at least 3 days. At 4, 6 and 24 hours after the drug, the amount of water and alcohol taken was recorded. The food intake was recorded at 24 hours, and 8-10 animals were used in each group.

The results below are presented as mean ± SEM. The alcohol intake (g/kg) is calculated by multiplying the volume of alcohol consumed (ml) by 10% and 0.7893 (density of alcohol) / body weight (kg), alcohol preference ( Alcohol preference), expressed as a percentage, is calculated as follows: (ml of alcohol consumed / milliliters of total fluid intake) x 100 (Rezvani and Grady, 1994; Rezvani et al., 1997). Between drug-treatment and Statistical differences between the control groups were compared using ANOVA and the Turkey Student's trial.

As shown in Table 4 below, Compound #8 reduced alcohol consumption in rats that preferred wine at 6 hours after administration (@50 and 100 mg/kg dose).

Example 14

As a specific embodiment of one of the oral compositions, 100 mg of the compound #8 prepared according to Example 7 was prepared as a finely divided lactose to prepare a total amount of 580 to 590 mg of the preparation to be filled into a hard capsule No. 0.

While the foregoing description is directed to the principles of the invention, and the embodiments of the invention They are equivalent.

Claims (6)

Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein R ¹ and R ² are each independently selected from the group consisting of free hydrogen and C _1-4 alkyl; R ⁴ is a group selected from the group consisting of free hydrogen and C _1-4 alkyl; a is an integer from 1 to 2. ; for Wherein b is an integer from 0 to 4; each R ⁵ is a group selected independently of free halogen and C _1-4 alkyl; used to make a pharmaceutical for the treatment of alcohol abuse or addiction. According to the use of the first aspect of the patent application, wherein R ¹ and R ² are each independently selected from the group consisting of free hydrogen and C _1-4 alkyl; R ⁴ is selected from the group consisting of hydrogen and lower alkyl; An integer from 1 to 2; for Wherein b is an integer from 0 to 2; each R ⁵ is a group independently selected from the group consisting of a free halogen and a C _1-4 alkyl group; or a pharmaceutically acceptable salt thereof. According to the use of the ^second aspect of the patent application, wherein R ¹ and R ² are each independently selected from the group consisting of free hydrogen and C _1-4 alkyl; R ⁴ is a group selected from the group consisting of free hydrogen and methyl; An integer from 1 to 2; For the selection of the following bases: 2-(2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(5-fluoro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] dioxins Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] dioxins Base, and 2-(8-chloro-2,3-dihydro-benzo[1,4] dioxins Base), or a pharmaceutically acceptable salt thereof. According to the use of the third aspect of the patent application, wherein R ¹ and R ² are each independently selected from the group consisting of free hydrogen and methyl; R ⁴ is a group selected from the group consisting of free hydrogen and methyl; a is 1 to 2 Integer For the selection of the following bases: 2-(2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] dioxins Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] dioxins Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] dioxins And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] dioxins Or a pharmaceutically acceptable salt thereof. According to the use of the first aspect of the patent application, wherein the compound of the formula (I) is selected from the group consisting of (2S)-(-)N-(6-chloro-2,3-dihydro-benzo[1,4] evil 2-ylmethyl)sulfonamide; and pharmaceutically acceptable salts thereof. A use of selected (2S)-(-)N-(6-chloro-2,3-dihydro-benzo[1,4] dioxins Use of -2-ylmethyl)sulphonamide and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of alcohol abuse or addiction.