TWI393563B - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity - Google Patents

Description

Use of a benzo-fused heterocyclic sulfonamide derivative for the treatment of obesity Cross-references to related applications

The present application claims the benefit of U.S. Provisional Application Serial No. 60/751,499, filed on Dec. 19, 2005, which is incorporated herein in its entirety by reference.

Field of invention

The present invention refers to the use of a benzo-fused fused sulfonamide derivative for the treatment of obesity, for promoting weight loss and/or for suppressing appetite.

Background of the invention

Obesity is a state in which adipose tissue is excessive. Although often referred to as weight gain, it is not necessarily - lean but muscularly developed individuals may be overweight according to arbitrary criteria, and the individual does not have too much fat. The continuous distribution of body weight in the population makes the medically meaningful difference between leanness and obesity seem a bit arbitrary. Obesity is then more effectively defined by assessing its association with rickets or mortality.

Although not a direct measure of fat rate, the most widely used method for determining obesity is the body mass index (BMI), which is equal to weight/height ² (expressed in kg/ ^m2 ). Other ways to quantify obesity include human measurement (skin-fold thickness), density determination (water weighing), computed tomography (CT) or magnetic resonance imaging (MRI), and electrical impedance. Data will use the population lives statistics (Metropolitan Life Tables), the men and women among all BMI midpoint of the line height and body size in the range of 19-26 kg / m ^2; in a similar BMI, women have more body than men fat. Based on clear data on the actual rickets rate, BMI 30 is most commonly used as a threshold for obesity in men and women. Large epidemiological studies show when BMI At 25 o'clock, all causes, metabolic and cardiovascular morbidity rates began to increase (although at very low rates), suggesting that the cut-off point for obesity should be reduced. Some authorities use the term overweight (instead of obesity) to describe individuals whose BMI falls between 25 or 27 and 30. A BMI between 25 and 30 should be considered medically meaningful and suitable for therapeutic intervention, especially in the presence of risk factors affected by obesity, such as hypertension and glucose intolerance.

Recent data from the National Health and Nutrition Census (NHANES) show that the percentage of adult obese adults (BMI > 30) has increased from 14.5% (between 1976 and 1980) to 22.5% (between 1998 and 1994). U.S. adults over the age of 20 and over between 1998 and 1991 have as much as 50% overweight (defined as BMI > 25). Because many systems with a BMI between 25 and 30 have substantial health risks, the growing popularity of medically significant obesity has caused great concern. Obesity is more common in women and the poor; the prevalence of children is also increasing at an alarming rate.

Obesity has a great negative impact on health. Mortality in obese obese individuals (>200% ideal body weight) is increased by a factor of twelve. Mortality increases with obesity, especially when obesity is associated with increased intra-abdominal fat (see above). It is also evident that the extent to which obesity affects a particular organ system is influenced by susceptibility genes that are diverse in the population. Compared with individuals with normal body weight, the risk of obese individuals leading to early death is increased by 50-100%. More than 300,000 deaths a year in the United States can be attributed to obesity.

There is still a need to provide effective treatment for obesity.

Summary of invention

The invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of obesity, for promoting weight loss and/or for suppressing appetite

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 1 to 2. Integer Is selected from the group consisting of: 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 When a is 1.

The invention further relates to the use of a compound of formula (II), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of obesity, for promoting weight loss and/or for suppressing appetite

The invention further relates to the use of at least one weight loss promoting agent and/or at least one appetite suppressant and a compound of formula (I) or formula (II) as described herein for the manufacture of a therapeutic obesity, for promoting weight loss and/or Or appetite-suppressing drugs. In one embodiment, the invention is directed to the use of at least one weight loss promoter and a compound of formula (I) (preferably compound #8) as described herein for use in the manufacture of a medicament for the treatment of obesity and/or To promote weight loss of pharmaceuticals.

Illustrative of the invention is the use of any of the above compounds for the manufacture of a medicament for the treatment of obesity. In another embodiment, the invention is the use of any of the above compounds for the manufacture of a medicament for promoting weight loss. In another embodiment, the invention is the use of any of the above compounds for the manufacture of a medicament for suppressing appetite. Further exemplified by the invention is the use of any of the compounds described herein for the manufacture of a medicament for delaying gastric emptying.

Detailed description of the invention

The invention refers to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof

among them , a, R ¹ , R ² and R ⁴ are as defined in the present application, and the use is for the manufacture of a medicament for treating obesity, promoting weight loss and/or suppressing appetite. The invention further refers to the use of any of the compounds described herein for the manufacture of a medicament for delaying gastric emptying.

The invention further relates to the use of at least one weight loss promoting agent and/or at least one appetite suppressant and a compound of formula (I) or formula (II) as described herein for the manufacture of a medicament for the treatment of obesity.

In a specific embodiment of the invention, the invention relates to the use of a compound of the above formula (I) or (II) or a pharmaceutical salt thereof for the manufacture of a medicament for the treatment of obesity, wherein the reduced weight is fat and in a more specific embodiment In the case of white adipose tissue.

In a specific embodiment of the present invention, the present invention relates to the use of the compound of the above formula (I) or (II) or a pharmaceutical salt thereof for the manufacture of a medicament for promoting weight loss, wherein the reduced weight is fat and is better. In a specific example, it is a white adipose tissue.

As used in this case, the term "obesity" is defined as a body mass index (BMI) greater than or equal to about 25, preferably greater than or equal to about 30 BMI. Thus, when used in this case, the term "obesity" includes subjects/patients who are overweight and clinically obese.

As used in this case, the term "weight loss enhancer" refers to any agent that promotes weight loss. Suitable examples include, but are not limited to, rimonabant, orlistat, sibutramine, mazindol, benzphetamine, phenmetrazine, Phentermine, diethylpropion, oxime, phenylpropanolamine, ephedrine, quinoline (quipazine), fluoxetine, sertraline, fenfluramine, dexfenfluramine, apomorphine, exendin, dehydrogenation Dehydroepiandrosterone, etiocholandione, testosterone, oxandrolone, topiramate and the like. Preferably, the weight loss promoting agent is rimonabant, topiramate, roche fresh or normetene. Similarly, in the present case, the term "appetite suppressant" refers to any appetite-suppressing agent or natural product including, but not limited to, an appetite suppressant that acts via an adrenergic mechanism, such as benzylidene or benzophenone. , phentermine, diethyldiethyl ketone, acetonide, normetene, phenylpropanolamine or ephedrine; an appetite suppressant acting via a serotonin mechanism, such as quinoline , fluoxetine, sertraline, fenfluramine or dexfenfluramine; an appetite suppressant acting via a dopamine mechanism, such as apomorphine; an appetite suppressant (such as histamine) via a histamine mechanism , H3 receptor modulators; enhancers of energy expenditure, such as beta-3 adrenergic co-agents, and stimulators of decoupled protein function; leptin and leptin; antagonists of neuropeptide Y; Hormone-1, 3 and 4 receptor modulators; cholecystokinin co-agents; glucagon-like peptide-1 (GLP-1) and isoforms (such as it); and males (such as Dehydroepiandrosterones and derivatives, such as the present cholanedione), steroids, anabolic steroids (such as oxidized methyl dihydro guanidone) and steroid hormones; galanthoamine receptor antagonists; cytokine agents, such as ciliary Neurotrophic factor; amylase inhibitor; intestinal stasis hormone synergist/drug; orexin/hypocretin antagonist; urocortin antagonist; bombesin Synergist; modulator of protein kinase A; adrenal cortex release Quasi drugs; cocaine and amphetamine regulated transcript of quasi drugs; calcitonin gene-related peptide quasi drugs; and fatty acid synthase inhibitors.

The term "subject" as used in this context 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 an active compound which, in a tissue system, animal or human, elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician, including alleviating the symptoms of the disease or condition being treated. Or the amount of the agent.

Wherein the invention refers to co-therapy or combination therapy comprising administering one or more compounds of formula (I) or formula (II) and one or more weight loss promoters and/or Or at least one appetite suppressant, "therapeutically effective amount" means the combined amount of the agents taken together such that the combined effect elicits the desired biological or medical response. For example, a therapeutically effective amount comprising a synergistic therapy with a compound of formula (I) or formula (II) and at least one weight loss promoter and/or at least one appetite suppressant will be therapeutic when administered together or sequentially. An amount effective to combine the amount of the compound of formula (I) or formula (II) with the weight loss enhancer and/or at least one appetite suppressant. In addition, those skilled in the art will appreciate that in the case of a therapeutically effective amount of synergistic therapy, such as the above examples, the amount of the compound of formula (I) or formula (II) and/or weight loss promoter and/or at least one appetite suppression The amount of the agent may be therapeutically effective or may be ineffective in treatment.

As used in this case, the terms "synergistic therapy" and "combination therapy" refer to the administration of one or more compounds of formula (I) or formula (II) with one or more weight loss promoters and/or appetite suppression. For treating a subject in need thereof, wherein the compound of formula (I) or formula (II) and the weight loss promoter and/or appetite suppressant are by any suitable means, simultaneously, sequentially , administered separately or in a single pharmaceutical formulation. When the compound of formula (I) or formula (II) and the weight loss promoter and/or appetite suppressant are administered in separate dosage forms, the number of doses administered per compound per day may be the same or different. The compound(s) of formula (I) or formula (II) and the weight loss promoter and/or appetite suppressant 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 (sc), transdermal, and transrectal. The compounds may also be administered directly to the nervous system including, but not limited to, intraspinal, intraventricular, intraventricular, intramedullary, intracisternal, intraspinal, and/or paravertebral delivery via intracranial or intraspinal needles. Routes of administration and/or catheters with or without a pumping device. The compound of formula (I) or formula (II) and the weight loss promoting agent and/or the appetite suppressant(s) may be divided or singled in parallel at the same or different times during the course of treatment according to simultaneous or alternating regimens. Formal investment.

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 still another embodiment of the present invention, each of R ¹ and R ² is 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 another embodiment of the invention, -(CH ₂ ) _a - is -CH ₂ -.

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

In one embodiment of the invention, a is one.

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

In a specific example of the present invention, Is selected from the group consisting of: In another embodiment of the present invention, Is selected from the group consisting of:

In a specific example of the present invention, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Dioxinyl, 2-(benzo[1,3] Methoxy), 3-(3,4-dihydro-benzo[1,4] Mercapto), 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] Base), 2-( Base, 2-(5-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-benzo[1,3] Methoxy), 2-(7-nitro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Base, 2-(8-chloro-2,3-dihydro-benzo[1,4] Base, 2-(2,3-dihydro-naphtho[2,3-b][1,4] And 2-(4-methyl-benzo[1,3] Maoji).

In another embodiment of the present invention, Is selected from the group consisting of 2-(benzo[1,3] Methoxy), 2-(2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] base). In another embodiment of the present invention, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] And 2-(6-bromo-2,3-dihydro-benzo[1,4] base).

In a specific embodiment of the invention, R ⁵ is selected from the group consisting of halogen and lower alkyl. In another embodiment of the invention, R ⁵ is selected from the group consisting of a chloro group, a fluoro group, a bromo group, and a methyl group.

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

In one embodiment of the invention, the compound of formula (I) is present as a mirror image-enriched mixture wherein the % image enrichment value (% ee) is greater than about 75%, preferably greater than about 90%, more preferably Greater than about 95%, optimally greater than about 98%.

Additional specific examples of the invention include those substituents selected among one or more of the variables defined herein (i.e., R ¹ , R ² , R ³ , R ⁴ , X-Y, and A) are independently selected. Any subset of substituents selected for any individual substituent or from the complete list defined in this case.

Representative compounds of the invention are listed in Table 1 below. Additional compounds of the invention are listed in Table 3. In Tables 1 and 2 below, the field at the beginning of "stereo" defines the stereo configuration of the heterocyclic carbon atom attached to the star-shaped bond. If no nomenclature is listed, the compounds are prepared as a mixture of stereoconfigurations. If the "R" or "S" designation is listed, the stereo configuration is based on the image-isomerically enriched starting material.

For the purposes of this case, unless otherwise stated, "halogen" means chlorine, bromine, fluorine and iodine.

For use in this case, the term "alkyl" , whether used alone or as part of a substituent, is intended to include both straight and branched chains, unless otherwise indicated. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, and the like. Unless otherwise indicated, "lower" used in conjunction with an alkyl group means a carbon chain composition composed of 1-4 carbon atoms.

In the case of this case, unless otherwise stated, "alkoxy" means an oxygen ether group of the above linear or branched alkyl group. For example, methoxy, ethoxy, n-propoxy, di-butoxy, tert-butoxy, n-hexyloxy and the like.

When used in this case, the "*" symbol indicates the presence of a stereo center.

When a particular group is "substituted" (e.g., alkyl, aryl, etc.), the group may have one or more substituents, preferably one to five, independently selected from the list of substituents. More preferably one to three substituents, most preferably one to two substituents.

The term "independently" in relation to a substituent means that when there may be more than one such substituent, the substituents may be the same or different.

In accordance with the standard nomenclature used throughout the disclosure, the end portion of the named side chain is described first, and the adjacent functionality of the near junction is continued. Thus, for example, a " phenyl-alkyl-amino-carbonyl-alkyl " substituent refers to a group of the formula

The abbreviations used in this specification, especially the reaction schemes and examples, are as follows: DCC = dicyclohexylcarbodiimide DCE = dichloroethane DCM = dichloromethane DIPEA or DIEA = diisopropylethylamine DMF =N,N-dimethylformamide DMSO = dimethyl hydrazine EDC = ethyl carbodiimide 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 activated carbon catalyst RP HPLC = reverse phase high pressure liquid chromatography RT or rt = room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography

If the compounds according to the invention have at least one pair of palm centers, they may thus be present as mirror image isomers. If the compounds possess two or more pairs of palm centers, they may additionally exist as diastereomeric mirror isomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the invention. Furthermore, several crystal forms of such compounds may exist as homomorphs and are intended to be included within the scope of the invention. In addition, several compounds may form solvates with water (i.e., hydrates) or general organic solvents, and such solvates are also intended to be encompassed within the scope of the invention.

For use in medicine, the compound salt of the present invention refers to a non-toxic "pharmaceutically acceptable salt" . However, other salts may be used in the preparation of the compounds according to the invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salt compounds include acid addition salts which can be, for example, by mixing a solution of the compound with a pharmaceutically acceptable acid (eg, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, A solution of succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid is formed. Further, if the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; A salt formed by an organic ligand, such as a quaternary ammonium salt. Thus, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, ethylenediamine Calcium acetate, camphor sulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, eto salt ), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, ethanol phthalate, hexyldiphenolate, hydrabamine, hydrobromic acid Salt, hydrochloride, hydroxynaphthoate, iodide salt, isothiohydroxy acid salt, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonic acid Salt, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, N-methyl glucoammonium salt, oleate, pamoate ( Embone, palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, times , Succinate, tannate, tartrate, teoclate (teoclate), tosylate, and valerate triethylammonium salt.

Representative acids and bases useful in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, deuterated amino acid, adipic acid, alginic acid, ascorbic acid, L- Aspartic acid, benzenesulfonic acid, benzoic acid, 4-ethylguanidinobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, citric acid, Caproic acid, caprylic acid, cinnamic acid, citric acid, cyclocyclyl acid, dodecyl sulfate, ethyl-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonate Acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxy-glutaric acid, glycol Acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic 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, orotic acid , oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-joy bran Amine acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid Undecylenic acid; and alkali, including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, two Ethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucosamine, seabamine, 1H-imidazole, L-isoamine, magnesium hydroxide, 4- (2-hydroxyethyl)-morpholine, piperazine , potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, aminobutyric triol and zinc hydroxide.

The compound of formula (I) can be prepared according to the procedure outlined in Reaction Scheme 1.

Thus, a suitably substituted compound of the formula (X) (a conventional compound or a compound prepared by a conventional method) is used in, for example, THF, The organic solvent of the alkane and the like is preferably at a temperature of from about 50 ° C to about 100 ° C, more preferably at about reflux temperature with a sulfonamide (preferred compound, preferably wherein the sulfonamide is from about 2 to about 5 equivalents) The amount) reacts to form the corresponding compound of formula (Ia).

Alternatively, a suitably substituted compound of the formula (X) (a conventional compound or a compound prepared by a conventional method) is used in an organic solvent such as DMF, DMSO and the like in a base such as TEA, DIPEA, pyridin and the like. The reaction with a suitably substituted compound of formula (XI) (a conventional compound or a compound prepared by a conventional method) is carried out in the presence of a compound of formula (I).

a compound of formula (X) (wherein for It can be prepared according to the method outlined in Reaction Scheme 2.

Thus, a suitably substituted compound of the formula (XII) (a conventional compound or a compound prepared by a conventional method, for example, as described in Reaction Scheme 3 above) is optionally used in an organic solvent such as acetonitrile and the like. Reaction with NH ₄ OH (a conventional compound) to give the corresponding compound of formula (XIII).

The compound of the formula (XIII) is reacted with a suitably selected reducing agent (for example, LAH and the like and the like) in an organic solvent such as THF, diethyl ether and the like to give the corresponding compound of the formula (Xa).

a compound of formula (X) (wherein Lined up It can be prepared according to the method outlined in Reaction Scheme 3.

Thus, a suitably substituted compound of the formula (XIV) (a conventional compound or a compound prepared by a conventional method) is in the presence of a coupling agent (for example, DCC and the like), optionally in an organic solvent such as acetonitrile and the like. Reacts with NH ₄ OH to form the corresponding compound of formula (XV).

The compound of the formula (XV) is reacted with an appropriately selected reducing agent (for example, LAH and the like) in an organic solvent such as THF, diethyl ether and the like to give the corresponding compound of the formula (Xb).

a compound of formula (X) (wherein Lined up And wherein a is 2) can be prepared according to the method outlined in Reaction Scheme 4.

Thus, a suitably substituted compound of formula (XVI) wherein J ¹ is a suitable leaving group, such as Br, Cl, I, benzenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl and the like a conventional compound or a compound prepared by a conventional method (for example, by activating a corresponding compound in which J ¹ is OH)-based in an organic solvent such as DMSO, DMF, THF, and the like, and cyanide (for example, Potassium cyanide, sodium cyanide and the like) are reacted to form the corresponding compound of formula (XVII).

The compound of formula (XVII) is reduced according to conventional methods, for example, by reaction with a suitable reducing agent such as LAH, borane and the like to give the corresponding compound of formula (Xc).

a compound of formula (X) (wherein Lined up And wherein a is 1) can be prepared according to the method outlined in Reaction Scheme 5.

Thus, a suitably substituted compound of the formula (XVIII) (a conventional compound or a compound prepared by a conventional method) is activated according to a conventional method to give a corresponding compound of the formula (XIX) wherein J ² is a suitable leaving group. Groups such as phenylsulfonyl, Cl, Br, I, methanesulfonyl, trifluoromethanesulfonyl and the like.

The compound of the formula (XIX) is in an organic solvent such as DMF, DMSO, acetonitrile or the like, preferably at a high temperature of from 50 ° C to about 200 ° C, more preferably at about reflux temperature with an phthalic acid imide salt (for example) The potassium phthalimide, sodium phthalate and the like are reacted to form the corresponding compound of formula (XX).

The compound of the formula (XX) is in an organic solvent such as ethanol, methanol and the like, preferably at a temperature of from about 50 ° C to about 100 ° C, more preferably at a reflux temperature and the like, and N ₂ H ₄ (a conventional compound) Reaction to produce the corresponding compound of formula (Xd).

Those skilled in the art will understand the compound of formula (X) (where Lined up , , , , or The same can be prepared according to conventional methods or, for example, according to the methods outlined in the above Reaction Schemes 2 to 5, by substituting the corresponding naphtho-fused compound for the benzo-fused starting material.

It will be further understood by those skilled in the art that if a single mirror image isomer (or a mixture of mirror image isomers, in which a mirror image isomer is enriched) of the compound of formula (X) is desired, then steps 1 through 5 are illustrated. The above process can be applied by replacing a suitable starting material with a single mirror image isomer (or a mixture of mirror image isomers in which a mirror image isomer is enriched).

Those skilled in the art will appreciate that if the reaction steps of the present invention can be carried out in a variety of solvent or solvent systems, the reaction step can also be carried out as a mixture of suitable solvents or solvent systems.

If a process for preparing a compound according to the invention produces a mixture of stereoisomers, the isomers can be separated by conventional techniques, such as preparative chromatography. The compound can be prepared in racemic form, or the individual mirror image isomers can be prepared by mirror specific synthesis or by analytical methods. The compound can be resolved, for example, by its standard techniques into its constituent mirror image isomers, for example by reaction with an optically active acid such as (-)-di-p-tolylmethyl-D-tartaric acid and/or (+ )-Di-p-tolylmethyl-L-tartaric acid forms a salt to form a diastereomeric enantiomer pair, followed by crystallization in sections and regeneration of the free base. The compound can also be resolved by formation of diastereomeric enantiomers or guanamine, followed by chromatographic separation and removal of the antagonistic aid. Alternatively, the compound can be resolved using a palm-shaped HPLC column.

During any method of preparing a compound according to the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by the use of a protecting group, such as those described 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. . The protecting group can be removed at a convenient subsequent stage by methods known in the art.

The invention further comprises a pharmaceutical composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition containing one or more of the compounds of the present invention as described herein as an active ingredient can be prepared by carefully mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical blending techniques. The carrier can take a wide variety of forms depending on the route of administration desired (e.g., oral, parenteral). Thus, in the case of liquid oral preparations - such as suspensions, elixirs and solutions - suitable carriers and additives include water, glycols, oils, alcohols, odorants, preservatives, stabilizers, colorants And analogs; in the case of solid oral preparations - such as powders, capsules and lozenges - suitable carriers and additives include starches, saccharides, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Things. Solid oral preparations may also be coated with a substance such as a saccharide or coated with an enteric coating to adjust the primary absorption site. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservative. Injectable suspensions or solutions can also be prepared using aqueous carriers together with suitable additives.

For the preparation of the pharmaceutical composition of the present invention, one or more compounds of the present invention as an active ingredient are carefully mixed according to a conventional pharmaceutical blending technique, and the compound or a plurality of compounds and a pharmaceutical carrier are carefully mixed, and the carrier can be administered according to the administration (for example, A variety of different forms are employed in the form of formulations, either orally or parenterally, such as intramuscularly. Any of the usual pharmaceutical vehicles can be employed in preparing the compositions within the oral dosage form. Thus, in the case of liquid oral preparations - for example, suspensions, elixirs and solutions - suitable carriers and additives include water, glycols, oils, alcohols, odorants, preservatives , coloring agents and the like; in the case of solid oral preparations - for example, powders, capsules, caplets, gelcaps and lozenges - suitable carriers and additives are included Starch, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Lozenges and capsules represent the most advantageous oral dosage unit form because of their ease of administration, in which case solid pharmaceutical carriers are obviously employed. If desired, the lozenge can be coated with a sugar coating or an outer casing by standard techniques. For parenteral dosage forms, the carrier will usually comprise sterile water, although it may include, for example, other ingredients such as to increase solubility or preservative. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspensions and the like may be employed. The pharmaceutical composition of the present invention will contain, per dosage unit (e.g., tablets, capsules, powders, injections, one teaspoon, and the like), the amount of active ingredient necessary to deliver the effective administration as described above. The pharmaceutical composition of the present invention will contain about 0.1-1000 mg per unit dosage unit (such as tablets, capsules, powders, injections, suppositories, one teaspoon, and the like) and may be administered in the following dosages: about 0.01-200.0 mg/kg. /day, preferably about 0.1 to 100 mg / kg / day, more preferably about 0.5 - 50 mg / kg / day, more preferably about 1.0 - 25.0 mg / kg / day, more preferably about 0.5 - 10.0 mg / kg / day Preferably, it is from about 1.0 to about 5.0 mg/kg/day or any range therein. However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the compound employed. It can be administered daily or post-periodic.

Preferably, the compositions are in unit dosage form, such as lozenges, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, autoinjections A device or suppository; for oral, parenteral, intranasal, sublingual or rectal administration, or by inhalation or insufflation. Alternatively, the composition may be in a form suitable for administration once a week or once a month; for example, a non-soluble salt of the active compound, such as a citrate, may be suitable for providing a reservoir for intramuscular injection. preparation. In order to prepare a solid composition such as a tablet, the main active ingredient is a pharmaceutical carrier, such as a conventional tablet, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, and phosphoric acid. Calcium or a rubber and other pharmaceutical diluents, such as water, are combined to form a solid pre-formulated composition comprising a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When it is mentioned that the pre-formulated compositions are homogeneous, meaning that the active ingredients are uniformly dispersed throughout the composition, the composition can be easily subdivided into equally effective dosage forms such as tablets, pills and capsules. The solid pre-formulated composition is then subdivided into unit dosage forms of the above type containing from 0.1 to about 1000 mg of the active ingredient of the present invention. The lozenges or pills of the novel compositions may be coated or otherwise blended to provide a dosage form with the advantage of prolonged action. For example, a lozenge or pill may comprise an inner layer dispensing and an outer layer dispensing component, the latter being in the form of a shell encased in the former. The two components may be separated by an enteric layer which is adapted to resist disintegration in the stomach and to allow the inner layer components to pass intact into the duodenum or to be delayed in release. A wide variety of materials can be used in such casing layers or garments, including a wide variety of polymeric acids along with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms which may be incorporated into the novel compositions of the present invention for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, flavored emulsifications containing edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Liquids and elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural rubbers such as tragacanth, acacia, alginate, polyglucose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrole Ketone or gelatin.

The method of treating depression in the present invention can also be carried out using a pharmaceutical composition comprising any of the compounds defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably from about 50 to 500 mg, and may constitute any form suitable for use in the mode of administration. Carriers include the necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, perfumes, sweeteners, preservatives, pigments, and outer coatings. Compositions suitable for oral administration include solid forms such as pills, troches, capsules, capsules (each comprising immediate release, long-acting release and sustained release formulations), granules and powders, and liquid forms, for example Solutions, syrups, elixirs, emulsions and suspensions. Forms which can be used for parenteral administration 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 administered in two, three or four divided doses per day. Moreover, the compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal patches well known to those of ordinary skill in the art. If administered in the form of a transdermal delivery system, the dosage is of course continuous rather than intermittent throughout the dosage regimen.

For example, in the case of oral administration in the form of a lozenge or capsule, the active pharmaceutical ingredient may be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Further, suitable binders, lubricants, disintegrants, and colorants may also be incorporated into the mixture as desired or desired. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic rubbers (such as acacia, tragacanth or sodium oleate, sodium stearate, Magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, acacia, bentonite, sansin, and the like.

Liquid forms include suitably flavored suspending or dispersing agents, such as synthetic and natural rubbers, for example, tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are desirable. When the intravenous administration is desired, an isotonic preparation which generally contains a suitable preservative is used.

The compounds of the present invention can be administered in any of the foregoing compositions according to established dosage regimens in the art whenever treatment for depression is desired.

The daily dose of the product can vary from 0.01 to 150 mg/kg per adult per day. For oral administration, the composition is preferably provided to contain 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 activities. The ingredients are in the form of a lozenge that is dose adjusted according to the symptoms of the patient being treated. An effective amount of the drug is usually supplied at a dosage level of from about 0.01 mg/kg to about 1500 mg/kg body weight per day. Preferably, the range is from about 0.1 to about 100.0 mg/kg body weight per day, more preferably from about 0,5 mg/kg to about 50 mg/kg, more preferably from about 1.0 to about 25.0 mg/kg body weight per day. . The compound can be administered in a regimen of 1 to 4 times per day.

The optimal dosage for administration can be readily determined by those skilled in the art and will vary with the particular compound employed, the mode of administration, the strength of the formulation, the mode of administration, and the condition of the condition. In addition, factors associated with the particular patient being treated, including the patient's age, weight, diet, and timing of administration will result in the need to adjust the dose.

Those skilled in the art will appreciate that in vivo and in vitro assays using suitable, conventional, and generally accepted cellular and/or animal models predict the ability of a test compound to treat or prevent a given condition.

Those skilled in the art will further understand that human clinical trials (including first-in-human, prescription and efficacy trials, in healthy patients and/or patients with established conditions) can be based on Methods well known in the clinical and medical fields are completed.

The following examples are presented to aid the understanding of the invention, and are not intended to be construed as limiting the invention in any way.

Example 1

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

Catechol (5.09 g, 46.2 mmol) was combined with potassium carbonate in acetonitrile and heated to reflux for one hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and the reaction was continued at reflux for 24 hours. The solution was allowed to cool to room temperature and filtered. The filtrate was evaporated to dryness. The combined organic solution was anhydrified on MgSO ₄ and concentrated. Chromatography (2% diethyl ether in hexane) gave 3-methyl-3,4-dihydro-2H-benzo[b][1,4] as a colorless oil. Hey.

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).

3-extended methyl-3,4-dihydro-2H-benzo[b][1,4] 呯 (5.00 g, 30.8 mmol) was dissolved in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL) was added at 0 °C. The reaction was stirred at RT for 5 hours. Aminosulfonic acid (6.97 g, 61.6 mmol) was added. The reaction was heated to reflux overnight. The reaction was cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 mL) was then evaporated. The solution was extracted with ethyl acetate (3 x 100 mL). The combined organic solution was anhydrified on MgSO _4. The solution was concentrated in vacuo and purified by chromatography (2% to EtOAc EtOAc) eluted , 4] two Ind-3-yl)methyl)amine.

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 (b, 2H), 3.16 (d, J = 4 Hz, 1H), 2.72 (d, J = 4 Hz, 1H), 2.30 (m, 1H).

Let ((3,4-dihydro-2H-benzo[b][1,4] two Indole-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g, 32.4 mmol) in anhydrous Acetone (60 mL) was combined and heated to reflux overnight. Chloroform was added and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and purified EtOAc (EtOAc:EtOAc

258.8(M+H ⁺ )

1H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 6.71 (b, 1H), 6.59 (b, 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] -2-ylmethyl)-sulfonamide (Compound #1)

Racemic 2,3-dihydro-1,4-benzoic acid 2-methylmethylamine (4.4 g, 26 mmol) and sulfonamide (5.1 g, 53 mmol) at 1,4 Acetone (100 mL) was combined and refluxed for 2 hours. The reaction was allowed to cool to room temperature and a small portion of solid was filtered and evaporated. The filtrate was evaporated to dryness <RTI ID=0.0> The solid was recrystallized from DCM to give the title compound as white solid.

Mp: 97.5-98.5 °C

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

H ¹ NMR (DMSO d6) δ 6.85 (m, 4H), 6.68 (bd s, 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] II Methyl-2-ylmethyl)sulfonamide (Compound #2)

Catechol (10.26 g, 93.2 mmol), sodium methoxide (25 wt% in methanol, 40.3 g, 186 mmol) and methyl dichloroacetate (13.3 g, 93.2 mmol) in anhydrous Combined in methanol (100 ml). The solution was heated to reflux overnight. The reaction was allowed to cool to room temperature, acidified with concentrated hydrochloric acid and then reduced to a volume of about 50 mL in vacuo. Water was added and the mixture was extracted with diethyl ether (3 x 100 mL). The combined organic solution was anhydrified on MgSO _4, and concentrated to a brown solid and is chromatographed (2% ethyl acetate in hexanes) as a colorless oil generates Benzo [1,3] Methyl 2-carboxylate.

MS (ESI): 195.10 (M+H ⁺ ).

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

P-benzo[1,3] Methyl 2-carboxylate (7.21 g, 40.0 mmol) was added ammonium hydroxide (29% in water, 10 mL) and a sufficient amount of acetonitrile (~5 mL) to homogenize the mixture. The solution was stirred at room temperature for two hours and then distilled water was added. Benzo[1,3] The oxo-2-carboxylic acid amide was precipitated as a white solid which was collected by filtration and used without further purification.

MS (ESI): 160.00 (M+H ⁺ )

¹ H NMR (300 MHz, DMSO), 6: 7.99 (s, wide, 1H), 7.72 (s, wide, 1H), 6.94 (m, 2H) 6.86 (m, 2H), 6.30 (s, 1H) ).

Benzo[1,3] Methyl-2-carboxylic acid decylamine (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1 M in THF, 39.5 mL, 39.5 mmol) was slowly added to the solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added to destroy excess LAH. Aqueous sodium hydroxide (3.0 M, 100 mL) was added and the solution was extracted ethyl acetate (3×100 mL). Rinsed with water, and the combined organic solution in the dehydrated MgSO _4. The solvent was evaporated to dryness to give C-benzo[1,3], as colorless oil. Methyl-2-yl-methylamine.

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] Methyl-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3.74 g, 38.9 mmol) in anhydrous Acetone (50 mL) was combined and the solution was heated to reflux overnight. The reaction was concentrated and the residue was crystallised eluted elute

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 (wide, 1H), 4.62 (wide, 1H), 3.64 ( d, J = 4 Hz, 2H).

Example 4

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

Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glysuccinate (22.8 g, 0.10 mol) The reaction was stirred at 60 ° C for 24 hours. The reaction was cooled to rt, diluted with EtOAc (EtOAc) The combined organic solution was washed 3 times with 10% potassium carbonate, washed once with water, washed once with brine and concentrated in vacuo to give a white solid, which was purified by flash column chromatography (DCM:MeOH - 50:1) , produced as solid ((2S)-2,3-dihydro-benzo[1,4] -2-yl)-methanol.

The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to 0 ° C, then p-toluenesulfonium chloride (13.0 g, 68 mM) was added and the mixture was allowed to react at room temperature Stir for 20 hours. The reaction was diluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layer was separated and the (500 mL) washed twice with 1N HCl, washed with water 4 times (150 mL), once dehydrated (MgS04 ₄₎ and evaporated to dryness in vacuo, a white solid was rinsed with a saline solution, which is rapid tube Column chromatography purification (Hept: EA-2:1) gave toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4] as white solid. -2-yl methyl ester.

The white solid was combined with potassium phthalimide (14.4 g, 78 mmol) in DMF (250 mL) and heated to reflux for 1 hour, cooled to room temperature and poured into vigorously stirred water. Stir in (1.5 liters) for 30 minutes. The white solid was filtered off, and the solid was washed with water, 2% NaOH and then with water several times, and allowed to air dry to give (2S)-2-(2,3-dihydro-benzo) as a white powdery solid. [1,4] two -2-ylmethyl)-isoindole-1,3-dione.

The powdery white solid was combined with hydrazine (2.75 g, EtOAc, EtOAc) The white solid was filtered and washed with EtOAc (EtOAc). The ether solution was dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield a pale yellow oil. The oil was purified by flash column chromatography (DCM: MeOH-10:1) A portion of the oil (4.82 g, 29 mmol) dissolved in 2-propanol (250 mL) was taken in 1N HCl (30 mL) After 3 hours, the mixture was cooled with ice for 2 hours. White flake solid ((2S)-C-(2,3-dihydro-benzo[1,4]) The corresponding HCl salt of 2-yl)-methylamine was removed by filtration and then recrystallized 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. DCM was dehydrated (NaSO ₄ ) and concentrated in vacuo to yield (2S)-C-(2,3-dihydro-benzo[ 1,4] two 2-yl)-methylamine.

[α] _D = -57.8 (c = 1.40, CHCl ₃ )

The oil (2.1 g, 12.7 mmol) and sulfonamide (2.44 g, 25.4 mmol) were The title compound was obtained as a white crystalline solid as a white solid.

Mp 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: analytical calculation: C, 44.25; H, 4.95; N, 11.47; S, 13.13 analysis found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.

Example 5

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

Racemic 2,3-dihydro-1,4-benzoic acid 2-methylmethylamine (8.25 g, 5.0 mmol) combined with triethylamine (1.52 g, 15 mmol) in DMF (10 mL) with dimethylamine sulfonium chloride (1.44 g) , 10 millimoles) while cooling in an ice bath. The reaction mixture was stirred for 3 hours under continuous cooling. The reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate solution with salt water rinse, dehydration (MgSO ₄₎ and concentrated to yield an oil in vacuo. The oil was purified by flash column chromatography (ethyl acetate: heptane - 1:1) to give a white solid which crystallised (ethyl acetate /hexane) The title compound.

Mp 76-78°C

MS 273 (MH ⁺ )

Elemental analysis: analytical calculation: C, 48.52; H, 5.92; N, 10.29; S, 11.78 analysis 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] -2-ylmethyl)-N-methylsulfonamide (Compound #7)

Racemic 2,3-dihydro-1,4-benzoic 2-Methylmethylamine (825 mg, 5 mmol) was dissolved in ethyl acetate (15 mL), refluxed for 30 min and concentrated in vacuo to give N-(2,3-dihydro as oil. -Benzo[1,4] -2-ylmethyl)-carbenamide.

The oil was dissolved in diethyl ether (25 mL) EtOAc (EtOAc) The reaction was quenched in an ice-bath and quenched with water (0.50 mL). The mixture was then stirred at room temperature for 1 hour. The solid was filtered, and the residue was crystallisjjjjjjjj The aqueous phase was basified with 1N NaOH and extracted with diethyl ether. The organic phase was dried (MgSO ₄₎ and concentrated in vacuo to yield as oil (2,3-dihydro - benzo [1,4] -2-ylmethyl)-methylamine.

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 oil (380 mg, 2.1 mmol) and sulfonamide (820 mg, 8.5 mmol) in two The mixture was combined with EtOAc (15 mL). The residue was purified by flash column chromatography (EtOAc EtOAc EtOAc

Mp 97-98°C

MS 257 (M ^-1 )

Elemental analysis: analytical calculation: 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 ) 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] -2-ylmethyl)-sulfonamide (Compound #8)

According to the procedure outlined in Example 4 above, 4-chloro catechol reacts to form (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] -2-yl)-methylamine and (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] A mixture of 2-yl)-methylamine (6-chloro group: 7-chloro isomer is about 3:1 ratio by RP HPLC).

The mixture was dissolved in 2-propanol (100 mL) and 1N HCl in diethyl ether was added until pH = 1.0 was obtained. The precipitated hydrochloride was filtered off (2.65 g) and recrystallized from methanol/IPA to yield white crystals. The white crystals were partitioned between DCM and dilute NaOH. The DCM is dehydrated and concentrated in vacuo to yield purified (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] 2-yl)-methylamine.

[α] _D = -67.8 (c = 1.51, CHCl ₃ )

The oil (7.75 mmol) and sulfonamide (1.50 g, 15.5 mmol) were Acetone (50 mL) was combined and refluxed for 2.0 hrs, cooled to room temperature and concentrated in vacuo to give a solid. The product was purified by flash column chromatography eluting with EtOAc EtOAc

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: analytical calculation: C, 38.78; H, 3.98; N, 10.05 analysis found: C, 38.80; H, 3.67; N, 9.99.

(2S)-C-(6-Chloro-2,3-dihydro-benzo[1,4] The filtrate of the crystalline hydrochloride salt of 2-yl)-methylamine was recovered (6-chloro group: 7-chloro isomer about 1:1) and concentrated in vacuo to give a solid which was partitioned. Between DCM (200 mL) and dilute NaOH (0.5 M, 50 mL). Once in DCM, dehydration (Na ₂ SO4) and concentrated in vacuo to yield an oil in a brine rinse, which by reverse phase HPLC (with 0.16% TFA in the 10-50% ACN with 0.20% TFA water Purification to produce (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] 2-yl)-methylamine residue.

The residue was combined with sulfonamide (0.90 g, 9.4 mmol) The mixture was combined and refluxed for 2.5 h, cooled to rt and concentrated in vacuo. The oil was purified by flash column chromatography using DCM/MeOH-10:1 to yield (2S)-(-)-N-(7-chloro-2,3-dihydro-benzene as white solid. And [1,4] two -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

-2-ylmethylsulfonamide (compound #10)

Make 2-carboxylic acid (4.5 g, 25 mM) was combined with HOBT (3.86 g, 25 mmol) in DCM (40 mL) and DMF (10 mL).

Dimethylaminopropylethylcarbodiimide (EDC, 4.84 g, 25 mmol) was added at rt and the reaction mixture was stirred 30 min. Ammonium hydroxide (2.26 mL, 33.4 mmol) was added and the mixture was stirred 16 hr. The reaction mixture was diluted with DCM (50 mL) and water (50 mL) and the mixture was adjusted to pH about 3.0 with 1N HCl.

The DCM was separated and the aqueous phase was extracted twice with DCM. The combined DCM phase was dried (Na ₂ SO ₄₎ and concentrated in vacuo to produce an oil, which was purified by flash column chromatography (ethyl acetate) to generate an oil.

An oil (5.35 g, 30 mmol) dissolved in THF (5 mL) was stirred with EtOAc EtOAc (EtOAc &lt hour. The reaction was quenched with water, stirred for 2 hours, the solution was decanted, dehydration (Na ₂ SO ₄₎ and concentrated in vacuo to yield the amine as an oil C- -2-yl-methylamine.

An oily amine (1.63 g, 10 mmol) with sulfonamide (1.92 g, 20 mmol) in two Acetone (50 mL) was combined and refluxed for 2 hours. The solution was cooled and concentrated in vacuo to give crystals crystals eluted eluting The solid was recrystallized from ethyl acetate / hexane to give a white solid. -2-ylmethylsulfonamide.

Mp 100-101°C

MS 241 (M ^-1 )

Elemental analysis: analytical calculation: C, 49.57; H, 5.82; N, 11.56; 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]di -2-yl)-ethylsulfonamide (compound #16)

Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3 dihydrobenzo[1,4] in DMSO (90 mL) (6.87 g, 30 mmol) and stirred at ambient temperature for 20 hours. The reaction mixture was later diluted with water (250 mL) and extracted twice with diethyl ether. The ether rinse with water, brine and then washed twice with water, dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield as a white solid of methyl 2-cyano - (2,3-dihydrobenzo [ 1,4] two ).

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)

2-cyanomethyl-(2,3 dihydrobenzo[1,4] ) Was dissolved in THF (50 ml) and was dissolved in of THF (80 mL, 80 mmol) was added a 1M BH _3, the reaction mixture was refluxed for 5 hours, then stirred at ambient temperature for 16 hours. It was cooled in an ice bath while 2N HCl was added until pH = 1.0 was reached. The reaction mixture was then stirred at room temperature for 1 h and concentrated in vacuo to give an oil. The oil was partitioned between 3N NaOH and diethyl ether, the ether solution with salt water rinse, dehydration (Na ₂ SO ₄₎ and concentrated in vacuo to yield crude 2- (2,3 dihydrobenzo [1, 4] two -2-yl)ethylamine.

MS (M+H) ⁺ 180.

Dissolve in two Alkane (100 ml) of crude 2-(2,3 dihydrobenzo[1,4] 2-yl)ethylamine was combined with sulfonamide (3.0 g, 31 mmol) and heated to reflux for 2 hours. The solution was cooled and concentrated in vacuo to give a crystallite crystallite. The solid was recrystallized from DCM to give the title compound as a solid.

MS(M ^-1 )257

MP 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: measurement: C, 46.48; H, 5.60; N, 10.81; S, 12, 41 Calculation: 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] -2-ylmethyl)-sulfonamide (Compound #29)

4,5-Dichlorocatechol (8.6 g, 48 mmol) was stirred with potassium carbonate (6.64 g, 48 mmol) in DMF (200 mL). (2R)-glycidyl sulfonate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 ° C for 24 hours. The reaction mixture was cooled to rt then diluted with EtOAc (EtOAc) The combined organic solution was flushed 3 times with 10% potassium carbonate, twice with salt water rinse, dehydration (MgSO ₄₎ and concentrated in vacuo to yield (2S) -2- (6,7- dichloro-2 ,3-dihydro-benzo[1,4] ) Methanol viscous oil.

(2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4] A methanolic oil (6.4 g, 27 mmol) was dissolved in pyridine (50 mL) cooled to 0. Then, p-toluenesulfonium chloride (5.2 g, 27 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hr. Diluted with diethyl ether and 1N HCl (750 ml) and the reaction mixture, the separated organic layer (250 ml), washed twice with 1N HCl, washed with water (150 ml), washed once, rinsed twice, dehydrated (MgSO ₄₎ with brine and was Concentrate in vacuo to form toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] -2-ylmethyl ester pale yellow solid.

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] 2-methylmethyl ester (8.0 g, 20.5 mmol) and potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 hour, cooled At room temperature, pour into vigorously stirred water (0.5 L) and stir for 30 minutes. The white solid was filtered off, and the solid was washed with water, 2% NaOH and then water, and then allowed to air dry to give (2S)-2-(6,7-dichloro-) as white powdery solid. 2,3-dihydro-benzo[1,4] -2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%).

The powdery white solid was combined with hydrazine (1.06 g, 33 mmol) in EtOH (EtOAc) The pH of the reaction mixture was adjusted to pH 1.0 by the addition of 1N HCl, and then the mixture was stirred for 15 min. The white solid was filtered and washed with EtOAc (EtOAc). The ether solution was dehydrated (Na ₂ SO ₄ ) and concentrated in vacuo to give (2S)-2-aminomethyl-(6,7-dichloro-2,3-dihydro-benzo[1, 4] two ) Viscous oil.

¹ H NMR (CDCl ₃ ): δ 6.98 (s, 1H), 6.96 (s, 1H), 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 oil (3.8 g, 16 mmol) and sulfonamide (3.1 g, 32.4 mmol) are attached to This was refluxed for 2 hours in EtOAc (EtOAc (EtOAc)MeOHMeOHMeOH The title compound of the crystalline solid.

MS[M-H] ^- 311.0

Mp 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: Elemental analysis: Measurement: 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] -2-ylmethyl)-sulfonamide (compound #36)

(2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] 2-Methylmethyl)-sulfonamide (1.2 g, 4.15 mmol) was prepared from 4-nitrocatechol according to the procedure outlined in Example 4. Then the (2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] The -2-ylmethyl)-sulfonamide was combined with 10% Pd/C in methanol (120 mL) and shaken in a hydrogen atmosphere (39 psi) for 3 hours at room temperature. The solid was filtered and washed with 10% EtOAc EtOAc. The crude product was dissolved in EtOAc (EtOAc) (EtOAc)

MS(M+H) ⁺ 260

¹ H NMR (DMSO d6): δ 10.2 (bd s, 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] -2-ylmethyl)-sulfonamide (Compound #19)

The title compound was prepared as a white solid.

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

In vivo testing of AKR/J obese mice It is well known in the art that AKR/J mice are highly susceptible to obesity due to diet. (Rossmeisl M, Rim JS, Koza RA, Kozak LP. Diabetes. 2003 Aug; 52(8): 1958-66.)

Male AKR/J mice (~20 g) (Jackson Laboratories, Bar Harbor, ME) 4-5 weeks old were housed independently in a shoe-type cage at 21 °C for 12 hours day and night. Mice were fed a high-fat diet for 8 weeks to cause obesity. Dietary composition is 45% energy for fat, 20% protein and 35% carbohydrate (Research Diets, D12451, New Brunswick, NJ).

Obese mice weighing between 35 and 46 grams were selected for the study. Mice were randomly assigned to the treatment group according to body weight at 13 weeks of age. Mice (0.2 ml at 11500-1700 hours) were orally administered with a vehicle control group (0.5% methylcellulose, pH 7.4) or vehicle containing compound #8 (300 mg/kg) once a day. The body weight and food intake of the mice were monitored every few days. On day 11, mice were anesthetized with pentamidine sodium (1 ml/kg, i.p., Sleepaway, Fort Dodge, Iowa). White adipose tissue (WAT) (post-abdominal fat) and skeletal muscle (gastrocnemius and soleus muscle) were taken out and weighed.

The data shown below is expressed as the mean and standard error values calculated using 9-10 mice per treatment group. The bilateral student t-test was used for statistical analysis. All animal studies follow the guidelines of the Institutional Animal Care and Use Committee.

After 10 days of treatment, mice treated with Compound #8 showed more weight loss than vehicle-treated mice. Weight loss was accompanied by a decrease in white adipose tissue - mice treated with Compound #8 reduced 26.6% of the ventral fat compared to vehicle treated mice, while there was no significant change in skeletal muscle mass. Thus, the ratio of fat to lean meat (white adipose tissue/skeletal muscle) of mice treated with Compound #8 was 16.8% lower than that of vehicle-treated mice (vehicle: 8.9 ± 0.4 vs Compound #8: 7.4 ± 0.5) , p<0.05). It was also observed that the mice treated with Compound #8 had reduced food intake from day 4 to day 10 relative to control animals. Compound #8 was also measured to delay gastric emptying to a statistically significant level (p < 0.05).

A comprehensive data sheet for measuring body weight, food intake, fat and muscle mass of Compound #8, vehicle-treated mice is shown in Table 4 below.

Thus, this data shows that Compound #8 is effective in promoting weight loss, wherein fat is reduced rather than muscle mass and is also effective in reducing food intake (ie, suppressing appetite).

Example 14

In-Body In-Body Test Compound #8 was suspended in 0.5% Methocel using a hand-held homogenizer to reduce particle size, and the magnetic stirrer and stirrer stage allowed the particles to remain evenly suspended during the administration period. 0.5% hydroxypropyl methylcellulose (Meduoxiu) was used as a carrier/control group.

Male AKR/J mice weighing between 35 and 46 grams were used for weight loss studies. AKR/J mice are extremely susceptible to obesity due to diet. 4-5 week old male AKR/J mice (average body weight of approximately 20 grams) (available from Jackson Laboratories, Bar Harbor, ME) were housed in a group of five cages at 21 ° C for 12 hours day and night cycle. Feeding in cages. All mice were quarantined for one week before being transferred to the animal processing room. Mice were fed a high-fat diet for 8 weeks to cause obesity. The dietary composition is 45% energy for fat, 20% protein and 35% carbohydrate (obtained from Research Diets, D12451, New Brunswick, NJ). As a non-obese control group, another group of age-competitive mice were fed a low-fat diet (available from Research Diets, D12450B, New Brunswick, NJ). Only mice that developed obesity - defined as between 35 and 46 grams of body weight - were selected for weight loss studies. Animals were first separated and fed alone for at least three days prior to drug treatment to allow for adaptation to the new environment.

The trial consisted of two separate studies: in the first study, 10 mice were given a vehicle control group of 0.5% Mido Show; 10 mice were treated with 300 mg/kg Compound #8 dissolved in vehicle; and 10 Only mice were dosed with 10 mg/kg Nome Ting (weight loss agent) dissolved in vehicle as a positive control group. In the second study, 48 mice were assigned to 4 treatment groups of 12 mice per group. The four groups were then treated with 0.5% Mondo (vehicle), 10 mg/kg Compound #8, 30 mg/kg Compound #8, and 100 mg/kg Compound #8 dissolved in vehicle.

The vehicle was orally administered with a tube (at 1500-1700 hours) once a day in a vehicle control group (0.5% Mondo, pH 7.4) or a vehicle containing Compound #8 for 10 days. The dosing volume was 5 ml per kg body weight (0.2 ml for 40 g mice). Mouse body weight and food intake were monitored periodically throughout the study. On day 11, mice were fasted for 4 hours during the photoperiod (food removed at 0600-1000 hours). An autopsy was performed 18 hours after the last dose. The mice were anesthetized with pentamibbitu sodium (1 ml/kg, intraperitoneal [ip] injection, SleepAway, Fort Dodge, Iowa), and blood was drawn by cardiac puncture using a 1 ml syringe and collected into tubes supplemented with heparin. . White adipose tissue (WAT) (posterior abdominal and inguinal fat pad), brown adipose tissue (BAT) and skeletal muscle (gastrocnemius and soleus muscle) and stomach contents were removed and weighed. Plasma samples were obtained by centrifugation of whole blood at 2000-3000 g for 10-20 minutes at 4 ° C and stored at -20 ° C for further measurement of insulin, HDL, LDL and total cholesterol and triglycerides.

After collecting two milliliters of blood by tail puncture, the blood glucose level was measured with a blood glucose meter (OneTouch UltraSmart, Lifescan, Milpitas, CA). Plasma insulin concentrations were measured using a rat/mouse insulin enzyme linked immunosorbent assay (ELISA) kit (EZRMI-13K, LINCO Research, St. Charles, Missouri). Blood samples were diluted 1:4 with charcoal-adsorbed mouse serum included in the ELISA kit. The rest of the process is in accordance with the manufacturer's instructions. Total fluorescence values were detected using an OriOn 1 microdisk luminometer (Berthold Detection Systems, Pforzheim, Germany). Plasma total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride concentrations were measured using a Bayer ADVIA 1650 blood chemistry analyzer (Bayer HealthCare LLC, Diagnostic Division, Tarrytown, NY). According to the manufacturer's manual, the cholesterol measurement system uses an enzyme method that converts cholesterol esterase and cholesterol oxidase and continues the Trinder endpoint; the scavenging/catalase method is used for HDL and LDL measurements; The enzyme method at the end of Tude is used for triglyceride measurements.

Data for the study were analyzed using standard two-sided Student t-tests and are presented in the table below as mean and standard error values. The fat/muscle ratio is calculated as follows: total weight of the groin and flank fat/muscle weight. The values listed in the table represent the mean ± SE (n = 9 ~ 10).

The average body weight of AKR/J mice before the start of the high fat diet was 21.7 ± 0.49 grams. After an eight-week high-fat diet, the mice weighed an average of 37.6 ± 0.45 grams. Mice that increased the most weight were selected for administration of Compound #8 or vehicle.

In the first study and as shown in Table 5 below, mice treated with 300 mg/kg Compound #8 exhibited significant weight loss after 10 days of dosing compared to vehicle treated mice. The weight loss effect was observed and continued after 3 days of treatment until the end of the study. Significant food intake inhibition was also observed three days after treatment with Compound #8 (compared to vehicle). In contrast, mice treated with the diet drug Nome Ting had weight loss after 3 days of treatment, but at the end of the study, the body weight showed no difference compared with the control group. Mice treated with Nome Ting saw a decrease in food intake from day 0 to day 3 but not from day 4 to day 9. All gastric contents measured at the end of the study were significantly more treated with Compound #8 (0.27 ± 0.05 g, p < 0.05) than vehicle treatment (0.16 ± 0.02 g).

table 5

After 10 days of dosing, mice treated with Compound #8 also showed - less white adipose tissue weight than vehicle. This resulted in a lower ratio of fat to muscle weight in the group of mice treated with Compound #8, as shown in Table 6 below. In Table 6 below, the ratio of fat to muscle is calculated as follows: total weight of groin and flank fat/muscle weight.

In the second dosing reaction study and as shown in Table 7 below, there was no significant (P > 0.05) weight loss or food intake inhibition in mice treated with 10, 30 and 100 mg/kg Compound #8. In this study, no tissue was collected and therefore no fat and muscle values were determined.

Example 15

As a specific specific example of the oral composition, 100 mg of Compound #8 prepared as in Example 7 was formulated with fully finely divided lactose to provide a total amount of 580 to 590 mg of the O-sized hard capsule.

While the description of the present invention is intended to be illustrative of the embodiments of the invention and the embodiments of the invention / or modification.

Claims (8)

Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating obesity, promoting weight loss or suppressing appetite, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and a C _1-4 alkyl group; a is an integer from 1 to 2; Is Wherein b is an integer from 0 to 4; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl. The use of claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and C _{1 a} group consisting of _-4 alkyl groups; a is an integer from 1 to 2; Is Wherein b is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen and C _1-4 alkyl; or a pharmaceutically acceptable salt thereof. The use of claim 2, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and C _1-4 alkyl; and R ⁴ is selected from hydrogen and methyl. a group formed; a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Dioxinyl, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(5-fluoro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(5-chloro-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] Base, 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] And, 2-(8-chloro-2,3-dihydro-benzo[1,4] Or a pharmaceutically acceptable salt thereof. The use of claim 3, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl; and R ⁴ is selected from the group consisting of hydrogen and methyl. Group; a is an integer from 1 to 2; Is selected from the group consisting of 2-{2,3-dihydro-benzo[1,4] Base, 2-(6-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-chloro-2,3-dihydro-benzo[1,4] Base, 2-(7-methyl-2,3-dihydro-benzo[1,4] Base, 2-(6-bromo-2,3-dihydro-benzo[1,4] And 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Or a pharmaceutically acceptable salt thereof. The use of the formula (1), wherein the compound of the formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1, 4] two a group consisting of -2-ylmethyl)-sulfonamide; and a pharmaceutically acceptable salt thereof. One selected from (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] The use of a compound of the group consisting of -2-ylmethyl)-sulfonamide and a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of obesity. One selected from (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] A compound of the group consisting of -2-ylmethyl)-sulfonamide and a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for promoting weight loss. One selected from (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] A compound of the group consisting of -2-ylmethyl)-sulfonamide and a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for suppressing appetite.