TWI393714B - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of depression - Google Patents

Description

Use of benzo-fused heterocyclic sulfonamide derivatives for the treatment of depression Cross-references to related applications

This application claims the benefit of U.S. Provisional Application No. 60/751,730, filed on Dec. 19, 2005, which is incorporated herein in its entirety by reference.

Field of invention

The present invention relates to the use of a benzofused heterocyclic sulfonamide derivative for the treatment of depression comprising monotherapy and synergistic therapy in combination with at least one antidepressant.

Background of the invention

Unipolar depression is defined as a daily depression that lasts for at least two weeks. Attack events can be characterized as sad, indifferent or indifferent, or sensitive and often associated with a variety of neurotrophic functions - including changes in sleep patterns, appetite or weight -, agitation or delay, fatigue, concentration and determination, dizziness, shame Feeling or guilty and thinking about death or want to die ( Harrison's Principles of Internal Medicine, 2000). The criteria for judging a depressive episode event include the appearance of five or more symptoms within the same 2 weeks, which represents a change in previous function; and at least one of the symptoms is depression or loss of interest or pleasure. Symptoms of depressive episodes include low mood; apparently loss of interest or pleasure for all or almost all activities throughout the day; non-diet diet with weight loss, or weight gain, or almost daily loss of appetite; almost daily insomnia Or lethargy; almost every day mental exercise is excited or delayed; almost daily tired or lose vitality; almost every day has a sense of worthless or too strong or inappropriate guilt; almost every day can not think, attention is not concentrated or hesitant; Death, repeated suicidal ideations without specific plans, suicidal attempts or specific plans for suicide. Moreover, these symptoms cause clinically significant distress or impairment of social, occupational or other important areas of function (Diagnostic and Statistical Manual of Mental Disorders , 4 th Edition, Text Revision, American Psychiatric Association, 2000).

Current treatment options for monopolar depression include monotherapy or combination therapy with different classes of drugs, including monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, and serotonergic adrenergic reuptake inhibition Agents, noradrenergic and specific serotonin agents, norepinephrine reuptake inhibitors, "natural products" (eg Kava-Kava, St. John's Wort), Dietary supplements (eg s-adenosylmethionine) and others. More specifically, the drugs used to treat depression include, but are not limited to, imipramine, amitriptyline, desipramine, nortriptyline, doce. Doxepin, protriptyline, trimipramine, maprotinline, amoxapine, trazodone, bupropion , chlomipramine, fluoxetine, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone ), venlafaxine, reboxetine, mirtazapine, phenyl (phenelzine), tranylcypromine and/or moclobemide (eg JMKENT, Lancet 2000 , 355, 911-918; JWWILLIAMS JR, CD.MULROW, E.CHIQUETTE, PHNOEL, C.AGUILAR , and J. CORNELL, Ann. Intern. Med. 2000 , 132 , 743-756; PJAMBROSINI, Psychiatr. Serv . 2000 , 51 , 627-633). Several such agents - including but not limited to serotonin reuptake inhibitors - are also used in the presence of depression and anxiety, such as anxiety depression (RBLYDIARD and O. BRAWMAN-MINTZER, J. Clin. Psychiatry 1998 , 59). , Suppl. 18 , 10-17; F. ROUILLON, Eur. Neuropsychopharmacol. 1999 , 9 Suppl . 3, S87-S92).

Clinically, 40-50% of depression patients who initially received antidepressant therapy did not feel that the symptoms of depression were relieved at the right time. This group is typical of refractory depression, that is, there is no "appropriate" response to "appropriate" treatment trials (ie sufficient duration of treatment) (RMBERMAN, M.NARASIMHAN, and DSCHARNEY, Depress.Anxiety 1997 , 5, 154-164). Furthermore, approximately 20-30% of patients with depression have partial or complete resistance to drug therapy, including combined therapy-residues (J. ANANTH, Psychother. Psychosom . 1998 , 67, 61-70; RJCADIEUX, Am. Fam. Physician 1998 , 58, 2059-2062). Gradually, the treatment of drug-resistant depression includes an intensive strategy that includes treatment with agents such as lithium, carbamazepine, and triiodothyronine and the like (M.HATZINGER and E.HOLSBOER-TRACHSLER, Wien .Med.Wochenschr. 1999 , 149, 511-514; CBNEMEROFF, Depress.Anxiety 1996-1997 , 4, 169-181; TAKETTER, RMPOST, PIPAREKH and K. WORTHINGTON, J. Clin. Psychiatry 1995 , 56 , 471-475 ;RTJOFFE, W. SINGER, AJLEVITT, C. MACDONALD, Arch. Gen. Psychiatry 1993 , 50, 397-393).

Mild depression is defined as an affective disorder characterized by chronic low mood for at least 2 years. Dysthymic disorder may have persistent or intermittent course, almost all day depressed, the number of days depressed the number of days depressed than non-emotional and more and for a period of at least 2 (Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition years, American Psychiatric Association, 1994 ).

On the other hand, a bipolar disorder is characterized by an unpredictable sway between emotions between mania and depression (type I bipolar disorder) or between manic and depression (type II bipolar disorder) ( Diagnostic and Statistical Manual) ^{of Mental Disorders, 4 th Edition,} American Psychiatric Association, 1994). Bipolar disorders are often deliberately limiting the use of antidepressants to avoid the risk of mania in bipolar conditions and the risk of rapid cycling in antidepressants (HJMOLLER and H.GRUNZE, Eur.Arch.Psychiatry Clin.Neurosci. 2000, 250 57-68; JRCALABRESE, DJRAPPORT, SEKIMMEL, and MDSHELTON, Eur. Neuropsychopharmacol. 1999 , 9, S109-S112). Furthermore, mood stabilizers for bipolar disorders have not been shown to have antidepressant effects (HJMOLLER and H. GRUNZE, Eur. Arch. Psychiatry Clin. Neurosci. 2000 , 250 , 57-68).

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

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 depression

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 depression

The invention further relates to a method of treating depression comprising administering to a subject in need thereof a therapeutically effective amount of at least one antidepressant and a compound of formula (I) or formula (II) as defined herein By.

Illustrating the invention is the treatment of severe depression, unipolar depression, refractory depression, drug-resistant depression, anxiety depression or mild depression, comprising administering a therapeutically effective amount of any of the above compounds or pharmaceutical compositions. Subjects in need of it.

In another embodiment, the invention relates to the treatment of treatment for severe depression, unipolar depression, refractory depression, drug-resistant depression, anxiety depression or mild depression, comprising at least one antidepressant together with Any of the above compounds or pharmaceutical compositions are administered to a subject in need thereof.

Detailed description of the 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 depression

among them , a, R ¹ , R ² and R ⁴ are as defined in the present application. The invention further relates to the treatment of depression comprising administering a therapeutically effective amount of a compound of formula (I) or formula (II), together with at least one antidepressant, to a subject in need thereof.

As used in this case, the term "depression" is defined as including severe depression (including single episodes and recurrence), unipolar depression, refractory depression, drug-induced depression, anxiety-induced depression, and mild depression ( Also known as dysthymic disorder. In addition, the term "depression" covers any episodes of depression, low-grade emotional disorders, medical conditions-induced depression, emotional disorders induced by medical conditions and similar to severe depressive episodes, and substance-induced disorders. the phenomenon of depression and mood disorders as well as his office did not specify the depressive disorders, such Department ^{of Mental disorders, 4 th Edition,} Text Revision, American Psychiatric Association, 2000 in the diagnostic criteria defined by the column in the diagnostic and Statistical Manual . Preferably, the depression is severe depression, unipolar depression, refractory depression, drug-resistant depression or anxiety-type depression. More preferably, the depression is a severe depression.

In the case of this case, the term "antidepressant" means any agent for the treatment of depression, unless otherwise specified. Suitable examples include, but are not limited to, monoamine oxidase inhibitors such as phenylethyl (phenelzine), tranylcypromine, moclobemide and the like; tricyclics such as imipramine, amitriptyline, desipramine ), nortriptyline, doxepin, protriptyline, trimipiramine, chlomipramine, amoxapine and the like Tetracyclics such as maprotin and analogs; acyclics such as nomifensine and the like; triazolopyridines such as trazodone and the like; Serotonin reuptake inhibitors, such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, and the like; serotonin receptors Antagonists, such as nefazadone and analogs; serotonin adrenergic reuptake inhibitors such as venlafaxine, milnacipran and analogs; norepinephrine Excitatory and specific serotonin agents, such as rice guanidine (mi) Rtazapine) and analogs; norepinephrine reuptake inhibitors, such as reboxetine and analogs; atypical antidepressants such as bupropion and analogs; natural products such as kalphape, St. John Grasses and analogues; dietary supplements such as s-adenosylmethionine and analogs; neuropeptides such as gonadotropin and analogues and analogs; compounds that target neuropeptide receptors, such as neurohormones Receptor antagonists and analogs; and hormones such as triiodothyronine and the like. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline.

Those skilled in the art can easily refer to appropriate references (eg, drug use instructions, FDA guidelines, Physician's Desk Reference, and the like) to easily determine known and/or marketed antidepressants and antipsychotics. Suggested dose level.

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 relates to a synergistic therapy or combination therapy comprising administering one or more compounds of formula (I) or formula (II) and one or more antidepressants, "therapeutically effective amount" means The combined amount of the agents taken together causes the combined effect to cause 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 antidepressant would be a therapeutically effective combined effect when administered together or sequentially (I) Or the amount of the compound of formula (II) and the amount of antidepressant. 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 the amount of antidepressant may be therapeutically effective individually. Or maybe the treatment is invalid.

As used in this case, the terms "synergistic therapy" and "combination therapy" refer to the need to treat one or more compounds of formula (I) or formula (II) with one or more antidepressants. a subject, wherein the compound(s) of formula (I) or formula (II) and the antidepressant agent(s) are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. . When the compound of formula (I) or formula (II) and the antidepressant(s) 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 antidepressant(s) can be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (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(s) of formula (I) or formula (II) and the antidepressant(s) may be administered in divided or single form in parallel at the same or different times during the course of treatment according to simultaneous or alternating regimens.

A specific embodiment of the invention is a treatment for depression comprising one or more compounds of formula (I) or formula (II) and one or more compounds selected from the group consisting of monoamine oxidase inhibitors , such as phenyl b , tranylcypromine, moclobemide and the like; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipa Ming, clomipramine, isopentampin and analogs; tetracyclics such as maprotiline and analogs; acyclics such as nomifensine and analogues; triazole pyridines such as trazodone And analogs; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, escitalopram oxalate and analogues; serotonin Body antagonists, such as nefazodone and analogs; serotonin adrenergic reuptake inhibitors such as venlafaxine, milnacipran, duloxetine and the like; norepinephrine Excitatory and specific serotonin agents, such as imipenem and analogs; norepinephrine reuptake inhibitors, such as reboxetine and analogs; atypical antidepressants such as bupropion and analogs; Natural products such as Kappa, St. John's Wort and the like; dietary supplements such as s-gland Methionine and analogs; and neuropeptides, such as gonadotropins and analogs and analogs; compounds that target neuropeptide receptors, such as neurohormone receptor antagonists and analogs; and hormones, such as three Iodine thymidine and its analogues.

A specific embodiment of the invention is a treatment for depression comprising one or more compounds of formula (I) or formula (II) and one or more compounds selected from the group consisting of monoamine oxidase inhibitors ; tricyclics; tetracyclics; acyclics; triazole pyridines; serotonin reuptake inhibitors; serotonin receptor antagonists; serotonin adrenergic reuptake inhibitors; serotonin norepinephrine Reuptake inhibitors; noradrenergic and specific serotonin agents; norepinephrine reuptake inhibitors; atypical antidepressants; natural products; dietary supplements; neuropeptides; targeted neuropeptide receptors a compound; and a hormone.

Preferably, one or more compounds of formula (I) or formula (II) are administered in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclics, serotonin Reuptake inhibitors, serotonin adrenergic reuptake inhibitors; noradrenergic and specific serotonin agents and atypical antidepressants.

More preferably, one or more compounds of formula (I) or formula (II) are combined with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclics and serotonin reuptake inhibitors. Cast.

Most preferably, one or more compounds of formula (I) or formula (II) are administered in combination with one or more compounds selected from the group consisting of serotonin reuptake inhibitors.

A specific embodiment of the invention is a treatment for depression comprising one or more compounds of formula (I) or formula (II) and one or more compounds selected from the group consisting of: phenyl , tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, different Penserpine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, duloxetine, imipenem, bupropion, thyroid Sustainer and triiodothyronine.

Preferably, one or more compounds of formula (I) or formula (II) are combined with one or more compounds selected from the group consisting of: phenylethyl , tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, different Penserpine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, imipenem and bupropion.

More preferably, one or more compounds of formula (I) or formula (II) are combined with one or more compounds selected from the group consisting of: phenylethyl , tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, different Penserpine, fluoxetine, sertraline, paroxetine, citalopram, dextroamphetamine and fluvoxamine.

Most preferably, one or more compounds of formula (I) or formula (II) are administered in combination with one or more compounds selected from the group consisting of fluoxetine, sertraline, and paroxetine. , citalopram and fluvoxamine.

A specific embodiment of the invention is a treatment for depression comprising one or more compounds of formula (I) or formula (II) and one or more compounds selected from the group consisting of neuropeptides, For example, thyroid stimulating hormone and analogs; compounds that target neuropeptide receptors, such as neurohormone receptor antagonists and analogs; and hormones such as triiodothyronine and the like.

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] Base), 2-(benzo[1,3] Zozolyl), 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-( Mercapto), 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] Azyl), 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] Azolyl).

In another specific example of the present invention, From the group consisting of: 2-(benzo[1,3] Azyl), 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 stereocenter.

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, pyridine or the like. The reaction with a suitably substituted compound of the formula (XI) (a conventional compound or a compound prepared by a conventional method) is carried out in the presence of a compound of the 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 naphthalene 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. The solid oral preparation may also be coated with, for example, a saccharide or 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, - for example, other ingredients which increase solubility or preservative properties. 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 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 ingot, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, and phosphoric acid. Calcium or gum 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 for 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, polyethylene Carbofuran 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 gums (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 gums, 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 200 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 lozenge form of the ingredient is used to adjust the dosage according to the symptoms of the patient to be treated. An effective amount of the drug is usually supplied at a dosage level of from about 0.01 mg/kg to about 200 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, and 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 dried over MgSO ₄ and concentrated to. Chromatography (2% diethyl ether in hexanes) afforded 3-methylene-3,4-dihydro-2H-benzo[b][1,4] 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-Methylene-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). Dried over MgSO ₄ the organic solutions combined. The solution was concentrated in vacuo and purified by chromatography (2% to EtOAc EtOAc) 4] two Ind-3-yl)methyl)amine.

MS (ESI): 180.1 (M+H ⁺ ) ^: NMR (m.m.) , 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 The alkane (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 The alkane (100 mL) was combined and refluxed for 2 h. 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 a 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 Zin-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 dried of MgSO _4, and concentrated to a brown solid, and chromatographed (2% ethyl acetate in hexanes) as a colorless oil generates Benzo [1,3] Methyl azole-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 oxazol-2-carboxylate (7.21 g, 40.0 mmol) was added with ammonium hydroxide (29% in water, 10 mL) and acetonitrile (~5 mL). The solution was stirred at room temperature for two hours and then distilled water was added. Benzo[1,3] The oxazolidine-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: 7.79 (s, wide, 1H), 7.72 (s, wide, 1H), 6.94 (m, 2H) 6.86 ( m, 2H), 6.30 (s, 1H).

Benzo[1,3] The oxazol-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 was dried of MgSO _4. The solvent was evaporated to dryness to give C-benzo[1,3] Zin-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] Zin-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3.74 g, 38.9 mmol) in anhydrous The alkane (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 ( broad web, 1H), 4.62 (wide format, 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) , which produced a 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), washed once with brine, dried (MgS04 ₄₎ and evaporated to dryness in vacuo to give a white solid which is flash tube Column chromatography purification (Hept: EA-2:1) gave a white solid toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4] -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, and then allowed to air dry to give a white powdery solid (2S)-2-(2,3-dihydro-benzo[ 1,4] two -2-ylmethyl)-isoindole-1,3-dione.

The pulverulent white solid was combined with EtOAc (EtOAc: 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, the dehydration DCM (NaSO ₄₎ and concentrated in vacuo to yield an oil of (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 crystals crystals crystals.

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 to brine, dried (MgSO ₄₎ and concentrated to yield an oil in vacuo. The oil was purified by flash column chromatography (ethyl acetate: heptane - 1:1) to afford a white solid. Title compound.

Mp 76-78 ° C MS 273 (MH ⁺ ) Elemental analysis: 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). 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 an 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 combined was taken up in EtOAc (15 mL). The residue was purified by flash column chromatography eluting elut elut elut elut elut

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 was dried and concentrated in vacuo to give a 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 The combined organics were combined with EtOAc (EtOAc)EtOAc. The product was purified by flash column chromatography eluting 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). DCM was rinsed with brine once, dried (Na ₂ SO4) and concentrated in vacuo to produce an oil, 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 with EtOAc (EtOAc)EtOAc. The oil was purified by flash column chromatography using DCM/MeOH-10:1 to yield (2S)-(-)-N-(7-chloro-2,3-dihydro-benzo) as a white solid. [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

Indole-2-ylmethylsulfonamide (Compound #10)

Make Indole-2-carboxylic acid (4.5 g, 25 mmol) 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 decanted, dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield the amine as an oil C- Ind-2-yl-methylamine.

An oily amine (1.63 g, 10 mmol) with sulfonamide (1.92 g, 20 mmol) in two The mixture was combined and refluxed for 2 hours in hexanes (50 mL). The solution was cooled and concentrated in vacuo to give crystals crystals eluted eluting The solid was recrystallized from ethyl acetate / hexanes to yield of <RTIgt;

Mp 100-101 ° C MS 241 (M ^-1 ) Elemental analysis: C, 49.57; H, 5.82; N, 11.56; S, 13.23 Analysis found: C, 49.57; H, 5.80; N, 11.75; 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, then washed twice with salt water, dried (Na ₂ SO ₄₎ and concentrated in vacuo to a white solid of methyl 2-cyano - (2,3-dihydro-benzo [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 to brine, dried (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.

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, washed twice in saline, dried (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, washed twice with brine, dried (MgSO ₄₎ and in 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) were combined in DMF (75 mL) and heated to reflux for 1 hour, cooled At room temperature, pour into vigorously stirred water (0.5 liters) and stir for 30 minutes. The white solid was filtered off, and the solid was washed with water, 2% NaOH and then with water, and then allowed to air dry to give (2S)-2-(6,7-dichloro-2) as a white powdery solid. ,3-dihydro-benzo[1,4] -2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%).

The powdery white solid was combined with EtOAc (EtOAc m. 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 dried (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 (MeOHMeOHMeOHMeOHMeOHMeOH The title compound of the solid.

MS[M-H] ^- 311.0 mp 119-121 ° C [α] _D = -53.4 ^O (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)-sulphonamide was combined with 10% Pd/C in methanol (120 mL) and shaken in a hydrogen atmosphere (39 psi) at room temperature for 3 hours. 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: 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

Rat Dominance-Compliance (DSR) In Vivo Test The DSR test is divided into two modes: Mania-dominated Behavioral Reduction Model (RDBM) and Depressive Obedience Reduction Model (RSBM). RDBM - in which the dominant animal is treated with a test compound - predicts the ability of the test compound to treat mania. RSBM - in which compliant animals are treated with test compounds - predicts the ability of test compounds to treat depression.

Male SD rats (140 to 160 grams) purchased from Charles River Laboratories Wilmington, MA were used in this assay. Rat delivery was received two weeks apart. Each batch of rats was subjected to five days of isolation, one week of acclimation, and one week of selection, followed by five weeks of drug or vehicle treatment of the selected pairs of rats.

Four rats were housed per cage. After the test from Monday to Thursday, food intake was limited to one hour per day. After the Friday test, the rats were given free access to food until they were fasted again on Sunday. Rats can drink water at any time. The use of the fasting period had little effect on weight gain, and the average body weight of the rats at the end of the study was approximately 300 grams. At the end of the experiment, the rats were sacrificed by decapitation, and the trunk blood and brain were collected for in-vitro experiments and drug concentration measurements.

The basic test device consists of two compartments connected by a tunnel that is only allowed to pass one rat at a time. On the floor at the midpoint of the tunnel is a container of sweet milk. This basic device was copied so that all four pairs of rats could be tracked simultaneously with video. The camera can distinguish between rats marked in different colors. Thus, the head of the rat was colored for video tracking, one cage was red and the other cage was yellow. Only one animal can access the feed bin at a time, but both animals can drink milk for five minutes a day. During the five minute period of each day, the video tracking software was used to record the time spent by each rat in the feed bin area and stored as a text file.

Rats were randomly divided into pairs to start the test. Each member of the pair is placed in the opposite compartment of the test device. Record the time each animal spent in the feed bin area. Animals are familiar with the new environment during the first week (five days) of the test. If all three criteria are met, the dominance is assigned to the animal with the highest score in the second week of the test. First, there must be a significant difference between the average daily drinking scores of the two animals (two-sided t-test, P < 0.05). Second, dominating animals must score at least 25% more than compliant animals. Finally, there is no "reversal" in the pairing week (in the case of separation, the putative compliance rat scores more than its dominant partner). Ideally, there is also minimal reversal during adaptation to the environment. Approximately 25 to 33 percent of the initial animal pairs meet these criteria and only those pairs continue to be used in the study.

After the experiment, the terminal blood sample (0.5-1.0 ml) was collected into a tube to which heparin was added. The blood samples were centrifuged to remove the cells, and then 200 microliters of the plasma supernatant was transferred to a clean vial, placed on dry ice, and stored in a freezer at -80 °C prior to analysis. Two hundred microliters of acetonitrile containing internal standards were added to 100 microliters of plasma or brain tissue to precipitate protein and/or tissue debris. The sample was centrifuged and the supernatant was removed for analysis by liquid chromatography-triple quadrupole mass spectrometer (LC-MS-MS). Calibration standards were prepared by adding an appropriate volume of stock solution directly to blank plasma or brain tissue homogenate and treating it in the same manner as the collected sample. Calibration standards were prepared from 0.01 to 10 microliters for quantification. LC-ESI-MS/MS (negative mode) analysis was performed using multiple reaction monitoring mode (MRM) to detect characteristic ions of test compounds.

Significant differences in time spent between dominating rats and compliant rats in the feed bin were performed using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA) by ANOVA and subsequent two-sided t-test (P < 0.05). Decide. The comparison of the treatment groups was performed using the normalized dominance level values of the pairs of matched animals. The dominance level is a measure of the social relationship between paired subjects. Dominant level (DL) = FTD-FTS, where FTD is the feed bin time of the dominant rat and FTS is the feed bin time of the compliant rat. The normalization system is implemented according to the following formula: Dominance level (nth week, expressed in %) = (dominant level (nth week)) / (dominant level (week 2)

Statistics of dominance level differences between the control group (paired rats treated with vehicle in both dominant animals and compliant animals) and the treatment group (constrained rats treated with drugs and the dominant rats were treated with vehicle) Significance was determined by ANOVA followed by t-test. The 50% response activity onset value (AOT-50) and the minimum and maximum response to the drug were based on a reduction in the dominance level using nonlinear regression analysis (GraphPad Software, Inc., San Diego, CA). Calculation. The normalized DL value is used for this calculation, where the DL value of the processing week is normalized to the percentage of the second week (pre-processed) value of the pair according to the above formula. Among these background values, the reaction minimum (DL) determines the positive activity of the drug, which corresponds to efficacy, because if the reaction to the drug is positive, the DL value is always reduced. In the case of a negative reaction to the drug (symptoms worsening), the DL value increases. If the drug does not have this type of activity, the maximum value of the reaction does not exceed 100%. Any maximum DL value that is significantly higher than the control value (about 100%) indicates the negative activity of the drug.

Compound #8 was assessed in a rat model of compliance with depressive behavior reduction (RSBM) (Malatynska, E., Rapp, R., Harrawood, D., and Tunnicliff, G., Neuroscience and Biobehaviora1 Review , 82 (2005) SOB-SIS; Malatyn Ska, E., and Knapp, RJ, Neuroscience and Biobehavioral Review , 29 (2005) 715-737).

More specifically, Compound #8 is 2.5 mg/kg (n=8), 12 mg/kg (n=12), 60 mg/kg (n=12) and 120 mg/kg (n=7) a day. One-time po (oral) administration of compliant rats for five weeks, while the dominant partner was given a vehicle (0.5% aqueous solution of methylcellulose). As a control group, additional groups of rats were treated with 10.0 mg/kg fluoxetine i.p. (n=10) and 30.0 mg/kg venlafaxine i.p. (n=6). All treatments were administered approximately 1 hour prior to testing. Compound #8 was observed to reduce compliance in a dose-dependent manner.

Significant differences between dominating rats and compliant rats were lost after the first week of treatment when the compliant animals were treated with Compound #8. This is true for all doses used, indicating that the onset of activity is independent of the amount administered. In contrast, when the compliant animals were treated with fluoxetine, significant differences between dominating rats and compliant rats were lost after the third week of treatment. (This data analysis method does not consider behavioral fluctuations that occur in the control group). To compare the effects of different drugs and administration, the data was normalized to the value of the initial control week.

The level of dominance (DL) of the compliant rat group treated with 2.5 mg/kg of Compound #8 was not significantly different from the control group. However, the group treated with 12.0 mg/kg Compound #8 showed significantly different DL values from the vehicle-treated control group after the second, fourth, and fifth weeks of treatment. Similarly, the group treated with 60 mg/kg Compound #8 showed a significantly different DL value relative to the vehicle, starting from the first week and continuing until 5 weeks of treatment. At the highest dose of Compound #8 (120 mg/kg), the DL value was significantly different from the control group after the first week, however, this significance disappeared after the second week of treatment.

Animals treated with fluoxetine (10 mg/kg) consistently showed increased compliance during the first week of treatment. This effect was not observed in the group treated with Compound #8 compared to animals treated with fluoxetine (10 mg/kg). For the 60.0 mg/kg administration of Compound #8, the difference in DL values from the group treated with fluoxetine had p < 0.001 after the first week and a statistical significance of p < 0.05 after the second week of treatment. . The normalized DL level of the pair treated with fluoxetine and compound #8 did not differ significantly between subsequent treatment cycles.

To estimate the activity onset time, the daily mean of the dominance and the feed bin time of the compliant animal pair was plotted and a significant difference between the two groups was calculated using a two-sided t-test. The first day of statistically significant loss of coincidence occurred on day 6 after treatment with 12.0 mg/kg of compound #8 and on day 4 after treatment with 60 mg/kg. There was no consistent loss of significance between the dominating rats treated with 2.5 mg/kg and 120.0 mg/kg Compound #8 and the compliant rat feed bin time.

To compare the activity onset time between treatments, the activity onset was estimated using a non-linear regression fit. The normalized daily DL values for each drug and administration were matched in a non-linear regression model. The 50% effect of the active start time (AOT ₅₀ ) and the compound #8 at 2.5 mg / kg, 12 mg / kg and 60 mg / kg Emax were 2.1; 5.3 and 1.6 days and the dose was not significant s difference. The maximum effect obtained in this analysis was 52.4 ± 32.7% (SEM), 87.9 ± 42.6% (SEM) and 116.9 ± 29.5% (SEM) for 2.5 mg/kg, 12 mg/kg and 60 mg/kg, respectively. And there is no significant difference between these administrations.

In summary, the effect of Compound #8 in the RSBM trial was dose-dependent, with an calculated ED ₅₀ of 6.6 ± 0.8 mg/kg [CI = 3.0-10.2] and an E _max of 131.4 ± 4.7% [CI = 111.3-151.5 ].

In this test, Compound #8 reduced compliance, indicating that the compound has antidepressant activity.

Example 14

Rat tail suspension test (acute) In the tail suspension test (TST) for assessing compound antidepressant activity, the mouse tail was suspended from a metal or plastic rod using a clip or scotch tape. The test is usually very brief, 5-7 minutes, and the amount of time the mouse is stationary is recorded manually or by automated means. In this test, an agent with antidepressant activity reduces the duration of immobility in the mouse.

The basic device for the tail suspension test consisted of a yellow plastic compartment (91 x 45 x 10 cm) divided into four active spaces separated by 25, 20, 20 and 25 cm wide and separated by a 0.75 cm thick yellow plastic wall. The mouse tail was suspended using a rubber clip (7 cm long) attached to a plastic rod placed at the top of the test chamber through its depth direction. Each experimental section was recorded by video and analyzed immediately by computer software ("Depression Scan" Clever Sys Inc.) for four animals. The computer's judgment of standing still was corrected using animals administered with lorazepam, and the computer's judgment of activity was corrected using animals treated with high doses of desipramine. Controls (carrier-treated animals) and animals treated with Compound #8 were analyzed under these calibration settings. The settings were adjusted for dark mice (CH3/HeJ and C57BI/6J strains) and white mice (Balb/cJ and A/J strains). The yellow background was used for dark mice and the blue background was used to record the activity of white mice.

The ability of a test compound to reduce static immobility duration or increase activity is measured using the TST procedure described above. Acute treatment with a clinically effective antidepressant and/or a novel compound that may have antidepressant properties in TST reduces the duration of restlessness while increasing mobility.

Data were analyzed using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA). To compare the effects of different doses of various drugs in TST on immobility, single factor analysis of variance (ANOVA) was used followed by Dunnett's multiple comparation test. The ED ₅₀ and E _max values of DMI, VLX, DLX and Compound #8 were calculated using a non-linear regression analysis using a single-phase exponential decay equation as a curve fit. ED ₅₀ and E _max values based two factor ANOVA with post test Bancroft (Bonferroni post-hoc test) comparison.

Evaluation CH ₃ / HeJ mice of different antidepressants and Compound # 8 in a dose - dependence of the reaction. Compound #8 was suspended in 0.5% methylcellulose. The positive control group included duloxetine (DLX), venlafaxine (VLX) and desipramine (DMI) (these are dissolved in 0.5% methylcellulose) and lorazepam (LOR) (which Ultrasonic oscillations were suspended in 0.5% methylcellulose dissolved in water). All drugs and carriers were administered orally (po) in a volume of 10 ml/kg.

Mice aged 5 weeks were ordered and the mice weighed 20 ± 5 grams at the start of the experiment. Animals were housed in plastic cages in groups of four, ambient temperature 21 ° C to 23 ° C, automated 12/12 hour day/night cycle and unlimited access to water and commercially available rodent food.

This component was tested in eight experiments to test the effects of different doses of Compound #8, positive control (DMI, VLX, DLX) and 5 mg/kg negative control (LOR). Each experiment included seven treatment groups of 4 animals per group. A total of 28 animals were used for each experiment. Every two consecutive experiments (1 & 2, 3 & 4, 5 & 6 and 7 & 8) are complete replication experiments with each other. This resulted in a total of eight animals per treatment group at the end of the study. A treatment group with four animals in each experiment was the vehicle treatment group. In addition to the vehicle treatment group, the effects of DMI (6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg and 120 mg/kg) and LOR (5 mg/kg) were tested in experiments 1 and 2 . Experiments 3 and 4 tested the effects of Compound #8 (6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg and 240 mg/kg). Experiments 5 and 6 tested the effects of DLX (6 mg/kg, 12 mg/kg, 3O mg/kg, 60 mg/kg, 120 mg/kg) and LOR (5 mg/kg). Experiments 7 and 8 tested the effects of VLX (6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg) and LOR (5 mg/kg). During the study, one mouse in the compound #812 mg/kg treatment group died due to omission administration, so this group included seven animals at the end of the study.

Compound #8 and all tested antidepressants reduced resting time and increased activity time during the 7-minute test session of CH3/HeJ mice. Compound #8 effect was statistically significant at 12 mg/kg, 60 mg/kg, and 120 mg/kg. The significance line was determined by comparison with the vehicle-treated parallel control group.

The DMI effect was statistically significant at 12, 30, 60 and 120 mg/kg. The VLX effect was statistically significant at 6, 12, 30, 60 and 120 mg/kg. The DLX effect was statistically significant at 60 and 120 mg/kg.

The ED ₅₀ and E _max values were calculated from these results by nonlinear regression analysis. The ED ₅₀ and E _max values are summarized in Table 5 below. There was no statistical significance for the ED ₅₀ values calculated for each treatment stationary and activity. Compound 8 # ED ₅₀ values significantly lower than the value of ED DLX _50, but with the value of ED DMI and VLX ₅₀ is not different. There was no significant difference in E _max values calculated for stationary and activity in Compound #8, but all tested antidepressants were significantly different. The resting E _max value of Compound #8 was also significantly lower than the value of the antidepressant.

In summary, the studies illustrated in this example show that Compound #8 has anti-depressant activity as a tail suspension measurement test. In our study conditions, Compound # ED 8 to ₅₀ was calculated to be 3.6 ± 2.9 mg / kg and the E _max calculated as 22.2 ± 6.1%.

Example 15

The Forced Swimming Test (Acute) Forced Swimming Test (FST) is a common procedure for screening for possible antidepressant properties of a compound. This test is also known as a behavioral despair test. Rodents placed in ordinary water-filled sinks exhibit a variety of escape or stationary behavior. Different types of antidepressants significantly increase escape behavior and/or reduce the latency or duration of restlessness. Since these effects are characteristic of clinically active antidepressants, compounds exhibiting such effects with unknown clinical activity are interpreted as having the potential to treat human mood disorders.

Compound #8 and maprotyline were dissolved in 10% polyethylene glycol stearate (Solutol). Venlafaxine and desipramine are dissolved in water. All drugs and their carriers were administered orally (p.o.) in a volume of 5 ml/kg.

Male SD rats (140 to 160 grams) purchased from Charles River Laboratories Wilmington, MA were used. Animals were subjected to a five-day isolation period prior to the experimental procedure.

Animals were housed in plastic cages in groups of four, ambient temperature 21 ° C to 23 ° C, automated 12/12 hour day/night cycle and unlimited access to water and commercially available rodent food. Except for routine replacement of litter, animals are not moved before the pre-test swimming section.

The study was divided into six experiments to test the effects of different doses of Compound #8, three positive control groups (desipramine, metoprine, venlafaxine) and one negative control group (Lolacitin). Each experiment included seven treatment groups of 4 animals per group. A total of 28 animals were used for each experiment. Two consecutive experiments (1 and 2, 3 and 4 and 5 and 6) were complete replication experiments with each other. This resulted in a total of eight animals per treatment group at the end of the study. A treatment group of four animals in each experiment was a vehicle treatment group. In addition to the vehicle treatment group, the effects of desipramine (3 mg/kg, 6 mg/kg, 12 mg/kg, 30 mg/kg and 60 mg/kg) and lorazepam (1 mg/kg) were Experiments 1 and 2 were tested. Experiments 3 and 4 tested the effects of Compound #8 (3 mg/kg, 6 mg/kg, 12 mg/kg, 30 mg/kg, 60 mg/kg and 120 mg/kg). Experiments 5 and 6 tested the effects of venlafaxine and maprotiline (12 mg/kg, 30 mg/kg and 60 mg/kg). During the study, one mouse in the desipramine 12 mg/kg treatment group died as a result of omission, so this group included seven animals at the end of the study.

The basic unit consists of a cylinder (46 cm high x 20 cm diameter) with a water depth of 30 cm and a temperature of 25 ± 1 °C. Experiment with the automated version of FST. The tubing used to automatically fill and empty the water connects the four cylinders. The cylindrical system was placed in a 25 cm wide compartment to visually separate the animals. Each 5-minute experimental section was recorded by video and analyzed in real time by computer software (Clever Systems, Inc.) for four animals. Use this software to record the time of standing still, swimming, climbing and escape. The four activity lines are defined as follows. Static: The animal floats still or acts only as necessary to keep its head on the water; climbing: the animal is moving vertically and vertically against the wall of the cylinder; swimming: the animal keeps its head with more than The degree necessary on the water surface moves horizontally back and forth in the cylinder; and escape: the sum of all intense active actions.

The ability of a test compound to reduce the duration or frequency of immobility or to change the time of swimming, climbing and escape is measured using the FST procedure described above. When administered between the pre-test segment and the test segment, clinically effective antidepressants and/or novel compounds with potential antidepressant properties reduce the duration or frequency of immobility in the FST. The results of this study described are focused on the stationary time during the 5-minute test session.

There are two swimming sections in each experiment. First, a 15-minute pre-test swim section was performed. The next 48 hours is a test session that lasts 5 minutes. Immediately after the swimming section is completed, place each animal under a heat lamp in a soft padded cage for approximately 15 minutes to avoid hypothermia.

The animal is pretreated with the vehicle or test compound shortly after completion of the pretest swimming section, 24 hours later and later in the 5 minute test section; that is, in two swimming sections occurring on 3 consecutive days Three injections were given to each animal. The time before the test section was 1 hour in the case of in situ simvamin, meptintin, venlafaxine, and lorazepam or 4 hours in the case of compound #8; in the maximum shock attack (MES) test Maximum effect time.

Data were analyzed using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA). To compare the effect of different doses of various drugs in the FST on immobility, single factor ANOVA was used followed by Down's multiple comparison test. The ED ₅₀ and E _max values of desipramine and Compound #8 were calculated using a non-linear regression analysis using a single-phase exponential decay formula as a curve fit. Using two-sided statistical t- test ₅₀ and the ratio of E _max value of ED.

All tested antidepressants reduced the resting time during the 5 minute test session. The desipramine effect was statistically significant at 6 mg/kg, 12 mg/kg, 30 mg/kg, and 60 mg/kg. The ED ₅₀ calculated by desipramine was 2.0 ± 0.1 mg / kg (CI = 1.3 - 3.3 mg / kg) and its E _max was 50.0 ± 8.4 seconds (CI = 31.8-57.7). The treatment effect of Compound #8 was statistically significant at 12 mg/kg, 60 mg/kg, and 120 mg/kg as compared to the vehicle-treated control group. The great variability between individual rats resulted in a no significant difference between the effect of Compound #8 at 30 mg/kg dose and the control group. Therefore, the static immobility data for the 30 mg/kg dose is not used in the ED ₅₀ calculation. The calculated ED ₅₀ for Compound #8 was 5.6 ± 0.6 mg/kg (CI = 2.2-15.6 mg/kg) and its E _max was 67.0 ± 11.6 seconds (CI = 30.3 - 103.8). ED ₅₀ value of the compound 8 # ED ₅₀ values significantly different from desipramine, p <0.001 (two-sided t- test). There was no statistically significant difference in the _Emax values of desipramine and Compound #8. Venlafaxine and meptintin (positive control group) were tested at three doses of 12 mg/kg, 30 mg/kg and 60 mg/kg. For both venlafaxine and maprotiline, the immobility of animals treated at doses of 30 mg/kg and 60 mg/kg was significantly different from the vehicle-treated control group. However, the data points are insufficient, so the ED _{50 of} the two drugs cannot be calculated. Lorazepam (negative control group) was tested at 1 mg/kg and showed no significant effect on the resting time of the rats during the test period. The results indicate that Compound #8 has an anti-depressant activity in the FST.

Example 16 Chronic Moderate Pressure Mode (Chronic)

In chronic mild stress (CMS) mode, rats exposed to a variety of mild stressors for a long time - in other behavioral, biochemical, and physiological lesions - are significantly less responsive to reward stimuli. This deficiency is usually monitored as a 1% reduction in sucrose solution consumption, but can also be viewed in other tests, such as position preference constraints or self-intracranial shocks. Since the secondary sensitivity to rewards seems to reflect a lack of pleasure (not feeling pleasure) - it is a core symptom of severe depression, the CMS program can be used as a suitable research tool in the study of antidepressant mechanisms.

Male Wistar rats were brought to the laboratory two months before the start of the experiment. Except as described below, the animals were housed separately and were free to access food and water and maintained at 12 hours day/night and fixed temperature (22 ± 2 ° C) and humidity (50 ± 5%).

The animals were first trained to consume 1% sucrose solution; the training consisted of eight 1-hour baseline tests in which sucrose was administered to the living cage, followed by 14 hours of food ban; sucrose intake was pre-weighed by the scale at the end of the test. The weight of the bottle containing the sucrose solution is measured. Thereafter, the consumption of sucrose was monitored throughout the experiment in a weekly interval under similar conditions.

Animals were divided into two proportional groups based on their sucrose uptake in the final test baseline. A chronic mild stress program for 7 weeks was applied to a group of animals. The weekly stress program includes: two fast or water-free periods, two 45-degree cage tilt periods, two intermittent illuminations (turning lights on or off every 2 hours), and two dirty cage periods (plus 250) ML water to sawdust litter), a pair of feeding period, two low-intensity stroboscopic lighting (150 flashes per minute) and three periods of no stress. All pressure sources were applied for 10-14 hours and were applied individually and continuously day and night. Control animals were housed in separate spaces and were not exposed to stressed animals. Before each sucrose test, the control animals were fasted and banned for 14 hours, but otherwise free access to food and water was obtained in the living cage.

Based on the sucrose intake after the first 2 weeks of stress, the stressed and control animals were subdivided into commensurate subgroups (n=8), and the animals received intraperitoneal administration once a day for the next five weeks. Carrier (0.5% methylcellulose, 1 ml/kg), Compound #8 (12 mg/kg, 30 mg/kg or 60 mg/kg), imipramine (10 g/kg) as a reference or Venlafaxine (10 mg/kg). The drug is administered at approximately 10.00 and the weekly sucrose test is performed 24 hours after the last drug injection. After five weeks, all treatments were stopped and after 24 hours, blood and/or brain samples of all animals were collected and sent to further biochemical analysis. Stress persists throughout the treatment period.

Animals are individually moved from their living space to another space for sacrifice. Then break it in a semi-random order. Immediately after sacrifice, the whole brain was removed, rapidly frozen in dry ice/n-heptane and stored in a -70 ° C, plastic vial. The dried blood to be taken from the plasma was collected into an EDTA tube containing EDTA (about 1.6 mg/ml blood). The EDTA blood was centrifuged directly at 1500 xg for 10 minutes at 4 °C. Plasma was aspirated and stored in microtubes at -70 °C. In addition, 2 batches of 20 ml of plasma taken from blank animals were prepared to generate a standard curve for the compound for bioassay.

All results obtained in this study were analyzed by three-subject factors (pressure/control, drug treatment, and successive sucrose tests) by variability analysis. The Fisher LSD test is used for post hoc comparison of the mean.

Chronic mild stress causes a gradual decrease in the consumption of 1% sucrose solution. In the final baseline test, all animals drank approximately 11 grams of sucrose solution. After the first 2 weeks of stress, the intake of the control group was maintained at a similar level, but the intake of stressed animals decreased to approximately 6 grams, resulting in a significant group effect [F (1, 84) = 87.204; p < 0.001 ]. This type of difference between the vehicle-treated control group and the stressed animal remained at a similar level in the remaining experiments.

Compared with vehicle administration, imipramine was inactive in the control animals [treatment effect: F(1,84)=1.578; NS] and caused significant treatment effects in stressed animals: F(1,84)=22.651 ;p<0.001 interacts with the number of weeks of treatment: F(5,84)=2.717; p=0.025]. Similarly, venlafaxine was inactive in the control animals [treatment effect: F(1,84)=0.208; NS] and caused significant treatment effects in stressed animals: F(1,84)=35,724; p< 0.001 interacts with the number of weeks of treatment: F (5, 84) = 3.219; p = 0.010].

Compared with the 0th week score, the increase in sucrose uptake in stressed animals reached statistical significance after four weeks of treatment with imipramine (p<0.05) and venlafaxine (p<0.01), and this effect remained after Continue to maintain. A stressed animal (No. 480) did not respond to venlafaxine treatment, but the statistical analysis did not exclude the animal.

Compared with the vehicle administration, Compound #8 did not cause significant treatment effects in the control animals [F(3,168)=1.198; NS] and the stressed animals [F(3,168)=1.676; NS], indicating that the compound was in CMS. Inactive in depression mode.

Example 17

The Resident/Intruder Trial (also known as the Chronic Social Stress Test) Behavioral Resident/Intruder Test is used to screen for antidepressant activity of the compound. Compound #8 was tested in this test according to Rygula, R., Abumaria, N., Fiugge, G., Fuchs, E., Ruther, E., Havemann-Reinecke, U., Behavioral Brain Research, 162 (2005), the procedure described in pp 127-134.

Tables 5, 6 and 7 below list the mean and standard error values for the following compound measurement parameters, po (oral) administered vehicle, control compound 10 mg/kg imipramine and 10 mg/kg venlafaxine, 60 mg/kg compound #8 with 120 mg/kg compound #8.

Compound #8 was active in the Resident/Invaders test, indicating that Compound #8 is expected to have antidepressant activity.

Example 18

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 (25)

A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of depression, 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; 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; 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. 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] Base, 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-(6-chloro-benzo[1,3] Azyl), 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] base). 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] base). 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. The use of the first aspect of the patent application, wherein the depression is selected from the group consisting of unipolar depression, refractory depression, drug-resistant depression, anxiety depression, and mild depression. The use of the first aspect of the patent application, wherein the depression is selected from the group consisting of severe depression, refractory depression, drug-resistant depression, and anxiety-type depression. The use of the first aspect of the patent application, wherein the depression is selected from the group consisting of unipolar depression, refractory depression, drug-resistant depression, and anxiety-type depression. For example, the application of the first paragraph of the patent scope, wherein depression is severe depression. (2S)-(-)-N-(6-Chloro-2,3-dihydro-benzo[1,4] Use of -2-ylmethyl)-sulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of depression. For example, the application of the scope of claim 10, wherein the depression is selected from The following groups are composed of unipolar depression, refractory depression, drug-resistant depression, anxiety depression, and mild depression. The use of claim 10, wherein the depression is selected from the group consisting of unipolar depression, refractory depression, drug-resistant depression, and anxiety-type depression. The use of claim 10, wherein the depression is selected from the group consisting of severe depression, refractory depression, drug-resistant depression, and anxiety-type depression. For example, the application of the scope of claim 10, wherein depression is severe depression. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of depression comprising synergistic therapy with a therapeutically effective amount of at least one antidepressant 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; 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 the formula (I), 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. The use of the scope of claim 15 wherein the antidepressant is selected from the group consisting of imipramine, amitriptyline, desipramine, Nortriptyline, doxepin, protriptyline, trimipramine, maprotinline, amoxapine, trazodone (or nortriptyline) Trazodone), bupropion, chlomipramine, fluoxetine, duloxetine, escitalopram, citalopram, Sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine ), mirtazapine, phenyl b (phenelzine), tranylcypromine, moclobemide, Kava-Kava, St. John's Wart, s-adenosylmethionine, thyroid stimulating A vasopressin, a neurohormone receptor antagonist and triiodothyronine. The use of the scope of claim 15 wherein the antidepressant is selected from the group consisting of monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin adrenergic resorption Inhibitor; normal adrenergic and specific serotonin stimulating agents and atypical Antidepressant. The use of the scope of claim 15 wherein the antidepressant is selected from the group consisting of: phenyl , tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, different Penserpine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, imipenem and bupropion. The use of claim 15 wherein the antidepressant is selected from the group consisting of a neuropeptide, a compound that targets a neuropeptide receptor, and a hormone. (2S)-(-)-N-(6-Chloro-2,3-dihydro-benzo[1,4] Use of -2-ylmethyl)-sulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of depression comprising synergistic therapy using a therapeutically effective amount of at least one antidepressant. The use of claim 21, wherein the antidepressant is selected from the group consisting of imipramine, amitriptyline, desipramine, nortriptyline, doxepin, Protriptyline, trimipramine, maprotiline, isoprene, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, dextroamphetamine, citrate Purlin, sertraline, paroxetine, fluvoxamine, nefazodone, venlafaxine, milnacipran, reboxetine, imipenem, phenylethyl , tranylcypromine, moclobemide, calprotectin, St. John's wort, s-adenosylmethionine, thyroid stimulating hormone, neurohormone receptor antagonist and triiodothyronine. The use of claim 21, wherein the antidepressant is selected from the group consisting of monoamine oxidase inhibitors, tricyclics, blood. A reuptake inhibitor, a serotonergic adrenergic reuptake inhibitor; a noradrenergic and specific serotonin agent and an atypical antidepressant. The use of the scope of claim 21, wherein the antidepressant is selected from the group consisting of: phenyl , tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, different Penserpine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, imipenem and bupropion. The use of claim 21, wherein the antidepressant is selected from the group consisting of a neuropeptide, a compound that targets a neuropeptide receptor, and a hormone.