ES2360135T3 - USE OF BENZO-CONDENSED HETEROCICLIC SULFAMIDS DERIVATIVES FOR THE TREATMENT OF MANIA AND BIPOLAR DISORDER. - Google Patents

Abstract

A compound of formula (I) ** Formula ** or a pharmaceutically acceptable salt thereof for use in the treatment of mania, wherein R1 and R2 are independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; it is selected from the group consisting of and in which b is an integer from 0 to 4; and in which c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; wherein "lower alkyl" refers to a carbon chain composition of 1-4 carbon atoms, provided that when it is or then a is 1.

Description

Field of the Invention

The present invention relates to the use of benzo-condensed heterocyclic sulfamide derivatives for the treatment of mania and bipolar disorder.

Background of the invention

Bipolar disorder is a psychiatric disorder characterized by unpredictable oscillations in the mood of mania (or hypomania) to depression. Some patients suffer only from recurrent attacks of mania, which in their pure form are associated with increased psychomotor activity; excessive social extroversion; decreased need for sleep; impulsivity and difficulty in judgment; and expansive, high-sounding and sometimes irritable mood. In severe mania, patients may experience delusions and paranoid thoughts indistinguishable from schizophrenia. Half of the patients with bipolar disorder present a mixture of agitation and psychomotor activation with dysphoria, anxiety and irritability. It can be difficult to distinguish mixed mania from agitated depression. In some bipolar patients (bipolar II disorder) - the complete criteria for mania are lacking and the required recurrent depressions are separated by periods of mild activation and increased energy (hypomania). In cyclothymic disorder, there are numerous hypomanic periods, usually of relatively short duration, alternating with clusters of depressive symptoms that fall, either in severity or duration, to meet the criteria of major depression. Mood fluctuations are chronic and should be present for at least 2 years before the diagnosis is made.

Manic episodes typically emerge over a period of days to weeks, but the appearance in hours is possible, usually in the early hours of the morning. An untreated episode of depression or mania can be as short as several weeks or last as long as 8 to 12 months and rare patients have a chronic course that does not remit. The term rapid cycling is used for patients who have four or more episodes of either depression or mania in a given year. This pattern occurs in 15% of all patients, almost all of whom are women. In some cases, rapid cyclization is linked to an underlying thyroid dysfunction and in others it is triggered iatrogenicly by prolonged treatment of antidepressants. Approximately half of the patients have sustained difficulties in performing work and psychosocial functioning.

Patients suffering from bipolar disorder typically complain about the following groups of symptoms, depending on whether they are in a "manic" or "high" phase versus a "depressed" or "low" phase. In the manic phase the symptoms include (a) increased physical and mental activity and energy (b) increased mood, exaggerated optimism and self-confidence; (c) excessive irritability, aggressive behavior; (d) decreased need for sleep without experiencing fatigue; (e) delusions of greatness, swollen sense of self-importance; (h) accelerated speech, accelerated thoughts, flight of ideas; (I) impulsivity, poor judgment, inability to concentrate; (j) reckless behavior and in the most serious cases, (k) delusions and hallucinations. Symptoms of the manic phase include, but are not limited to (a) prolonged sadness or unexplained crying periods; (b) significant changes in appetite and sleep patterns; (c) irritability, anger, worry, agitation, anxiety; (d) pessimism, indifference; (e) loss of energy, persistent lethargy; (f) feelings of guilt, worthlessness; (g) inability to concentrate, irresolution; (h) inability to take pleasure from previous interests, social withdrawal; (I) unexplained aches and pains and (j) recurring thoughts of death and suicide.

Bipolar disorder is common, affecting approximately 1% of the population in the United States. The onset is typically between 20 and 30 years of age, but many individuals report premorbid symptoms in late childhood or early adolescence. The prevalence is similar for men and women; Women are likely to have more depressive episodes and men are likely to have more manic episodes during life.

Lithium carbonate is the mainstay of the treatment of bipolar disorder, although sodium valproate and olanzapine are equally effective in acute mania, as is lamotrigine in the depressive phase. The response rate to lithium carbonate is 70 to 80% in acute mania, with beneficial effects appearing in 1 to 2 weeks. Lithium also has a prophylactic effect in the prevention of recurrent mania and, to a lesser extent, in the prevention of recurrent depression. Serious side effects of lithium administration are rare, but less serious complaints such as gastrointestinal discomfort, nausea, diarrhea, polyuria, weight gain, skin rashes, alopecia and edema are common.

In the treatment of acute mania, lithium is started at 300 mg twice a day or three times a day and the dose is then increased by 300 mg every 2 to 3 days to achieve blood levels of 0.8 to 1.2 meq / l. Because the therapeutic effect of lithium may not appear until after 7 to 10 days of treatment, the complementary use of lorazepam (1 to 2 mg every 4 hours) or clozepam (0.5 to 1 mg every 4 hours) may be Beneficial to control agitation. Antipsychotics are indicated in patients with severe agitation who respond only partially to benzodiazepines.

2

Valproic acid is an alternative in patients who cannot tolerate lithium or respond poorly to it. Valproic acid may be better than lithium for patients who experience rapid cyclization (that is, more than four episodes in a year) or who have mixed or dysphoric mania. Tremor and weight gain are the most common side effects; Hepatotoxicity and pancreatitis are rare toxicities. Carbamazepine and oxcarbazepine,

5 although not formally approved by the U.S. Food and Drug Administration (FDA) for bipolar disorder, have clinical efficacy in the treatment of acute mania. Preliminary evidence also suggests that other anticonvulsant agents such as levtiracetam, zonisamide and topiramate may have some therapeutic benefit.

The recurring nature of bipolar mood disorder needs maintenance treatment. Compliance is often a matter and often requires recruitment and education of affected family members. 10 Efforts to identify and modify psychosociological factors that can activate episodes are important, as is an emphasis on regularity of lifestyle. Antidepressant medications are sometimes required for the treatment of severe sudden depressions, but their use should generally be avoided during maintenance treatment due to the risk of precipitating mania or accelerating the frequency of the cycle. Loss of efficacy over time can be observed with any of the mood stabilizing agents. In such

15 situations, an alternative agent or an alternative therapy is usually useful. US5753693 describes the use of topiramate in the treatment of manic-depressive bipolar disorders.

There remains a need to provide effective treatment for mania and / or for bipolar disorder. Preferably, the treatment of bipolar disorder comprises treatment of depression and mania. More preferably, the treatment of bipolar disorder comprises the treatment of depression, mania and cyclization.

20 that are characteristic of the disorder.

Summary of the invention

The present invention relates to a method for the treatment of mania and / or bipolar disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula

(I)

image 1

in which R1 and R2 are independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2;

image2

30 is selected from the group consisting of

image2

3

image3

in which b is an integer from 0 to 4; and in which c is an integer from 0 to 2;

 each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; provided that when

image2

is

image2

or

image2

15 then a is 1;

or a pharmaceutically acceptable salt thereof.

The present invention further relates to a method for the treatment of mania and / or bipolar disorder comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (II)

Four. Five

image2

10

fifteen

twenty

25

or a pharmaceutically acceptable salt thereof.

The present invention further relates to a method for the treatment of mania comprising co-therapy with a therapeutically effective amount of at least one antipsychotic and a compound of formula (I) or formula (II) as described herein. . The present invention further relates to a method for the treatment of bipolar disorder comprising co-therapy with a therapeutically effective amount of at least one antidepressant and / or at least one antipsychotic and a compound is of formula (I)

or of formula (II) as described herein. The present invention further relates to a method for the treatment of bipolar disorder comprising co-therapy with a therapeutically effective amount of at least one mood stabilizer and a compound of formula (I) or of formula (II) as described in This document.

The treatment of mania comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described above is exemplifying the invention. The bipolar disorder treatment comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described above is exemplifying the invention.

In one embodiment, the present invention relates to the treatment of mania. In another embodiment, the present invention relates to the treatment of bipolar mania. In another embodiment, the present invention relates to the treatment of bipolar depression. In another embodiment, the present invention relates to the treatment of bipolar disorder. In another embodiment, the present invention relates to the treatment of bipolar cyclization. In another embodiment, the present invention relates to the treatment of depression and mania associated with bipolar disorder. In yet another embodiment, the present invention relates to the treatment of depression, mania and cyclization associated with bipolar disorder. In yet another embodiment, the present invention relates to a method for treating bipolar disorder comprising cyclization stabilization. Thus, in one embodiment, the present invention relates to a method of stabilizing bipolar cyclization.

Detailed description of the invention

The present invention relates to a method for the treatment of mania and / or bipolar disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula

(I)

image4

or a pharmaceutically acceptable salt thereof; in which

image2

a, R1, R2 and R4 are as defined herein. More specifically, the compounds of the present invention are useful for the treatment of mania, regardless of the cause. Additionally, the compounds of the present invention are useful for the treatment of depression, mania and / or cyclization that are characteristic of, symptomatic of or associated with bipolar disorder.

The present invention further relates to disorders for the treatment of mania, bipolar depression, bipolar mania, bipolar cyclization and / or bipolar disorder comprising administering to a subject in need of the same co-therapy with at least one antidepressant and / or at less an antipsychotic agent and / or at least one mood stabilizer and a compound of formula (I) or formula (II) as described herein.

5

Bipolar disorder is a psychiatric disorder characterized by unpredictable mood swings from mania (or hypomania) to depression. As used herein, the term "bipolar disorder" will include bipolar I disorder (for example, individual manic episode, most recent hypomanic episode, most recent manic episode, most recent mixed episode, most recent depressive episode, and most recent nonspecific episode) , bipolar II disorder, cyclothymic disorder and bipolar disorder not otherwise specified (according to these terms are defined by their diagnostic criteria, in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Review, American Psychiatric Association, 2000 (DSM -IV-TR)). Preferably, bipolar disorder is characterized by depressive and manic (or hypomanic) phases, in which the phases are cycled. Preferably, the bipolar disorder is bipolar disorder I or bipolar disorder II.

As used herein, the term "mania" must include mania or a manic mood phase, regardless of the underlying cause. As used herein, the term "bipolar mania" is intended to mean the mania associated with, characteristic of or symptomatic of a bipolar disorder. Thus, the methods of treating the bipolar mania of the present invention refer to the procedures that treat mania and / or the manic phase of bipolar disorders.

As used herein, the term "bipolar depression" is intended to mean depression associated with, characteristic of or symptomatic of a bipolar disorder. Thus, the procedures for treating bipolar depression of the present invention refer to procedures that treat depression and / or the depressed phase of bipolar disorders.

As used herein, unless otherwise noted the terms "cyclization" or "bipolar cyclization" shall refer to the alternation of mood between depressive and manic phases characteristic of bipolar disorders. Thus, the present invention includes methods for the stabilization of said cyclization, including, but not limited to, reducing the frequency of the cyclization and / or decreasing the magnitude of the manic and / or depressive phases.

As used herein, the term "mood stabilizer" will include any pharmaceutical agent that controls mood including, but not limited to, lithium, valproic acid, sodium valproate, carbamazepine, lamotrigine, topiramate and the like. More specifically, a mood stabilizer is any pharmaceutical agent that stabilizes patients' mood can act as an antidepressant, an antimaniac or both and influences the patient's mood towards euthymia.

As used herein, unless otherwise noted, the term "antidepressant" shall mean any pharmaceutical agent that treats depression. Suitable examples include monoamine oxidase inhibitors such as phenelzine, tranylcypromine, moclobemide; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepine, protriptyline, trimipramine, clomipramine, amoxapine; tetracyclics such as maprotiline, non-cyclics such as nomifensin; triazolopyridines such as trazodone; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine; serotonin receptor antagonists such as nefazadone; noradrenergic reuptake inhibitors of setotonin such as venlafaxine, milnacipran; specific noradrenergic and serotonergic agents such as mirtazapine; norepinephrine reuptake inhibitors such as reboxetine; atypical antidepressants such as bupropion, natural products such as Kava-Kava, hypericum; dietary supplements such as s-adenosylmethionine; and neuropeptides such as thyrotropin release hormone and the like; compounds that mark neuropeptide receptors such as neuroquinine receptor antagonists; and hormones such as triiodothyronine. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertaline.

As used herein, the term "antipsychotic" is intended to include, but is not limited to (a) typical or traditional antipsychotics, such as phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazine). , thioxanthenes (for example, thiothixen, flupentixol), butyrophenones (for example, haloperidol), dibenzoxazepines (for example, loxapine), dihydroindolones (for example, molindone), substituted benzamide (for example, sulpride, amisulpride); and (b) atypical antipsychotics, such as sodium divalproate, paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222 (Organon); and others such as sonepiprazole, aripiprazole, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho).

More specifically, atypical antipsychotics include:

2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] benzodiazepine, known as olanzapine and described in US Patent No. 5,229,382 as useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, moderate anxiety states and psychosis; with a recommended dosage of 5-30 mg / day, preferably 5-10 mg / day (Physician's Desk Reference; Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, 2000);

8-Chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazepine, known as clozapine and described in US Patent No. 3,539,573, effectively clinic in the treatment of schizophrenia described in Hanes, et al., Psychopharmacological Bulletin, 24, 62 (1988)); with a recommended dosage of 12.5-600 mg / day, preferably 250-450 mg / day (Physician's Desk Reference; Kaplan & Sadock's Comprehensive Textbook of

6

Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, 2000);

3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido- [1,2 -a] pyrimidin-4-one; known as risperidone and described in US Patent No. 4,804,663 as useful for the treatment of psychotic diseases; with a recommended dosage of 0.25-16 mg / day, preferably 1-16 mg / day, more preferably 2-8 mg / day (Physician's Desk Reference; Kaplan & Sadock's Comprehensive Textbook of Psychiatry; Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, 2000);

3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) piperidino] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido- [1,2 -a] pyrimidin-4-one, known as paliperidone, also known as 9-hydroxy-risperidone, described in US Patent 5,5158,952, useful for the treatment of psychotic disorders, with dosages contemplated in the range from 0.01 mg / kg to approximately 2 mg / kg body weight per day;

1- [2- [3- [5-Chloro-1- (4-fluorophenyl) -1H-indol-3-yl] -1-piperidinyl] ethyl] imidazolidin-2-one, known as sertindole and described in the Patent United States No. 4,710,500, with United States Patent No. 5,112,838 and United States Patent No. 5,238,945 which describe the use of sertindole for the treatment of schizophrenia; with a starting dose of 4 mg / day, with increments of 4 mg every other day up to 24 mg / day, with final recommended dosage range of 12 to 20 mg / day (Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, pages 2467-2468, 2000);

5- [2- (4-dibenzo [b, f] [1,4] thiazepin-11-yl-1-piperazinyl) ethoxy] ethanol, known as quetiapine and described in US Patent No. 4,879,288 to the treatment of schizophrenia; with a recommended dosage of 25-800 mg / day, preferably 150-750 mg / day (Physician’s Desk efferent; Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, 2000);

5- [2- [4- (1,2-dibenzoisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H-indole-2-one, known as ziprasidone and described in U.S. Patent No. 4,831,031 and in U.S. Patent No. 5,312,925, with its usefulness in the treatment of schizophrenia disclosed in U.S. Patent No. 4,831,031; with a recommended dosage of 40-160 mg / day, with a preferred dosage for maintenance treatment and relapse prevention of 40 to 60 mg twice daily (Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Seventh Edition, Volume II, Lippincott Williams & Wilkins: Philadelphia, pages 2470-2471, 2000); and sodium hydrogen bis (2-propylpentanoate), also known as divalproex sodium, described in US Patent No. 5212326, with a dosage recommended for the treatment of mania at an initial dosage of 750 mg / day with a dosage Maximum recommended of 60 mg / kg / day (Physicians Desk).

The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human being, which has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein, means that the amount of active compound or pharmaceutical agent that facilitates the biological or medical response in a tissue, animal or human system that is being examined by a researcher, veterinarian, medical doctor or other clinical worker, which includes relief of the symptoms of the disease or disorder being treated.

Wherein the present invention is intended for co-therapy or combination therapy, which comprises administration one

or more compound (s) of formula (I) or formula (II) and one or more antipsychotics or antidepressants, "therapeutically effective amount" will mean that the combination of agents taken together facilitates the desired biological or medicinal response. For example, the therapeutically effective amount of co-therapy comprising administration of a compound of formula (I) or formula (II) and at least one antidepressant and / or at least one antipsychotic would be the amount of the compound of formula (I) or of formula (II) and the amount of the antidepressant and / or antipsychotic that when taken together or sequentially have a combined effect that is therapeutically effective. Additionally, it will be recognized by someone skilled in the art that in the case of co-therapy with a therapeutically effective amount, as in the previous example, the amount of the compound of formula (I) or formula (II) and / or the amount of the Antidepressant and / or antipsychotic individually may or may not be therapeutically effective.

As used herein, the terms "co-therapy" and "combination therapy" shall mean treatment of a subject in need thereof by administering one or more compounds of formula (I) or formula (II) in combination with one or more antidepressant (s) and / or antipsychotic (s), in which the compound (s) of formula (I) or formula (II) and the antidepressant (s) and / or the antipsychotic (s) ) are administered by any means, simultaneously, sequentially, separately or in an individual pharmaceutical formulation. Where the compound (s) of formula (I) or formula (II) and the antidepressant (s) and / or antipsychotic (s) are administered in separate dosage forms, the number of dosages administered per day For each compound it can be the same or different. The compound (s) of formula (I) or formula (II) and the antidepressant (s) and / or antipsychotic (s) can be administered through the same or different routes of administration. Examples of suitable administration procedures include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal and rectal. The compounds can also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular routes of administration; intracerebroventricular, intrathecal, intracisternal, intraspinal and / or perispinal by means of needles and / or intracranial catheters or

7

intravertebral with or without pumping devices. The compound (s) of formula (I) or formula (II) and the antidepressant (s) and / or antipsychotic (s) can be administered according to simultaneous or alternating regimens, at the same time or at different times during the course of therapy, concurrently in divided doses or in individual doses.

In one embodiment, the present invention relates to a method for the treatment of depression associated with

or characteristic of or symptomatic of bipolar disorder. In another embodiment, the present invention relates to a method for the treatment of mania associated with or characteristic of or symptomatic of bipolar disorder. In yet another embodiment, the present invention relates to a method for the treatment of cyclization (between depression and mania or between the depressive and manic phases) associated with or characteristic of or symptomatic of bipolar disorder.

In an embodiment of the present invention R1 is independently selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention R2 is selected from the group consisting of hydrogen and methyl. In yet another embodiment of the present invention R1 and R2 are each hydrogen or R1 and R2 are each methyl.

In one embodiment of the present invention - (CH2) a- is selected from the group consisting of –CN2- and –CH2-CH2-. In another embodiment of the present invention - (CH2) a- is –CH2-.

In one embodiment of the present R4 is selected from the group consisting of hydrogen and methyl, preferably, R4 is hydrogen.

In an embodiment of the present invention a is 1.

In one embodiment of the present invention b is an integer from 0 to 2. In another embodiment of the present invention c is an integer from 0 to 2. In another embodiment of the present invention b is an integer from 0 to 1 .

In another embodiment of the present invention c is an integer from 0 to 1. In yet another embodiment of the present invention the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1. In still Another embodiment of the present invention b is an integer from 0 to 2 and c is 0.

In an embodiment of the present invention,

image2

25 is selected from the group consisting of

image2

image2

Y

image2

8

In another embodiment of the present invention,

image2

is selected from the group consisting of

image2

In an embodiment of the present invention,

image2

10

is selected from the group consisting of 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (benzo [1,3] dioxolyl), 3- (3,4-dihydro-benzo [1, 4] dioxepinyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-fluoro-2,3-dihydro-benzo [1,4] dioxinyl), 2 - (chromanyl), 2- (5-fluoro-2,3-dihydrobenzo [1,4] dioxinyl), 2- (7-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- ( 6-chloro-benzo [1,3] dioxolyl), 2- (7-nitro-2,3-dihydrobenzo [1,4] dioxinyl),

2- (7-Cetyl-2,3-dihydro-benzo [1,4] dioxinyl), 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6- Bromo-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (8-chloro-2, 3-dihydro-benzo [1,4] dioxinyl), 2- (2,3-dihydro-naphtho [2,3-b] [1,4] dioxinyl) and 2- (4-cetyl-benzo [1,3 ] dioxolyl). In another embodiment of the present invention,

image2

20 is selected from the group consisting of 2- (benzo [1,3] dioxolyl), 2- (2,3-dihydrobenzo [1,4] dioxinyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-cetyl-2,3-dihydro-benzo [1,4] dioxinyl ), 2- (6-Bromo-2,3-dihydro-benzo [1,4] dioxinyl) and 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxinyl). In another embodiment of the present invention,

image2

9

is selected from the group consisting of 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-cetyl-2,3-dihydro-benzo [1,4] dioxinyl) and 2- ( 6-Bromo-2,3-dihydro-benzo [1,4] dioxinyl).

In one embodiment of the present invention R5 is selected from the group consisting of halogen and lower alkyl: In another embodiment of the present invention R5 is selected from chlorine, fluoro, bromine and methyl.

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

In one embodiment of the present invention the compound of formula (I) is present as an enantiomerically enriched mixture, in which the enantiomeric enrichment in% (ee in%) is greater than

About 75%, preferably greater than about 90%, more preferably greater than about 95%, most preferably greater than about 98%.

Additional embodiments of the present invention include those in which the substituents selected for one or more of the variables defined herein (ie R1, R2, R3, R4, XY and A) are independently selected to be any substituent individual or any subgroup of substituents selected from

15 the complete list as defined in this document.

Representative compounds of the present invention are as listed in Table 1 below. Additional compounds of the present invention are as listed in Table 3. In Tables 1 and 2 below, the "stereo" heading column defines the stereo configuration in the carbon atom of the heterocycle attached on the most important bond. Where no designation is listed, the compound was prepared as a mixture of

20 stereo settings. Where a designation of "R" or "S" is listed, the stereo configuration is based on the enantiomerically enriched starting material.

Table 1: Representative Compounds of Formula (I)

 image5

image2

 image5

ID No.:

image2 Stereo (CH2) to NR4 R1 R2 image5

one

2- (2,3-dihydrobenzo [1,4] dioxinyl) � CH2 NH H H�

2

2- (benzo [1,3] dioxolyl) � CH2 NH H H�

3

3- (3,4-dihydro-2H-benzo [1,4] dioxepinyl) � CH2 NH H H�

4

2- (2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

5

2- (2,3-dihydrobenzo [1,4] dioxinyl) R CH2 NH H H�

6

2- (2,3-dihydrobenzo [1,4] dioxinyl) � CH2 NH methyl methyl�

7

2- (2,3-dihydrobenzo [1,4] dioxinyl) � CH2 N (CH3) H H�

8

2- (6-Chloro-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

9

2- (6-fluoro-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

10 Table 2: Additional Compounds of the Present Invention

(CONT.)

10

2- (chromanyl) � CH2 NH H H�

13

2- (5-fluoro-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

14

2- (7-Chloro-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

fifteen

2- (6-Chlorobenzo [1,3] dioxolyl) � CH2 NH H H�

16

2- (2,3-dihydrobenzo [1,4] dioxinyl) � CH2CH2 NH H H�

18

2- (7-nitro-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

19

2- (7-methyl-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

twenty

2- (5-Chloro-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

22

2- (8-methoxy-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

24

2- (6-Bromo-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

29

2- (6,7-dichloro-2,3-dihydroenzo [1,4] dioxinyl) S CH2 NH H H�

30

2- (8-Chloro-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

33

2- (2,3-dihydronaphth [2,3-b] [1,4] dioxinyl) �� CH2 NH H H�

35

2- (4-methylbenzo [1,3] dioxolyl) � CH2 NH H H

 image5

ID No.:

Stereo X NR14 R11 R12 image5

2. 3

2- (5-methoxy-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

26

2- (6-methylcarbonyl-2,3-dihydrobenzo [1,4] dioxinyl) S CH2 NH H H�

32

2- (6-methoxycarbonyl-2,3-dihydrobenzo [1,4] dioxynil) �� CH2 NH H H�

3. 4

2- (6-hydroxymethyl-2,3-dihydrobenzo [1,4] dioxinyl) �� CH2 NH H H�

36

2- (7-amino-2,3-dihydro-benzo [1,4] dioxinyl) �� CH2 NH H H

As used herein, unless otherwise noted, "halogen" shall mean chlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term "alkyl" if used alone or as part of a substituent group, includes linear and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and pentyl. Unless otherwise noted, "lower" when used with alkyl means a carbon chain composition of 1-4 atoms of

10 carbon

As used herein, unless otherwise noted, "alkoxy" will designate an oxygen ether radical of the straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy

eleven

and n-hexyloxy.

As used herein, the notation "*" will denote the presence of a stereogenic center.

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

With reference to the substituents, the term "independently" means that when more than one such substituent is possible, such substituents may be the same or different from each other.

In the standard nomenclature used through this disclosure, the end portion of the designated side chain is described first, followed by the functionality adjacent to the junction point. Thus, for example, a "phenyl-alkylamino-carbonyl-alkyl" substituent refers to a group of the formula

image2

The abbreviations used in the specification, particularly the Schemes and Examples, are as follows:

DCC =

Dicyclohexylcarbodiimide

DCE

Dichloroethane

 DCM

Dichloromethane

DIPEA or DIEA =

Diisopropylethylamine

DMF

N, N-dimethylformamide

DMSO

Dimethylsulfoxide

EDC

Ethylcarbodimide

Et3N or ASD =

Triethylamine

Et2O =

Diethyl ether

EA or EtaAc =

Ethyl acetate

EtOH

Ethanol

IPA =

2-propanol

Hept =

Heptane

HOBT =

1-hydroxybenzotriazole

HPLC =

High Pressure Liquid Chromatography

LAH =

Aluminum Lithium Hydride

M or MeOH =

Methanol

NMR =

Nuclear magnetic resonance

Pd-C =

Palladium in Carbon Catalyst

RP HPLC =

Reverse Phase High Pressure Liquid Chromatography

TA or ta =

Room temperature

ASD =

Triethylamine

TFA =

Trifluoroacetic Acid

�

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 THF = Tetrahydrofuran

TLC = Thin Layer Chromatography

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It should be appreciated that all these isomers and mixtures thereof are included within the scope of the present invention. In addition, some of the crystalline forms for the compounds may exist as polymorphs and as such are desired to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also desired to be encompassed within the scope of this invention.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." However, other salts may be useful in the preparation of compounds according to this invention or their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds include acid addition salts that can be formed, for example, formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid and phosphoric acid. In addition, when the compounds of the invention carry an acid moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example, sodium or potassium salts; alkaline earth metal salts, for example, calcium or magnesium salts; and salts formed with suitable organic ligands, for example, quaternary ammonium salts. Thus, pharmaceutically representative salts include the following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dichlorohydrate, edetate, edisilate, stolate, silate, fumarate, gluceptate, gluconate, glutamate, glycinate hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsilate, nitrate, methyl ammonium, ammonium salt, ammonium salt, ammonium salt pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethyliodide and valerate.

Representative acids and bases that can be used in the preparation of pharmaceutically acceptable salts include the following:

acids that include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) - camphoric acid, camphorsulfonic acid , (+) - (1S) -camfor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, acid 2-Hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, 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, naf acid Talent-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 acid - pyroglutamic, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) - L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; Y

Bases include ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methyl glucamine, hydrabamine, 1H-imidazole, L -lisin, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

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

13

image2

Scheme 1

Accordingly, a properly constituted compound of formula (X), a known compound or a compound prepared by known procedures, is reacted with sulfamide, a known compound,

5 preferably in which the sulfonamide is present in an amount in the range of about 2 to about 5 equivalents. In an organic solvent such as THF, dioxane preferably at elevated temperature in the range of about 50 ° C to about 100 ° C, more preferably at about reflux temperature, to provide the corresponding compound of formula (la).

Alternatively, a suitably substituted compound of formula (X), a known compound or a compound

10 prepared by known procedures, is reacted with a suitably substituted compound prepared by known procedures, in the presence of a base such as TEA, DIPEA, pyridine in an organic solvent such as DMF, DMSO to provide the corresponding compound of formula (I).

The compounds of formula (X) in which

image2

They can be prepared according to the procedure outlined in Scheme 2.

image2

20 Scheme 2

14

Accordingly, a suitably substituted compound of formula (XII), a known compound or a compound prepared by known procedure (for example as described in Scheme 3 above) is reacted with NH4OH, a known compound, optionally in a organic solvent such as acatonitrile to provide the corresponding compound of formula (XIII).

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

The compounds of formula (X) in which

image2

10 is selected from

image2

They can be prepared according to the procedure outlined in Scheme 3.

image2

15 �

Scheme 3

Accordingly, a suitably substituted compound of formula (XIV), a known compound or a compound prepared by known procedures, is reacted with NH40H, in the presence of a coupling agent such as DCC, optionally in an organic solvent such as acetonitrile providing the

20 corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably selected reducing agent, such as LAH in an organic solvent such as THF, diethyl ether to provide the corresponding compound of formula (Xb).

The compounds of formula (X) in which

image2

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is selected from:

image2

and where a is 2, they can be prepared according to the procedure outlined in Scheme 4.

image2

5 Scheme 5

Accordingly, a suitably substituted compound of formula (XVI) in which J1 is a suitable leaving group such as Br, CI, I, tosyl, mesyl, triflyl a known compound or a compound prepared by known procedures (for example, by activating the corresponding compound in which J1 is OH), it is reacted with a cyanide such as potassium cyanide, sodium cyanide, in an organic solvent such as DMSO,

10 DMF, THF, providing the corresponding compound of formula (XVII).

The compound of formula (XVII) is reduced according to known procedures, for example by reacting with a suitable reducing agent such as LAH, borane, by providing the corresponding compound of formula (Xc).

The compounds of formula (X) in which

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image2

is selected from

image2

and in which a is 1, they can be prepared according to the procedure outlined in Scheme 5.

16

image2

Scheme 5

Accordingly, a suitably substituted compound of formula (XVIII), prepared by

5 known procedures, according to a known procedure for providing the corresponding compound of formula (XIX), wherein J2 is a suitable leaving group, such as tosylate, CI, Br, I, mesylate and triflate.

The compound of formula (XIX) is reacted with a phthalimide salt such as potassium phthalimide, sodium phthalimide, in an organic solvent such as DMF, DMSO, acetonitrile, preferably, at an elevated temperature in the

10 ranges from 50 ° C to about 200 ° C, more preferably, at about reflux temperature, providing the corresponding compound of formula (XX).

The compound of formula (XX) is reacted with N2H4, a known compound, in an organic solvent such as ethanol and methanol, preferably, at an elevated temperature in the range from about 50 ° C to about 100 ° C, more preferably, at approximately reflux temperature, to provide the

Corresponding compound of formula (Xd).

 Someone skilled in the art will recognize that the compounds of formula (X) in which

image2

is selected from

17

image2

they can be prepared in a similar way according to known procedures or for example, according to the procedures outlined in Schemes 2 to 5 above, by selecting and replacing the condensed naphthyl compounds for the benzo-condensed starting materials.

Someone skilled in the art will further recognize that where an individual enantiomer (or a mixture of enantiomers in which an enantiomer is enriched) of a compound of formula (X) is desired, the above procedures as described in Schemes 1 to 5 it can be applied by replacing the corresponding individual enantiomer (or the mixture of enantiomers in which an enantiomer is enriched) with the appropriate starting material.

Someone skilled in the art will recognize that where a reaction step of the present invention can be carried out in a variety of solvents or solvent systems, said reaction step can also be carried out in a mixture of suitable solvents or of suitable solvent systems.

Where the processes for the preparation of the compounds according to the invention cause mixing of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form, or the individual enantiomers can be prepared either by enantiospecific synthesis or by redisolution. The compounds may, for example, be redissolved in their enantiomeric components by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-) - di-p-toluoyl-D-tartaric acid and / or (+) - di-p-toluoyl-L-tartaric acid by fractional crystallization and free base regeneration. The compounds can also be redissolved by formation of diastereomeric esters or diastereomeric amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be redissolved using a chiral HPLC column. During any of the processes for the preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules involved. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &

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P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups can be removed in a subsequent convenient state using methods known in the art.

The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient of the invention can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compound formation techniques. The vehicle can take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable vehicles and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; For solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or may be enterically coated such as to modulate the main site of absorption. For parenteral administration, the vehicle will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Suspensions or injectable solutions may also be prepared using aqueous vehicles together with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is (s) intimately mixed with a pharmaceutical vehicle according to conventional pharmaceutical compound formation techniques, which vehicle can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any usual pharmaceutical means can be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable vehicles and additives include water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents, for solid oral preparations such as, for example, powders , capsules, oval tablets and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders and disintegrating agents. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which solid pharmaceutical vehicles are obviously employed. If desired, the tablets may be coated with sugars or enteric coated by standard techniques. For parenteral administration forms, the vehicle will usually comprise sterile water, mixed with other ingredients, for example, for purposes such as aid in solubility or for preservation, may be included. Injectable suspensions can also be prepared, in which liquid vehicles, suspending agents can be used. The pharmaceutical compositions herein will contain, per dosage unit, for example, tablets, capsule, powder, injection, teaspoon of teaspoon, an amount of the active ingredient necessary to administer a dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, for example, tablet, capsule, powder, injection, suppository, teaspoon of teaspoon, from about 0.1-1000 mg and may be given at a dosage of approximately 0.01-200.0 mg / kg / day, preferably from about 0.1 to 100 mg / kg / day, more preferably from about 0.5-50 mg / kg / day, more preferably from about 1.0- 25.0 mg / kg / day or any interval mentioned. The dosages, however, can be varied depending on the requirements of the patients, the severity of the condition being treated, and the compound being used. The use of either daily administration or post-periodic dosing can be used.

Preferably these compositions are in unit dosage forms such as tablets, capsules, powders, granules, sterile parenteral solutions or suspensions, aerosol or liquid dose sprayers, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, rectal administration or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for weekly or monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, can be adapted by providing a preparation for intramuscular injection. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example additional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or rubbers and other pharmaceutical diluents, for example water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is regularly dispersed throughout the composition such that the composition can be easily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 1000 mg of the active ingredient of the present invention. Tablets or pills of the novel composition may be coated or otherwise formed compounds to provide a dosage form that provides the advantage of prolonged action. For example, the tablet or pill may comprise an internal dosage and an external dosage component, the latter being in the form of a wrapper over the first. The two components can be separated by a phase

19

enteric that serves to resist disintegration in the stomach and allows the internal component to pass intact inside the duodenum or be delayed in its release. A variety of the material can be used for such enteric phases or coatings, such materials including a number of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms in which the novel compositions of the present invention can be incorporated for administration orally or by injection, include, aqueous solutions, suitably flavored syrups, oral or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Dispersion or suspending agents suitable for aqueous suspensions include synthetic and natural gums such as gum tragacanth, gum arabic, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The process of treating depression described in the present invention can also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.

The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably about 50 to 500 mg, of the compound and may be constituted in any form suitable for the mode of administration selected. The vehicles necessarily include inert pharmaceutical excipients, including binders, suspending agents, lubricants, flavorings, sweeteners, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, oval tablets, capsules (each including immediate release, regulated release and sustained release formulations), granules and powders and liquid formulations, such as solutions, syrups , elixirs, emulsions and suspensions. Useful forms for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, the compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. In addition, the compounds for the present invention can be administered intranasally by means of topical use of suitable intranasal vehicles, or by means of transdermal skin patches well known to those of normal skill in that technique. To be administered in the form of a transverse administration system, the administration of dosage will, of course, be more continuous than intermittent throughout the dosing regime.

For example, for oral administration in the form of a tablet or a capsule, the active drug component may be combined with a non-toxic, oral pharmaceutically acceptable inert carrier such as ethanol, glycerol and water. In addition, when desired or necessary, binders can also be incorporated; lubricants, disintegrating agents and suitable coloring agents estimated in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth gum or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, acetate of sodium and sodium chloride. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum.

Liquid forms in suspending agents or dispersants suitably flavored such as synthetic or natural gums, for example gum tragacanth, gum arabic, methylcellulose. For parenteral administration, sterile suspensions and solutions are desired.

Isotonic preparations containing generally suitable preservatives are used when intravenous administration is desired.

The compounds of this invention can be administered in any of the preceding compositions and in accordance with dosage regimens established in the art each time depression treatment is needed.

The daily dosage of the products can be varied over a wide range from 0.01 to 200 mg / kg per adult human per day. For oral administration, the compositions may preferably be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0 , 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is normally supplied at a dosage level of about 0.01 mg / kg to about 200 mg / kg of body weight per day. Preferably, the range is from about 0.1 to about 100.0 mg / kg of body weight per day, more preferably, from about 0.5 mg / kg to about 50 mg / kg, more preferably, from about 1.0 up to approximately 25.0 mg / kg body weight per day. The compounds can be administered on a regimen of 1 to 4 times a day.

Optimal dosages for administration can be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration and the progression of the morbid condition. In addition, the factors associated with the particular patient being treated, including patient age, weight, diet and administration time, will result in the need to adjust dosages.

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Someone skilled in the art will recognize that both in vivo assays and in vitro assays using known and generally accepted cell models and / or animals are predictive of the ability of a test compound to treat or avoid a given disorder.

Someone skilled in the art will further recognize that clinical trials in humans including trials first tested in humans, dose oscillation and efficacy trials, in healthy patients and / or in those suffering from a given disorder, can be completed accordingly. with procedures well known in clinical and medical techniques.

The following Examples are set forth to aid in the understanding of the invention, and are not intended and will not be construed to limit in any way the invention set forth in the claims that follow.

Example 1

((3,4-dihydro-2H-benzo [b] [1,4] dioxepin-3-yl) methyl) sulfamide (Compound No. 3)

image2

Catechol (5.09 g, 46.2 mmol) and potassium carbonate in acetonitrile were combined and heated at 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 cooled to room temperature and filtered. The filtrate was evaporated and the residue was diluted with water and extracted with diethyl ether (3 x). The combined organic solution was dried over MgSO4 and concentrated. Chromatography (2% ethyl ether in hexane) provided 3-methylene-3,4-dihydro-2H-benzo [b] [1,4] dioxepine as a colorless oil.

MS (IEP): 163.2 (M + H +).

1H NMR (300 MHz, CDCI3), � 6.94 (m, 4H), 5.07 (s, 2H), 4.76 (s, 4H).

3-methylene-3,4-dihydro-2H-benzo [b] [1,4] dioxepine (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 mixture was heated at reflux overnight. The reaction was cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 ml) was added. The solution was extracted with ethyl acetate (3 x 100 ml). The combined organic solution was dried over MgSO4. The solution was concentrated in vacuo and purified by chromatography (2% to 8% methanol in dichloromethane) to provide ((3,4-dihydro-2H-benzo [b] [1,4] dioxepin-3-yl) methyl) Amine as a colorless oil.

MS (IEP): 180.1 (M + H +).

1H NMR (300 MHz, DMSO), �: 6.92 (m, 4H), 4.21 (m, 2H), 4.07 (m, 2H), 3.33 (width, 2H), 3, 16 (d, J = 4 Hz, 1H), 2.72 (d, J = 4 Hz, 1H), 2.30 (m, 1H).

((3,4-dihydro-2H-benzo [b] [1,4] dioxepin-3-yl) methyl) amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g, 32.4 mmol) were combined in dry dioxane (60 ml) and heated at reflux overnight. Chloroform was added and the precipitate was filtered off. The filtrate was concentrated in vacuo and purified by chromatography (2% to 8% acetone in dichloromethane) to give the title compound as an off-white solid.

258.8 (M + H +).

1H NMR (300 MHz, DMSO), �: 6.92 (m, 4H), 6.71 (width, 1H), 6.59 (width, 2H), 4.19 (m, 2H), 4, 04 (m, 2H), 3.00 (m, 2H), 2.39 (m, 1H).

Example 2

N- (2,3-dihydro-benzo [1.4] dioxin-2-ylmethyl-sulfamide (Compound No. 1)

21 5

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Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (4.4 g, 26 mmol) and sulfamide (5.1 g, 53 mmol) were combined in 1,4-dioxane (100 ml) and combined. they refluxed for 2 h. The reaction was cooled to room temperature and a small amount of solid was filtered and discharged. The filtrate was evaporated in vacuo and the residue was purified using flash column chromatography (DCM: Methanol -10: 1) to provide a white solid. The solid was recrystallized from DCM to provide the title compound as a white solid.

mp: 97.5 - 98.5 ° C Elemental Analysis: Anal. Calc .: C, 44.25; H, 4.95; N, 11.47; S, 13.13. Elemental Analysis: Anal. Found: C, 44.28; H, 4.66; N, 11.21; S, 13.15. 1 H NMR (DMSO d6) � 6.85 (m, 4H), 6.68 (da s, 3H, NH), 4.28 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (m, 1H),

3.10 (m, 1 H).

Example 3 (Benzo [1,3] dioxol-2-ylmethyl) sulfamide (Compound No. 2)

image2

Catechol (10.26 g, 93.2 mmol), sodium methoxide (25% by weight in methanol, 40.3 g, 186 mmol) and methyl dichloroacetate (13.3 g, 93.2 mmol) were combined in dry methanol (100 ml). The mixture was heated at reflux overnight. The reaction was cooled to room temperature, acidified by the addition of concentrated hydrochloric acid and then reduced in volume under vacuum to approximately 50 ml. Water was added and the mixture was extracted with diethyl ether (3 x 100 ml). The combined organic solution was dried with MgSO4, concentrated to a brown solid and chromatographed (2% ethyl acetate in hexane) to provide benzo [1,3] dioxol-2-carboxylic acid methyl ester as a colorless solid.

MS (IEP): 195.10 (M + H +).

1H NMR (CDCI3), �: 6.89 (width, 4H), 6.29 (s, 1H), 4.34 (c, J = 7 Hz, 2H), 1.33 (t, J = 7 Hz, 3H).

To the benzo [1,3] dioxol-2-carboxylic acid methyl ester (7.21 g, 40.0 mmol) was added ammonium hydroxide (29% in water, 10 ml) and sufficient acetonitrile to make the mixture homogeneous (~ 5 ml). The solution was stirred for two hours at room temperature and then distilled water was added. The benzo [1,3] dioxol-2-carboxylic acid amide precipitated as a white solid and was collected by filtration and used without further purification.

MS (IEP): 160.00 (M + H +).

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

Benzo [1,3] dioxol-2-carboxylic acid amide (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 ml). Lithium aluminum hydride (LAH, 1M in THF, 39.5 ml; 39.5 mmol) was added slowly to the solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added destroying the LAH in excess. Aqueous sodium hydroxide (3.0 M, 100 ml) was added and the solution was extracted with ethyl acetate (3 x 100 ml). The combined organic solution was washed with water and dried over MgSO4. The solvent was evaporated to provide C-benzo [1,3] dioxol-2-yl-methylamine as a colorless oil.

MS (IEP): 152.1 (M + H +).

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Four. Five

1H NMR (CDCI3), �: 6.87 (m, 4H), 6.09 (t, J = 4 Hz, 1H), 3.13 (d, J = 4 Hz, 2H). C-benzo [1,3] dioxol-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3.74 g, 38.9 mmol) were combined in dry dioxane

(50 ml) and the solution was heated at reflux overnight. The reaction was concentrated and the residue was chromatography (2% to 10% acetone in dichloromethane) to provide the title compound as a white solid. MS (IEP): 230.0 (M + H +). 1H NMR (CDCI3), �: 6.87 (m, 4H), 6.25 (t, J = 4 Hz, 1H), 4.79 (width, 1H), 4.62 (width, 1H), 3.64 (d, J = 4 Hz, 2H).

Example 4 (2S) - (-) - N- (2,3-Dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (Compound No. 4)

image2

Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) in DMF (250 ml) were stirred and the (2R) -glycidyl tosylate reaction (22) was added , 8 g, 0.10 mol) and the reaction was stirred at 60 ° C for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to provide a white solid that was purified by flash column chromatography (DCM: Methanol-50: 1 ) providing ((2S) -2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol as a solid.

The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 ml) cooled to 0 ° C, p-toluenesulfonyl chloride (13.0 g, 68 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction was diluted with diethyl ether (1 L) and 1 N HCl (1.2 L). The organic phase was separated and washed twice with 1N HCI (500 ml), 4 times with water (150 ml), once with brine, dried (MgSO4) and evaporated in vacuo to provide a white solid that was purified by flash chromatography (HeptEA -2: 1) to provide toluene-4-sulfonic acid (2S) -2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl ester as a white solid.

The white solid was combined with potassium phthalimide (14.4 g, 78 mmol) in DMF (250 ml) and heated at reflux for 1 hour, cooled to room temperature and poured into vigorously stirred water (1.5 L ) and stirred 30 min. The white solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and allowed to air dry providing one (2S) -2- (2,3-dihydro-benzo [1,4 ] dioxin-2-ylmethyl) -isoindol-1,3-dione as a white powdery solid.

The powdery white solid was combined with hydrazine (2.75 g, 86 mmol) in EtOH (225 ml) and heated at reflux for 2 h, cooled to room temperature and 1 N HCl was added at pH 1.0 and stirred for 15 min. The white solid was filtered and washed with fresh EtOH (solid waste) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to provide a light yellow oil. The oil was purified by flash column chromatography (DCM: MeOH -10: 1) to provide an oil. A part of the oil (4.82 g, 29 mmol) in 2-propanol (250 ml) was treated with 1 N HCI (30 ml) and heated in a steam bath until it became homogeneous and then allowed to cool to temperature ambient. After 3 h, the mixture was cooled on ice for 2 h. A white squamous solid (the corresponding HCI salt of (2S) -C- (2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine) was filtered separately and then recrystallized again from of 2-propanol providing a white solid.

[�] D = -69.6 (c = 1.06, EtOH).

The white solid was partitioned between DCM and diluted NaOH and the DCM was dried (NaSO4) and evaporated in vacuo to afford (2S) -C- (2,3-dihydro-benzo [1,4] dioxin-2-yl) - Methylamine as an oil.

[�] D = -57.8 (c = 1.40, CHCI3).

The oil (2.1 g, 12.7 mmol) and sulfamide (2.44 g, 25.4 mmol) were refluxed in dioxane (75 ml) for 2 h and the crude product was purified by column chromatography ultrafast (DCM: MeOH 10: 1) providing a white solid, which was recrystallized from DCM providing the title compound as a white crystalline solid.

mp 102-103�.

[�] D = -45.1 ° (c = 1.05, M);

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1H NMR (DMSOd6) � 6.86 (m, 4H), 6.81 (da 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: Anal. Calc .: C, 44.25; H, 4.95; N, 11.47; S, 13.13. Anal. Found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.

Example 5 N- (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -N ', N'-dimethylsulfamide (Compound No. 6)

image2

Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) in DMF (10 ml) were combined and cooled in an ice bath as dimethylsulfamoyl chloride (1.44 g, 10 mmol) was added. The reaction mixture was then cooled for 3 hours with continuous cooling. The reaction mixture was partitioned between ethyl acetate and water and the ethyl acetate solution was washed with brine, dried (MgSO4) and evaporated in vacuo to provide an oil. The oil was purified using flash column chromatography (ethyl acetate: Heptane -1: 1) to provide a white solid, which was recrystallized (ethyl acetate / Hexane) to give the title compound as a white flocculant solid.

mp 76-78 ° C

MS 273 (MH +).

Elemental Analysis:

Anal. Calc .: C, 48.52; H, 5.92; N, 10.29; S, 11.78.

Anal. Found: C, 48.63; H, 5.62; N, 10.20; S, 11.90.

1H NMR (CDCI3) � 6.87 (m, 4H), 4.59 (da 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] dioxin-2-ylmethyl) -N-methylsulfamide (Compound No. 7)

image 1

Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (825 mg, 5 mmol) was dissolved in ethyl formate (15 ml), refluxed for 30 minutes and evaporated in vacuo to afford N- ( 2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -formamide as an oil.

The oil in diethyl ether (25 ml) was treated with 1 M LAH in THF (9.0 ml, 9.0 mmol) at 0 ° C and stirred for 5 h at room temperature. The reaction was cooled in an ice bath and quenched with water (0.50 ml), followed by 3 N NaOH (0.50 ml) and water (0.50 ml). The mixture was then stirred at room temperature for 1 h. The solid was filtered and the filtrate was evaporated in vacuo to provide a residue that was partitioned between 1N HCl and diethyl ether. The aqueous phase was basified with 1 N NaOH and extracted with diethyl ether. The organic phase was dried (MgSO4) and evaporated in vacuo to afford (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -methyl amine as an oil.

MS 180 (MH +).

1H NMR (CDCI3) � 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).

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The oil (380 mg, 2.1 mmol) and sulfonamide (820 mg, 8.5 mmol) were combined in dioxane (15 ml), refluxed for 1.5 hours and evaporated in vacuo to provide a crude residue. . The residue was purified by column chromatography (ethyl acetate / Heptane 1: 1) and the resulting solid was recrystallized from ethyl acetate / Hexane to give the title compound as a white solid.

5 mp 97-98�. MS 257 (M-1). Elemental Analysis: Anal. Calc .: C, 46.50; H, 5.46; N, 10.85; S, 12.41. Anal. Found: C, 46.48; H, 5.65; N, 10.90; S, 12.07.

10 1 H NMR (CDCI3) � 6.86 (m, 4H), 4.52 (sa, 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] dioxin-2-ylmethyl) -sulfamide (Compound No. 8)

image2

Following the procedure set forth in Example 4 above, 4-chlorocatechol was reacted to provide a mixture of (2S) -C- (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine and (2S) -C- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine (about 3: 1 ratio of 6-chloro: 7-chloro isomers by HPLC RP).

The mixture was dissolved in 2-propanol (100 ml) and 1 N HCl in diethyl ether was added until pH = 1.0 was achieved. The hydrochloride salt that precipitated was filtered (2.65 g) and recrystallized from methanol / lPA to give white crystals. The white crystals were partitioned between DCM and diluted NaOH. The DCM was dried and evaporated in vacuo

providing purified (2S) -C- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine as an oil.

[�] D = -67.8 (c = 1.51, CHCI3).

The oil (7.75 mmol) and the sulfonamide (1.50 g, 15.5 mmol) were combined in dioxane (50 ml) and refluxed for 2.0 h, cooled to room temperature and evaporated to vacuum providing a solid. The product is

25 purified by means of a flash column using DCM / methanol 20: 1 to provide the title compound as a white solid.

MS 277 (M-1).

[�] D = -59.9 ° (c = 1.11, M).

1H NMR (CDCI3) � 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, 30 11.5 Hz, 1H), 4.05 (dd, J = 7.1, 11.5 Hz, 1H), 3.45 (m, 2 H).

Elemental Analysis:

Anal. Calc .: C, 38.78; H, 3.98; N, 10.05.

Anal. Found: C, 38.80; H, 3.67; N, 9.99.

The filtrates of the crystallized (2S) -C- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine hydrochloride salt

35 previously prepared were recovered (about 1: 1 of 6-chloro: 7-chloro isomers) and evaporated in vacuo to provide a solid, which was partitioned between DCM (200 ml) and diluted NaOH (0.5 M, 50 ml) The DCM solution was washed once with brine, dried (Na2SO4) and evaporated in vacuo to provide an oil, which was purified by reverse phase HPLC (10-50% ACN with 0.16% TFA in water with 0.20% TFAQ) providing (2S) -C- (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine as a residue.

The residue was combined with sulfonamide (0.90 g, 9.4 mmol) in dioxane (25 ml) and refluxed for 2.5 hours, cooled to room temperature and evaporated in vacuo to provide an oil. The oil was purified by flash column chromatography using DCM / methanol-10: 1 to provide (2S) - (-) - N- (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl ) -sulfamide as a white solid.

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MS 277 (M-1).

1H NMR (CDCI3 / CD3OD) � 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).

image2

Example 8

Chroman-2-ylmethylsulfamide (Compound No. 10)

Chroman-2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol) were combined in DCM (40 ml) and DMF (10 ml). Dimethylaminopropylethylcarbodiimide (EDC, 4.84 g, 25 mmol) was added at room temperature and the reaction mixture was stirred for 30 minutes. Ammonium hydroxide (2.26 ml, 33.4 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with DCM (50 ml) and water (50 ml) and the pH of the mixture was adjusted to approximately pH = 3.0 with 1 N HCI. The DCM was separated and the aqueous phase was extracted twice. with DCM. The combined DCM phase was dried (Na2SO4) and evaporated in vacuo to provide an oil, which was purified with flash column chromatography (ethyl acetate) to provide an oil.

The oil (5.35 g, 30 mmol) in THF (90 ml) was stirred as 1M LAH in THF (36 ml, 36 mmol) was added and the reaction mixture was then stirred at room temperature for 20 h. The reaction was quenched with water, stirred for 2 hours, the solution was decanted, dried (Na2SO4) and evaporated in vacuo to afford C-chroman-2-yl-methylamine as an oily amine.

The oily amine (1.63 g, 10 mmol) and the sulfonamide (1.92 g, 20 mmol) were combined in dioxane (50 ml) and refluxed for 2 hours. The solution was cooled and evaporated in vacuo to provide an oil, which was purified by column chromatography (DCM: Methanol 10: 1) to provide a white solid. The solid was recrystallized from ethyl acetate / hexane to provide chroman-2-ylmethylsulfamide as a white solid.

mp 100-101 �.

MS 241 (M-1).

Elemental Analysis:

Anal. Calc .: C, 49.57; H, 5.82; N, 11.56; S, 13.23.

Anal. Found: C, 49.57; H, 5.80; N, 11.75; S, 13.33.

Example 9

2- (2,3-dihydro-benzo [1,4] dioxin-2-yl) -ethylsulfamide (Compound No. 16)

image2

Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl- (2,3-dihydrobenzo [1,4] dioxin) (6.87 g, 30 mmol) in DMSO (90 ml) and stirred at room temperature for 20 h. The reaction mixture was then diluted with water (250 ml) and extracted twice with diethyl ether. The diethyl ether was washed with water, then washed twice with brine, dried (Na2SO4) and evaporated in vacuo to afford 2-cyanomethyl- (2,3-dihydrobenzo [1,4] dioxin) as a white solid.

1H NMR (CDCI3) � 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

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(d, J = 6.1 Hz, 2H).

The 2-cyanomethyl- (2,3-dihydrobenzo [1,4] dioxin) was dissolved in THF (50 ml) and 1M BH3 in THF (80 ml, 80 mmol) was added and the reaction mixture was refluxed for 5 h, then stirred at room temperature for 16 h. With ice bath cooling, 2N HCl was added until pH = 1.0 was reached. The reaction mixture was then stirred for 1 hour at room temperature and evaporated in vacuo to provide an oil. The oil was partitioned between 3 N NaOH and diethyl ether, and the diethyl ether solution was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 2- (2.3 dihydrobenzo [1,4] dioxin-2 -il) crude ethylamine.

MS (M + H) + 180.

The crude 2- (2,3-dihydrobenzo [1,4] dioxin-2-yl) ethylamine in dioxane (100 ml) was combined with sulfamide (3.0 g, 31 mmol) and heated at reflux for 2 hours . The solution was cooled and evaporated in vacuo to provide an orange solid, which was purified by column chromatography (DCM: MeOH-10: 1) to provide a white solid. The solid was recrystallized from DCM to provide the title compound as a solid.

MS (M-1) 257

PF 101-103 ° C (corr.).

1H NMR (CDCI3): � 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:

Measured: C, 46.48; H, 5.60; N, 10.81; S, 12.41.

Calculated: C, 46.50; H, 5.46; N, 10.85; S, 12.41.

Example 10 (2S) - (-) - N- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (Compound No. 29)

image2

4,5-Dichlorocatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) in DMF (200 ml) were stirred. (2R) -glycidyltosylate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 ° C for 24 h. The reaction mixture was cooled to room temperature and then diluted with ice water (600 ml) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, twice with brine, dried (MgSO4) and evaporated in vacuo to provide a viscous oil of (2S) -2- (6,7-dichloro-2 , 3-dihydro-benzo [1,4] dioxin) methanol.

The oil (2S) -2- (6.7 dichloro-2,3-dihydro-benzo [1,4] dioxin) methanol (6.4 g, 27 mmol) was dissolved in pyridine (50 ml) cooled to 0 ° C. Then, p-tolue nosulfonyl chloride (5.2 g, 27 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with diethyl ether and 1 N HCl (750 ml) and the organic phase was separated and washed twice with 1 N HCl (250 ml), once with water (150 ml), twice with brine , dried (MgSO4) and evaporated in vacuo to provide light yellow solid of ester (2S) -6,7-dichloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl of toluene-4 acid -sulfonic.

1H NMR (CDCI3): � 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 (8.0 g, 20.5 mmol) dioxin-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with phthalimide of potassium (6.1 g, 33 mmol) in DMF (75 ml) and heated at reflux for 1 hour, cooled to room temperature and poured into water with vigorous stirring (0.5 l) and then stirred 30 min . The white solid was filtered and the solid was washed several times with water, 2% NaOH and water again and then allowed to air dry providing (2S) -2- (6,7-dichloro-2,3-dihydro- benzo [1,4] dioxin-2-ylmethyl) -isoindol-1,3-dione (6.0 g, 80%) as a white powdery solid.

The white powdery solid was combined with hydrazine (1.06 g, 33 mmol) in EtOH (80 ml) and heated under reflux for

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2 hours, then cooled to room temperature. 1N HCl was added by adjusting the pH of the reaction mixture to pH 1.0 and the reaction mixture was then stirred for 15 minutes. The white solid was filtered and washed with fresh EtOH (solid waste) and the filtrate was evaporated in vacuo to a solid, which was partitioned between ethyl ether and dilute aqueous NaOH. The diethyl ether solution was dried (Na2SO4) and evaporated in vacuo to provide a viscous oil of (2S) -2-aminomethyl- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxin).

1H NMR (CDCI3): � 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 part of the oil (3.8 g, 16 mmol) and sulfonamide (3.1 g, 32.4 mmol) in dioxane (100 ml) were refluxed for 2 h and the crude product was purified by flash column chromatography. (DCM: MeOH 20: 1) providing the title compound as a white solid, which was recrystallized from ethyl acetate / hexane to provide the title compound as a white crystalline solid.

MS [M-H] -311.0.

mp 119-121 ° C.

[�] D = -53.4 ° (c = 1.17, M)

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

Elemental Analysis:

Elemental Analysis:

Measured: C, 34.52;

H, 3.22; � N, 8.95; CI, 22.64; S, 10.24

Calculated: C, 34.64; �

H, 2.68; N, � 8.87; CI, 22.94; S, 10.35.

Example 11

(2S) - (-) - N- (7-amino-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (Compound No. 36)

image2

(2S) - (-) - N- (2,3-dihydro-7-nitro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (1.2 g, 4.15 mmol) was prepared, at starting from 4-nitrocatechol according to the procedure outlined in Example 4. The (2S) - (-) - N- (2,3-dihydro-7-nitro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide, was then combined with 10% Pd / C in methanol (120 ml) and stirred under a hydrogen atmosphere (268,905 pascals (39 psi)) at room temperature for 3 hours. The solids were filtered and washed with 10% M in DCM and the filtrate was evaporated in vacuo to afford the crude product. The crude product was dissolved in 0.2 N HCl (25 ml), frozen and lyophilized to provide the title compound as a white flaky solid, as the corresponding hydrochloride salt.

MS (M + H) + 260

1H NMR (DMSO d6): � 10.2 (da 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] dioxin-2-ylmethyl) -sulfamide (Compounds No. 19)

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image2

The title compound was prepared according to the procedure described in Example 4 above, starting with 4-methylcatechol, providing a white solid, which was recrystallized from ethyl acetate / hexane to provide the title compound as a white solid.

MS [M-H] -257.

1H NMR (CDCI3): � 6.76 (m, 1H), 6.66 (m, 2H), 4.80 (m, 1H), 4.57 (da s, 1H), 4.40 (m , 1H), 4.28 (m, 1H), 4.03 (dd, J = 6.9, 11.4 Hz, 1H), 3.45 (m, 2H), 2.25 (s, 3H) .

Elemental Analysis

Calculated: C, 46.50; H, 5.46; N, 10.85; S, 12.41

Found: C, 46.65; H, 5.60; N, 10.84; S, 12.61.

Example 13

Dominant-Submissive Relations (DSR) in Live Rat Test

The DSR trial is divided into two models: Reduction of the Dominant Behavior Model (RDBM) of mania and Reduction of the Submissive Behavior Model (RSBM) of depression. RDBM, in which dominant animals are treated with test compound, is predictive of the ability of the test compound to treat mania. RSBM, in which submissive animals are treated with the test compound, is predictive of the ability of the test compound to treat depression.

Male Sprague Dawley rats (140 to 160 g) from Charles River Laboratories Wilmington, MA were used in this test. Shipments of rats were received at two week intervals. Each shipment was through a quarantine of five days, acclimatization period of one week and selection procedure of one week, followed by five weeks of treatment with drug or vehicle to those selected couples.

The rats were housed four per cage. Access to food was restricted to one hour per day after testing Monday through Thursday. After testing Friday, the rats had free access to food until they fasted again on Sunday. At no time was the water rats deprived. The periods of deprivation of food used had little effect on weight gain since the average weight of the rats was approximately 300 g at the end of the study. At the conclusion of the experiment, the rats were sacrificed by decapitation, the blood was collected from the trunks and brains for in vitro experiments and for drug concentration measurements.

The basic test apparatus consisted of two chambers connected by a tunnel only long enough to allow a rat to pass through it at once. On the ground, in the middle of the tunnel was a container of sweetened milk. This basic apparatus was replicated, so that a total of four pairs of rats can be tracked by video simultaneously. The camera can distinguish rats marked by different colors. Thus, the heads of the rats were colored for the purpose of tracking with video, red in one cage and yellow in the other. Only one animal at a time can have comfortable access to the feeder, but both animals can drink milk during the five-minute daily session. During the five-minute daily sessions, the time spent in the feeder area for each rat was recorded using the video tracking software and saved in a text file.

The test began with a random assignment of rats in pairs. Each member of a couple was placed in an opposite chamber of the test apparatus. The time spent in the feeder area for each animal was recorded. During the first week (five days) of testing the animals became accustomed to the new environment. Dominance was assigned to the animal with the highest rating during the second week of testing if three criteria were achieved. First, there must be a significant difference (two-tailed t-test, p <0.05) between the average daily drink ratings of both animals. Second, the valuation of the dominant animal must have been at least 25% larger than the valuation of the submissive animal. Finally, there should be no "investments" during the couple selection week where the theoretically submissive rat exceeds the valuation of its dominant partner on isolated occasions. Ideally there were minimal investments during acclimatization week as well. Approximately twenty-five to thirty percent of the initial animal couples met these criteria and only these couples continued in the study.

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Significant differences were determined between the time spent at the feeder by the dominant and submissive rats by ANOVA using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA) followed by a two-tailed t-test (P <0.05). Comparisons were made between treatment groups using standardized dominance level values in the paired animals. The level of dominance is a value that measures the social relationship between matched subjects. Dominance Level (DL) = FTD-FTS where FTD is the feeding time of the dominant rats and FTS is the feeding time of the submissive rats. Normalization was carried out according to the formula:

Dominance Level (week n in%) = (Dominance Level (week n)) / (Dominance Level (week 2))

The statistical significance of the difference in dominance level between the control group (pairs of rats where both dominant and submissive animals were treated with vehicle) and the treatment group (submissive rats were treated with drug and dominant rats with vehicle) was determined with ANOVA, followed by a t-test. The value of the activity onset time at 50% response (AOT-50) and the minimum and maximum drug response was calculated based on the reduction of the dominance level value using nonlinear regression analysis (GraphPad Software, Inc ., San Diego, CA). The normalized DL values were used for this calculation, where the DL values per treatment week were normalized as a percentage of the value of the second week (pretreatment) of that couple according to the above formula. In these adjustments, the minimum response (DL) determined positive drug activity, which corresponds to efficacy, provided that the DL values were always reduced if the response to a drug was positive. In the case of the negative response to a drug (worsening of symptoms), the DL values were increased. If the drug did not have such activity, the maximum response did not exceed 100%. Any maximum DL value significantly higher than the control value (approximately 100%) indicated negative drug activity.

Compound No. 8 was evaluated in the RDBM of rats according to the procedure described in more detail below.

The dominant rat groups were treated orally each day with Compound No. 8; at 0.05 mg / kg (n = 4), at 0.5 mg / kg (n = 6), at 2.5 mg / kg (n = 6), at 5.0 mg / kg n = 6) and at 50.0 mg / kg (n = 3). A vehicle control group of dominant rats was treated with 0.5% methylcellulose (n = 3) and a second control group of dominant rats was treated intraperitoneally every day with sodium valproate at 30 mg / kg (n = 6 from of 2 studies of n = 3 each).

All treatments were administered approximately 1 hour before the test.

All treatments started on Saturday after the second week of testing (selection week). Compound No. 8 was administered orally (p.o). When dominant animals were treated with Compound No. 8 at 0.05 mg / kg, 0.5 mg / kg and 50.0 mg / kg, the difference between dominant and submissive rats was lost after the first week of treatment; and after the second week of treatment when administered at 2.5 mg / kg and 5.0 mg / kg. Similarly, when the dominant animals were treated with sodium valproate, the difference between dominant and submissive rats was also lost after the first week of treatment. In this embodiment, it was observed that the permissiveness of dominant rats treated with Compound No. 8 or with sodium valproate was increased. Thus the dominant rats treated allowed their submissive partners to increase their feeding time.

Comparing effects of drugs and different doses, the data were normalized to the weekly initial control values. The strongest effect of Compound No. 8 was observed at a dosage of 0.5 mg / kg with a significant difference in level of dominance (DL) values between vehicle and rats treated with compound starting in the second week and continuing to through the duration of the treatment of 5 weeks. Higher doses of Compound No. 8 (2.5 mg / kg, 5.0 mg / kg and 50.0 mg / kg) showed a weaker response, which was not significantly different from that observed with the dose of 0.5 mg / kg

In comparison, animals treated with sodium valproate (30 mg / kg) consistently showed a decreased level of dominance after the second week of treatment with the effect increasing in the following weeks. The effect of lithium chloride (100 mg / kg) was significantly different from the control only after the third week of treatment.

To estimate time of onset activity (AOT), the daily average values for feeding time of pairs of dominant and submissive animals were planned and the significant differences between these two groups were calculated using two-tailed t-test. The first day of lack of statistical significance took place after treatments with Compound No. 8 at 0.05 mg / kg on the 3rd day; at 0.5 mg / kg on the 4th day, at 2.5 mg / kg on the 10th day, at 5.0 mg / kg on the 11th day and at 50.0 g / kg on the 3rd day.

To compare activity onset time (AOT) between different treatments, the time of onset of activity was estimated from the nonlinear regression adjustment. The nonlinear regression model was adjusted for each drug and normalized daily DL values.

AOT50 for Compound No. 8 at 0.05 mg / kg and 0.5 mg / kg was significantly shorter than that of lithium.

The effects of Compound No. 8 on the RDBM were dose dependent, with a calculated ED50 of 0.03 ± 0.004

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mg / kg [CI = 0.01-0.04] and Emax of 116.4 ± 2.3% [CI = 109.2-123.6].

In this test, Compound No. 8 reduced the dominant behavior by indicating that the compound is active as an antimaniac agent.

Example 14

Dominant-Submissive Relations (DSR) in Live Rat Test

The DSR trial is divided into two models: Reduction of the Dominant Behavior Model (RDBM) of mania and Reduction of the Submissive Behavior Model (RSBM) of depression. RDBM, in which dominant animals are treated with test compound, is predictive of the ability of the test compound to treat mania. RSBM, in which submissive animals are treated with the test compound, is predictive of the ability of the test compound to treat depression.

Male Sprague Dawley rats (140 to 160 g) from Charles River Laboratories Wilmington, MA were used in this test. Shipments of rats were received at two week intervals. Each shipment was through a quarantine of five days, acclimatization period of one week and selection procedure of one week, followed by five weeks of treatment with drug or vehicle to those selected couples.

The rats were housed four per cage. Access to food was restricted to one hour per day after testing Monday through Thursday. After testing Friday, the rats had free access to food until they fasted again on Sunday. At no time was the water rats deprived. The periods of deprivation of food used had little effect on weight gain since the average weight of the rats was approximately 300 g at the end of the study. At the conclusion of the experiment, the rats were sacrificed by decapitation, the blood was collected from the trunks and brains for in vitro experiments and for drug concentration measurements.

The basic test apparatus consisted of two chambers connected by a tunnel only long enough to allow a rat to pass through it at once. On the ground, in the middle of the tunnel was a container of sweetened milk. This basic apparatus was replicated, so that a total of four pairs of rats can be tracked by video simultaneously. The camera can distinguish rats marked by different colors. Thus, the heads of the rats were colored for the purpose of tracking with video, red in one cage and yellow in the other. Only one animal at a time can have comfortable access to the feeder, but both animals can drink milk during the five-minute daily session. During the five-minute daily sessions, the time spent in the feeder area for each rat was recorded using the video tracking software and saved in a text file.

The test began with a random assignment of rats in pairs. Each member of a couple was placed in an opposite chamber of the test apparatus. The time spent in the feeder area for each animal was recorded. During the first week (five days) of testing the animals became accustomed to the new environment. Dominance was assigned to the animal with the highest rating during the second week of testing if three criteria were achieved. First, there must be a significant difference (two-tailed t-test, p <0.05) between the average daily drink ratings of both animals. Second, the valuation of the dominant animal must have been at least 25% larger than the valuation of the submissive animal. Finally, there should be no "investments" during the couple selection week where the theoretically submissive rat exceeds the valuation of its dominant partner on isolated occasions. Ideally there were minimal investments during acclimatization week as well. Approximately twenty-five to thirty percent of the initial animal couples met these criteria and only these couples continued in the study.

The terminal blood samples (0.5-1.0 ml) were collected after the experiment in heparinized tubes. Blood samples were centrifuged for cell removal and then transferred 200 ml of plasma supernatant to a clean vial, placed on dry ice, and subsequently stored in a freezer at -80 ° C before analysis. Two thousand milliliters of acetonitrile containing internal standard was added to 100 ml of plasma or brain tissue precipitating proteins and / or tissue residues. The samples were centrifuged and the supernatant was removed for analysis by liquid chromatography-quadruple triple mass spectrometry (LC-MS-MS). Calibration standards were prepared by adding appropriate volumes of stock solution directly into blank plasma or brain tissue homogenates and treated identically to the collected samples. Calibration standards were prepared in the range of 0.01 to 10 �M for quantification. CL-IE-EM / EM analysis (negative mode) was performed using multiple reaction monitoring (MRM) for detection of characteristic ions for the test compound.

Significant differences were determined between the time spent at the feeder by the dominant and submissive rats by ANOVA using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA) followed by a two-tailed t-test (P <0.05). Comparisons were made between treatment groups using standardized dominance level values in the paired animals. The level of dominance is a value that measures the social relationship between matched subjects. Dominance Level (DL) = FTD-FTS where FTD is the feeding time of the dominant rats and FTS is the feeding time of the submissive rats. Normalization was carried out according to the formula:

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Dominance Level (week n in%) = (Dominance Level (week n)) / (Dominance Level (week 2))

The statistical significance of the difference in dominance level between the control group (pairs of rats where both dominant and submissive animals were treated with vehicle) and the treatment group (submissive rats were treated with drug and dominant rats with vehicle) was determined with ANOVA, followed by a t-test. The value of the activity onset time at 50% response (AOT-50) and the minimum and maximum drug response was calculated based on the reduction of the dominance level value using nonlinear regression analysis (GraphPad Software, Inc ., San Diego, CA). The normalized DL values were used for this calculation, where the DL values per treatment week were normalized as a percentage of the value of the second week (pretreatment) of that couple according to the above formula. In these adjustments, the minimum response (DL) determined positive drug activity, which corresponds to efficacy, provided that the DL values were always reduced if the response to a drug was positive. In the case of the negative response to a drug (worsening of symptoms), the DL values were increased. If the drug did not have such activity, the maximum response did not exceed 100%. Any maximum DL value significantly higher than the control value (approximately 100%) indicated negative drug activity.

Compound No. 8 was evaluated in the Submissive Rat Behavior Reduction Model (RSBM) of depression (Malatynska, E., Rapp, R., Harrawood, D. and Tunnicliff, G., Neuroscience and Biobehavioral Review, 82 (2005) 306-313; Malatynska, E. and Knapp, RJ, Neuroscience and Biobehavioral Review, 29 (2005) 715-737).

More specifically, compound # 8 was administered p.o. (orally) to the submissive rats at 2.5 mg / kg (n = 8), 12 mg / kg (n = 12), 60 mg / kg (n = 12) and 120 mg / kg (n = 7), once a day for 5 weeks while the dominant partners were dosed with vehicle (0.5% aqueous methylcellulose). As controls, additional groups of rats i.p. with fluoxetine at 10.0 mg / kg (n = 10) and i.p. with venlafaxine at 30.0 mg / kg (n = 6). All treatments were administered approximately 1 hour before the test. Compound No. 8 was observed by reducing submissive behavior in a dose dependent manner.

When submissive animals were treated with Compound No. 8, the significant difference between dominant and submissive rats was lost after the first week of treatment. This was true for all doses used, indicating that the onset of activity was dose independent. In contrast, when submissive animals were treated with fluoxetine the significant difference between dominant and submissive rats was lost after the third week of treatment. (This data analysis procedure does not take into account the fluctuation of behavior that takes place within the control group). Comparing different effects of drugs and doses the data were normalized to the weekly initial control values.

The Dominance Level (DL) values in the group of submissive rats treated with doses of 2.5 mg / kg of Compound No. 8 did not differ significantly from the control. However, the group treated with Compound No. 8 at 12.0 mg / kg showed significantly different DL values of vehicle treated controls after the second, fourth or fifth week of treatment. Similarly, the group treated with Compound No. 8 at 60 mg / kg showed a significant difference in DL values relative to the vehicle starting in the first week and continuing for the duration of the 5-week treatment. At the highest dose (120 mg / kg), the Compound is no. 8, the DL values were significantly different from the control group after the first week, however, this significance dissipated after the second week of treatment.

Animals treated with fluoxetine (10 mg / kg) consistently showed increased susceptibility during the first week of treatment. In comparison to animals treated with fluoxetine (10 mg / kg), the groups treated with Compound No. 8 did not show this effect. At a dose of 60.0 mg / kg of Compound No. 8, the difference in DL values with fluoxetine treated group was statistically significant at p <0.001 after the first week and at <0.05 after the second week of treatment . There was no significant difference between normalized DL levels of couples treated with fluoxetine and Compound No. 8 during weeks of subsequent treatment.

To estimate time of activity onset, the daily average values for feeding time of dominant and submissive pairs of animals were planned and significant differences between these two groups were calculated using the two-tailed t-test. The first day of consistent lack of statistical significance took place after treatment with Compound No. 8 at 12.0 mg / kg on the 6th day and at 60 mg / kg on the 4th day. There was no consistent loss of significance between the feeding time of dominant and submissive rats after treatment with Compound No. 8 at 2.5 mg / kg and at 120.0 mg / kg.

To compare the time of onset of activity between different treatments, the time of onset of activity was estimated from the non-linear regression adjustment. The nonlinear regression model was adjusted for each drug and for standardized daily dose DL values. The Activity Onset Time for this purpose of 50% (AOT50) and the Emax for Compound No. 8 at 2.5 mg / kg, 12 mg / kg and 60 mg / kg was 2.1; 5.3 and 1.6 days, respectively and was not significantly different between doses. The maximum effect derived from this analysis was 52.4 ± 32.7% (SEM), 87.9 ± 42.6% (SEM) and 116.9 ± 29.5% (SEM) for the dose of 2, 5 mg / kg, 12 mg / kg and 60 mg / kg respectively and it was not significantly different between these doses.

In summary, the effect of Compound No. 8 in the RSBM trial was dose dependent, with a calculated ED50

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6.6 ± 0.8 mg / kg [CI = 3.0-10.2] and Emax of 131.4 ± 4.7% [CI = 111.3-151.5].

In this test, Compound No. 8 reduced the submissive behavior indicating that the compound is active as an antidepressant agent.

Examples 15-17 Repeated Electrical Stimulation and Bipolar Cycle

The discussion in the current literature suggests that the underlying repeated electrical stimulation mechanisms may be similar to the bipolar cyclization mechanism and / or may be related to mood stabilization. Thus, the trials of repeated electrical tonsil stimulation and repeated hippocampal electrical stimulation described in more detail below can be predictive of the ability of a test compound to treat cyclization associated with, characteristic of or symptomatic of bipolar disorder. (Ghaemi, SN, Boiman, EE and Goodwin, FK, Soc. Of Bio. P, (1999), vol. 45, pages 137-144; Stoll, AL and Severus, WE, Harvard Rev. P, July / August ( 1996), Vol. 4, No. 2, page 77-89).

Example 15

Tonsil Repeated Electrical Stimulation Test (Repeated Electrical Stimulation Prevention)

Briefly, the test procedure was as follows. Sprague-Dawley rats, adult males, weighing between 250-300 g were obtained from Charles River, Wilmington, MA. All animals were housed in a 12:12 hour light-dark cycle and were allowed free access to both food (Prolab RMH 3000) and water except when they were removed from the cage for experimental procedures. The animals were cared for in a manner consistent with the recommendations in the National Research Council Publication, "Guide for the Care and Use of Laboratory Animals" in a temperature-controlled, pesticide-free facility. Repeated electrical stimulations were routinely carried out between 9 AM - 2 PM avoiding any circadian variations.

Compound No. 8 was triturated in a small volume of 0.5% methylcellulose, sonicated for 10 minutes, and brought to a final volume with 0.5% methylcellulose. Compound No. 8 was administered systemically (ip) in a volume of 0.04 ml / 10 g body weight and all tests were carried out at the predetermined time of the 0.5 hour peak effect after administration. ip.

The ability of Compound No. 8 to block the expression of attacks activated by the amygdala was determined as follows. The rats were anesthetized with a cocktail of ketamine (120 mg / kg, i.p.) and xylazine (12 mg / kg, i.p.). Under aseptic conditions, a bipolar electrode (Plastic One, Roanoke, VA) was stereotactically implanted within the right vasolateral tonsil (AP -2.2, ML -4.7, DV -8.7; Paxinos and Watson). The anteroposterior and lateral measurements were from the bregma, while the dorsoventral measurement was from the surface of the skull. Sterile cranial screws (3-4) were implanted for the indifferent reference electrode. The electrodes were fixed using dental cement and acrylic. The wound was closed using sterile 18/8 Michel suture hooks (Roboz, Gaithersburg, MD). The neomycin antibiotic ointment was applied to the wound and an individual dose of penicillin (60,000 IU, im, AgriLabs) was administered to each rat before returning them to clean cages during a week of postoperative recovery.

Repeated electrical stimulation of the tonsil was carried out after according to the following protocol. After a brief acclimatization (<5 minutes) to the recording chamber, baseline EEG records (MP 100, Biopac Systems Inc., Goleta, CA) were obtained. The rats were randomized receiving either vehicle (0.5% methylcellulose) or Compound No. 8 (75 mg / kg, i.p.) (n = 10 rats per group). On the day of the experiment, a single dose of Compound No. 8 was administered or 0.5% methylcellulose was administered 30 minutes before the amygdala stimulation (200 Å for 2 seconds). The assessment of behavioral attacks and the duration of AD were recorded for rats in each treatment group. The behavioral attack ratings were determined using the Racine scale; that is, 0 = no answer; phase 1 = grooming / hyperactivity; phase 2 = head / tremor balancing, phase 3 = spasticity of unilareral anterior limbs; phase 4 = spasticity with rearing; and phase 5 = generalized tonic-spastic attack with rearing and fall (Racine, 1972). Activity after discharge (AD) was recorded digitally for up to 180 seconds after the stimulation train and the duration of the main AD was measured. Rats were considered fully activated when they presented five generalized Phase 4 or 5 attacks. Daily stimulations were continued for 13 consecutive days in all three groups until the rats in the vehicle-treated group were fully activated (ie, five attacks consecutive in Phase 4 or 5). At this time, all rats were left a stimulus-free and drug-free period of one week; after which they were retested in the absence of drugs with the same stimulus used during the acquisition phase (i.e., days 1-13). Rats treated with Compound No. 8 were subsequently stimulated once a day until they reached a fully activated state.

The duration after discharge (AD) both in the groups treated with vehicle and in the groups treated with Compound No. 8 presented a progressive increase during the course of the acquisition phase of repeated electrical stimulations. No statistical difference was observed between treatment groups.

Compound No. 8 prevented the acquisition of the full generalized activated attack. This conclusion is based on the finding that the evaluation of attacks of the drug-free and stimulus-free period remained

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significantly lower than that of the rats in the vehicle-treated group (Compound No. 8 = 1.4 ± 0.40 vs. vehicle = 4.6 ± 0.24). Additionally, when stimulated in the absence of a drug, the evaluation of rats' attacks in the treatment of Compound No. 8 was increased at a rate that was parallel to that observed in rats treated with vehicle - backing the conclusion that the Compound No. 8 delayed the acquisition of activation by several days.

The results of this study demonstrated that Compound No. 8 has the ability to modify the development of repeated electrical stimulation in the activated rat model of partial epilepsy tonsil. These results are consistent with the conclusion that Compound No. 8 has disease modifying effects. This conclusion in the finding that the assessment of attacks, at the conclusion of the drug-free and stimulation-free period, of rats in the treatment group with Compound No. 8 remained significantly lower than in rats treated with vehicle. In addition, once the stimulation protocol was resumed in the absence of a drug, the attack assessment progressed at a rate that was parallel to the vehicle treated group.

The finding that the assessment of attacks, but not the duration after discharge, in the compound treatment group one week after the stimulus and in the drug-free week was markedly lower than that of the vehicle-treated group suggests that the Compound 8 prevented the acquisition of generalized attack secondarily but not the focal attack.

Example 16

Hypocampic Repeated Electric Activation Model (Status Interruption Activated)

Activated attacks provide an experimental model of focal attacks, allowing scientists to study complex brain networks that can contribute to the spread and generalization of attacks from a focus.

In the present model of hypocampic electrical stimulation, adult male Sprague-Dawley rats (300-400 g) were surgically implanted with bipolar electrodes located in the hippocampus. The rats were activated by repetitive electrical stimulation (50 Hz, 10 s series of 1 ms, biphasic 200 �A pulses every 30 min for 6 h every two days for a total of 60 stimulations) resulting in bilateral phase motor attacks 5. One week later, the rats received 2-3 stimulations above the threshold administered every 30 minutes before treatment with test compound, ensuring stability of the behavioral stimulation phase and after the duration of the discharge. Fifteen minutes after the last stimulation, a single dose of vehicle or test compound i.p. was administered intraperitoneally. (intraperitoneally). After 15 min, each rat was then stimulated every 30 min for 3 to 4 h. After each stimulation, the ratings of each individual attack and the duration of each discharge were recorded. The means ± group SEM were calculated for each parameter.

Eight rats were used per dose and a minimum of four doses establishing a value of ED50. Efficacy was measured as the ability of a compound by modifying the attack rating (dispersion severity) and the duration after discharge (ADD; excitability) of generalized attacks.

Using this approach, a compound that reduces the rating of atques from 5 to 3 without any effect on the ADD suggests the usefulness of the compound for the treatment of generalized attacks secondarily. In contrast, a compound that reduces the assessment of attacks from 5 to less than 1, also reduces ADD, suggests the usefulness of the compound for the treatment of focal attacks. Thus, according to the theories presented in the current bibliography (Ghaemi, SN, Boiman, EE and Goodwin, FK, Soc. Of Bio. Psychiatry, (1999), vol. 45, pages 137-144; Stoll, AL and Severus , WE, Harvard Rev. P, July / August (1996), Vol. 4, No. 2, pages 77-89) a decrease in the assessment of the attack and / or ADD can be predictive of the ability of a compound of test to treat proper cyclization with bipolar disorder.

Compound No. 8 (formulated in a 0.5% aqueous solution of methylcellulose) exhibited anticonvulsant activity in this model with an ED50 = 68.5 ± 1.3 mg / kg (corresponding to a decrease in the assessment of attacks on 45 min, and peak activity at 165 min). Attack ratings were significantly reduced from 5 to 1 in 4 out of 8 rats (p = 0.0003). There was no significant effect on ADD (p = 0.07). Ethosuximide was ineffective in model; while phenytoin, carbamazepine and valproic acid significantly suppressed attack activity, but at doses associated with toxicity.

In this model, 6 out of 8 rats showed a significant reduction in overall attack activity (<3 rating) after treatment with Compound No. 8, as shown in Figure 5. Similar protection was observed for valproic acid ( at toxic doses> 300 mg / kg) and carbamazepine (at toxic doses> 26 mg / kg).

The Comparison Results from this trial are listed in Table 4, below.

Table 4: Evaluation of Compound No. 8 and Reference Drugs in the Hypocampic Repeated Electrical Stimulation Test

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Dose (mg / kg), i.p.

Average Attack Rating Duration After Download (% control) �

Compound No. 8.

100 TD50 ~ 100 2.1 ± 0.5 (P = 0.0003) 153 ± 24% (P = 0.07) �

Ethosuximide

250 TD50 = 189 5 ± 0.1 (P = 0.20) 78 ± 13% (P = 0.03) �

Phenytoin

30 TD50 = 15 4.3 ± 0.3 (P = 0.02) 209 ± 43% (P = 0.02) �

Carbamazepine

75 TD50 = 26 2.3 ± 0.6 (P = 0.005) 72 ± 13% (P = 0.02) �

Valproic acid

350 TD50 = 316 0.3 ± 0.2 (P <0.0001) 3 ± 1% <0.0001) �

ED50 = average therapeutic dose; DT50 = medium toxic dose P = paired t test; of a tail

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Example 17

Stimulated Rat Model in the Lamotrigine Resistant Tonsil (Stimulated State Disruption)

Compound No. 8 was evaluated in a rat model stimulated in the lamotrigine resistant tonsil (LTG) (NINDS). Repeated electrical stimulation of the amygdala is less severe than repeated hypocampic electrical stimulation, so that many AEDs are effective against activated attacks on the amygdala, but are ineffective against activated hypocampic attacks. For example, lamotrigine can significantly reduce assessment of tonsil and ADD stimulation (ED50 = 25 mg / kg, ip, CI = 4-50 mg / kg; rating -2; reduced ADD by 62%), but is unable to protect against stimulated hippocampus attacks.

In the LTG-resistant tonsil stimulation model, the rats were administered with LTG (5 mg / kg, i.p., every day) during the acquisition phase of repeated electrical stimulation. This dose was shown to have no effect on repeated electrical stimulation by itself, but leads to the development of fully stimulated rats that are resistant to the anticonvulsant effects of LTG. Once stimulated (stimulation above the current pulse threshold of 150 �A biphasic 60 Hz for 1 second; -2 weeks), the rats were retested with a high dose of LTG (45 mg / kg, ip) one week later ensuring resistance. After a rinsing period of 3-4 days, the rats received 2-3 stimulations above the threshold administered every 30 min before treatment with Compound No. 8 (or vehicle) ensuring stability of the behavioral attack phase and after the duration of the download. Fifteen minutes after the last stimulation, i.p. a single dose of vehicle or test compound. After 15 min, each rat was stimulated every 30 min for 3 to 4 h. After each stimulation, individual attack ratings and durations after discharges were recorded. The mean ± group EEM was calculated for each parameter.

Compound No. 8 (75 mg / kg, i.p., n = 9) significantly reduced the attack score and duration after discharge. Eight out of nine rats were protected so that the attack rating was reduced from 5 to 0.8 and the duration after discharge was reduced by 86% (from 73 seconds to 10 seconds). Four of the nine rats presented ataxia and sedation at this dose.

Example 18

Tail Suspension Test (Acute)

In the tail suspension test (TST) to evaluate compounds for antidepressant activity, the mice were suspended by their tails to a metal or plastic rod using Scotch hook or tape. The test is usually quite short, 5-7 min, and the amount of time the mice spend immobile is recorded either manually or with an automated device. Agents that have antidepressant activity decrease the duration of immobility of mice in this assay.

The basic apparatus for the test of suspension of the tails consisted of a yellow plastic chamber (91 x 45 x 10 cm) divided into four enclosures of 25, 20, 20 and 25 cm wide separated by yellow plastic walls of 0, 75 cm thick The mice were suspended by their tails using a rubber hook (7 cm length) attached to the plastic rod of a test chamber halfway to its depth dimension. Each experimental session was recorded on video and analyzed for four animals in real time by computer software

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("Depression Tracking" Clever Sys Inc.). The computer justification of immobility was calibrated with the use of animals dosed with lorazepam while it was calibrated with the high dose of animals treated with desipramine. Control, vehicle treated animals and animals treated with Compound No. 8 were analyzed with appropriate adjustments. The settings were adjusted separately for dark (CH3 / HeJ and C57BI / 6J) and white (Balb / cJ and A / J) strains. A yellow background was used for dark mice and a blue background was used to record the movements of white mice.

The ability of a test compound to decrease the duration of immobility, or to increase mobility was measured using the TST procedure described above. Acute treatment with clinically effective antidepressants and / or with novel compounds that have antidepressant properties decreases the duration of immobility and at the same time increases mobility in TST.

Data were analyzed using GraphPad Prism software (GraphPad Software, Inc. San Diego, CA). For the comparison of the effect of different doses for various drugs on immobility in TST, single direction analysis of variance (ANOVA) was used.

followed by Dunnett's multiple comparison tests. The values of DE50 and Emáx were calculated for DMI, VLX, DLX and Compound No. 8 using non-linear regression analysis with phase exponential decrease equation for curve fitting. The DE50 and Emáx values were compared using two-way ANOVA and Bonferroni post hoc test.

The dose response was evaluated for different antidepressants and for Compound No. 8 in CH3 / HeJ mice. Compound No. 8 was suspended in 0.5% methylcellulose. Positive controls included duloxetine (DLX), venlafaxine (VLX)

and desipramine (DMI) which were dissolved in 0.5% methylcellulose and lorazepam (LOR) which was suspended in 0.5% methylcellulose in water by sonication. All drugs and vehicles were administered orally (p.o.) by probe in a volume of 10 ml / kg.

The mice were ordered 5 weeks of age and at the beginning of the experiment their weight was 20 ± 5 g. The animals were housed in groups of four in plastic cages at an ambient temperature of 21 ° C to 23 ° C with one cycle

12/12 automated light / dark and access to water and a commercial rodent meal on demand.

This group was divided into eight experiments testing the effects of Compound No. 8, the positive controls (DMI, VLX, DLX) at different doses and the negative control (LOR) at 5 mg / kg. Each experiment consisted of seven treatment groups with four animals per group. A total of 28 animals were used per experiment. Every two consecutive experiments (1 and

2, 3 and 4, 5 and 6 and 7 and 8) were exact replicas of each other. This resulted in a total number of eight animals per treatment group at the end of the study. A treatment group of four animals in each experiment was a vehicle treated group. In addition to the vehicle-treated group, the effects of DMI at 6 mg / kg, 12 mg / kg, 30 mg / kg, 60 mg / kg and 120 mg / kg and LOR at 5 mg / kg were tested in experiments 1 and 2. Experiments 3 and 4 tested the effects of Compound No. 8 at 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 on 6 mg / kg, 12 mg / kg, 30 mg / kg, 60 mg / kg, 120 mg / kg and LOR at 5 mg / kg. Experiments 7 and 8 tested the effects of VLX at 6 mg / kg, 12 mg / kg, 30 mg / kg, 60 mg / kg, 120 mg / kg and LOR at 5 mg / kg. In the course of the study, a mouse died due to an erroneous dose in the group treated with Compound No. 812 mg / kg, so that this group consisted of seven animals at the end of the study.

Compound No. 8 and all tested antidepressant drugs decreased immobility time and increased mobility time in CH3 / HeJ mice during a 7-minute test session. The effects of Compound No. 8 were statistically significant at 12 mg / kg, 60 mg / kg and 120 mg / kg. Significance was determined in comparison to parallel controls treated with vehicle.

The effects of IMD were statistically significant at 12, 30, 60 and 120 mg / kg. The effects of VLX were statistically significant at 6, 12, 30, 60 and 120 mg / kg. The DLX effects were statistically significant at 60 and 120 mg / kg.

The values of DE50 and Emáx were calculated from these results by non-linear regression analysis. The values of DE50 and Emáx are listed in Table 5 below. The ED50 values calculated for immobility and mobility were not significantly different between treatments. The value of DE50 for Compound No. 8 was significantly lower than the value of DE50 for DLX but not different from the values of DE50 for DMI and VLX. The Emax values calculated for immobility and mobility were not significantly different for Compound No. 8 but were significantly different for all tested antidepressants. The immobility value of Emáx for Compound No. 8 was also significantly lower than the values of antidepressant drugs.

Table 5: DE50 and DEmax values for Different Drugs in TST

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Mobility image5

Drug

ED50 in mg / kg DE50 EEM CI�

Compound No. 8

3.6 2.9 -4.6 - 11.8�

DMI

24.4 9.0 -0.5 - 49.3�

VLX

21.1 8.4 -2.1 -44.4�

DLX

61.5 20.9 3.6-119.3�

Drug

% of Emax of C Emáx EEM CI�

Compound No. 8

95.6 13.0 59.4 -131.7�

DMI

195.7 24.9 126.7-264.7�

VLX

412.6 53.9 263.0-562.2�

DLX

175.5 28.3 96.9 -254.2�

Immobility image5

Drug

DE50 in mg / kg EEM of DE50 CI image5

Compound No. 8

5.6 3.3 1,7-12,1�

DMI

27.4 16.0 11.3-55.0�

VLX

25.0 15.4 8.8-55.1�

DLX

31.4 15.7 22.4 -42.6�

Drug

% of Emáx de C EEM of Emáx CI image5

Compound No. 8

22.2 6.1 2.8-41.6�

DMI

38.5 6.3 18.5-58.5�

VLX

63.7 11.1 28.4-98.9�

DLX

80.4 6.4 59.9 -100.9

In summary, the studies described in this example showed that Compound No. 8 has antidepressant-like activity, as measured by the tail suspension test. The ED50 for Compound No. 8 was calculated as 3.6 ± 2.9 mg / kg and the Emax was calculated as 22.2 ± 6.1% in the condition of our study.

5 Example 19

Forced Swimming Test (Acute)

The Forced Swimming Test (FST) is a procedure commonly used to track compounds for possible antidepressant properties. This test is also the test of behavioral despair. Rodents located in family tanks with water have a wide variety of escape behaviors or

10 immobility. Antidepressant drugs of different classes markedly increase different kinds of escape behaviors and / or decrease latency or duration of immobility. Provided that these effects are characteristic of clinically active antidepressants, compounds with unknown clinical activity that show such effects on FST are interpreted to have the potential to treat human mood disorders.

Compound No. 8 and maprotiline were dissolved in 10% solutol. Venlafaxine and desipramine were dissolved in water. 15 All drugs and their vehicles were administered orally (p.o.) by probe in a volume of 5 ml / kg.

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55

Male Sprague Dawley rats (140 to 160 g) were used from Charles River Laboratories Wilmington, MA. The animals went through a quarantine period of five days before undergoing the experimental procedure.

The animals were housed in groups of four in plastic cages at an ambient temperature of 21 ° C to 23 ° C with a 12-hour light / dark cycle and with access to water and commercial rodent food on demand. The animals were not handled except for the routine bed change before the pre-swim session.

The study was divided into six experiments that tested the effects of Compound 8, three positive controls (desipramine, maprotiline, venlafaxine) and a negative control (lorazepam) at different doses. Each experiment consisted of seven treatment groups with n = 4 animals per group. A total of 28 animals were used per experiment. Two consecutive experiments (1 and 2, 3 and 4 and 5 and 6) were exact replicas of each other. This resulted in a total number of eight animals per treatment group at the end of the study. A treatment group of n = 4 animals in each experiment was a vehicle treated group. In addition to the vehicle-treated group, the effects of desipramine at 3 mg / kg, 6 mg / kg, 12 mg / kg, 30 mg / kg and 60 mg / kg and lorazepam at 1 mg / kg were tested in experiments 1 and 2 In experiments 3 and 4 the effects of Compound No. 8 at 3 mg / kg, 6 mg / kg, 12 mg / kg, 30 mg / kg, 60 mg / kg and 120 mg / kg were tested in experiments 5 and 6 the effects of venlafaxine and maprotiline at 12 mg / kg, 30 mg / kg and 60 mg / kg were tested. In the course of the study a rat died due to an erroneous dose in the group treated with desipramine 12 mg / kg, so that this group consisted of seven animals at the end of the study.

The basic apparatus consisted of a cylinder (46 cm high x 20 cm in diameter) filled with water 30 cm deep, at a temperature of 25 ± 1 ° C. The automated version of the FST was used in carrying out the experiments. A plumbing installation for automatic filling and emptying of water connected the four cylinders. The cylinders were placed in the dividing chambers 25 cm wide separating the animals visually. Each 5-minute experimental session was videotaped and analyzed in real time by computer software (Clever Systems, Inc.) for four animals at a time. The times of immobility, swimming, climbing and escape were recorded using the software. The four activities are defined as follows. Immobility: the animal floats without moving or makes only those movements necessary to keep its head out of the water; Climb: the animal moves vigorously vertically while scratching the wall around the cylinder; Swimming: the animal moves its body horizontally around the cylinder more than necessary to keep its head out of the water; and Escape: sum of all vigorous active movements.

The ability of a test compound to decrease the duration or frequency of immobility, or changes in swimming, climbing and escape times, was measured using the FST procedure described above. Clinically effective antidepressants and / or novel compounds that have potential antidepressant properties decrease the duration or frequency of immobility in FST when administered between pre-test sessions and test sessions. The analysis of the results in the described studies focused on the immobility time during the 5-minute test session.

There were two swimming sessions in each experiment. First, a pre-test swim session was conducted for 15 minutes. After 48 hours later there was a 5 minute session. After completing a swimming session, each animal was placed under a heat lamp in a cage with a soft bed for approximately 15 minutes avoiding hypothermia.

The animals were pre-treated with a vehicle or test compound after completing the prenatation session, then 24 hours later and then shortly before the 5 minute session; that is, three injections were given to each animal between the two swimming sessions that took place on three consecutive days. The time before the test session was 1 hour for desipramine, maprotiline, venlafaxine, lorazepam or 4 hours for Compound No. 8; the time of the maximum effect in the test of the attacks of maximum shocks (MONTH).

Data were analyzed using GraphPad Prism software (GraphPad Software; Inc. San Diego, CA). For the comparison of the effect of different doses for various drugs on immobility in FST, one-way ANOVA was used followed by the Dunnett multiple comparison test. The values of DE50 and Emáx were calculated for desipramine and Compound No. 8 using nonlinear regression analysis with an exponential decay equation of a phase for curve fitting. The ED50 and Emáx values were statistically compared using a two-tailed test.

All tested anti-depressant drugs decreased immobility time during a 5-minute test session. The effect of desipramine was statistically significant at 6 mg / kg, 12 mg / kg, 30 mg / kg and 60 mg / kg. The ED50 calculated for desipramine was 2.0 ± 0.1 mg / kg (CI = 1.3 - 3.3 mg / kg) and its Emax was 50.0 ± 8.4 seconds (CI = 31.8 - 57 , 7). The treatment effect with Compound No. 8 was statistically significant at 12 mg / kg, 60 mg / kg and 120 mg / kg compared to controls treated by vehicle. The great variability between individual rats made the effect of the 30 mg / kg dose of Compound No. 8 not significantly different from the control. For this reason, the immobility data for doses of 30 mg / kg were not used in the calculation of ED50. The ED50 calculated for Compound No. 8 was 5.6 ± 0.6 mg / kg (CI = 2.2 - 15.6 mg / kg) and its Emax was 67.0 ± 11.6 seconds (CI = 30.3-103.8). The DE50 value for Compound No. 8 was significantly different from the DE50 value for desipramine at p <0.001 (two-tailed t-test). There was no statistically significant difference between Emax values for desipramine and Compound # 8.

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40

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they tested venlafaxine and maprotiline (positive controls) only at three doses of 12 mg / kg, 30 mg / kg and 60 mg / kg. The immobility of the animals treated in the dose of 30 mg / kg and 60 mg / kg was significantly different from controls treated per vehicle for both venlafaxine and maprotiline. However, there were too few data points to calculate an ED50 for these two drugs. Lorazepam (negative control) was tested at 1 mg / kg and showed no significant effect on the immobility time of the rats during the testing session. The results indicated that Compound No. 8 had activity similar to antidepressants in the FST.

Table 6: DE50 and Emáx values for Compound No. 8 and DMI in the FST

ED50 in mg / kg

EEMDE50 from IC DE50 % Of EMÁX EEMEmax from EMÁX� IC

Compound 8.

No. 5.6 0.6 2.2 - 15.6 57.0 11.6 30.3-103.8�

DMI

2.0 0.1 1.3-3.3 50.0 8.4 31.8-57.7

Example 20

Chronic Soft Stress Model (Chronic)

In the chronic mild stress model (CMS), rats subjected to a variety of mild �rian��res over a prolonged period of time show, among other behavioral, biochemical and physiological alterations, a substantial decrease in responsiveness to rewarding stimuli. This deficit is usually monitored by a decrease in the consumption of 1% sucrose solution, but it can also be seen in other tests, such as site preference conditioning or intracranial self-stimulation. Provided that the subsensitivity to reward seems to reflect anhedonia (inability to experience pleasure), which is a central symptom of major depressive disorders, the CMS procedure can serve as an adequate research tool in studies within the mechanisms of antidepressant action .

Male Wistar rats were taken inside the laboratory two months before the start of the experiment. Except as described above, the animals were housed individually with freely available food and water and kept in light / dark for 12 hours and under conditions of constant temperature (22 ± 2 ° C) and constant humidity (50 ± 5%).

The animals were first trained by consuming a 1% sucrose solution; the training consisted of eight 1-hour baseline tests in which sucrose was present, in the home cage, after 14 hours of deprivation of water and food; Glucose uptake was measured by weighing pre-weighed bottles containing sucrose solution at the end of the test. Subsequently, sucrose consumption was monitored, under similar conditions, at weekly intervals throughout the entire experiment.

Based on their sucrose uptake in the final baseline test, the animals were divided into two matched groups. A group of animals underwent the chronic mild stress procedure for a period of 7 consecutive weeks. Each week of stress regime consisted of: two periods of deprivation of food or water, two periods of cage inclination 45 degrees, two periods of intermittent lighting (lights on and off every 2 h), two periods of dirty cage (250 ml of water in sawdust bed), a period of matched housing, two periods of low density strobe lighting (150 glows / min) and three periods of non-stress. All �rian��res were 10-14 hours long and were applied individually and continuously, day and night. Control animals were housed in separate rooms and had no contact with stressed animals. They deprived themselves of food and water during the 14 hours preceding each sucrose trial, but otherwise food and water were freely available in the home cage.

Based on their sucrose uptake after the initial 2 weeks of stress, both stressed and control animals were each further divided into paired subgroups (n = 8) and for five subsequent weeks received daily intraperitoneal vehicle administration (methylcellulose at 0.5%, 1 ml / kg), Compound No. 8 to 12 mg / kg, 30 mg / kg or 60 mg / kg, imipramine at 10 g / kg or venlafaxine at 10 mg / kg as reference treatments. The drugs were administered at approximately 10.00 and weekly sucrose tests were carried out 24 hours after the last drug injections. After five weeks all treatments were terminated and 24 hours later blood and / or brain samples were collected from all animals and subjected to additional biochemical analysis. Stress was continued throughout the entire period of treatment.

Animals were individually removed from their accommodation rooms to another sacrifice room. Then they were beheaded in a semi-randomized order. The whole brains were removed, quickly frozen in dry ice / n-heptane immediately after sacrifice and stored in plastic vials at -70 ° C. Blood was collected from the trunk for plasma in EDTA tubes containing EDTA (approximately 1.6 mg / ml of blood). EDTA blood was centrifuged directly at 1500 x g for 10 min at 4 ° C. The plasma was aspirated and

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stored in Eppendorf tubes at -70 ° C. Additionally, 2 batches of 20 ml of plasma were prepared from animals that have not been previously treated generating a standard curve of bioassay compound.

All the results obtained in this study were analyzed by multiple analysis of variance with three factors between subjects (stress / control, drug treatments and successive sucrose tests). Fisher's LSD test was used for media comparisons after this.

Chronic mild stress caused a gradual decrease in the consumption of 1% sucrose solution. In the final baseline test, all animals drank approximately 11 g of sucrose solution. After the initial two weeks of stress, the uptake remained at a similar level in controls but fell to approximately 6 g in stressed animals, resulting in a significant group effect. [F (1.84) = 87,204; p <0.001]. Such a difference between control animals and stressed animals treated with vehicle persisted at a similar level during the rest of the experiment.

Compared to vehicle administration, Imipramine was inactive in the controls [Treatment effect: F (1.84) = 1,578; NS] and caused significant treatment effect: F (1.84) = 22.651; p <0.001 and interaction Treatment x Weeks: F (5.84) =

2,717; p = 0.025] in stressed animals. Similarly, Venlafaxine was inactive in controls [Treatment effect: F (1.84) = 0.208; NS] and caused significant treatment effect: F (1.84) = 35.724; p <0.001 and interaction Treatment x Weeks: F (5.84) = 3,219; p = 0.010] in stressed animals.

Compared to Week 0 scores, increases 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 their effect was maintained. since then. A stressed animal (no 480) does not respond to venlafaxine treatment but was not excluded from statistical analysis.

As compared to vehicle administration, Compound No. 8 does not cause significant treatment effects in control [F (3,168) = 1,198; NS] or in stressed animals [F (3,168) = 1,676; NS], indicating that the compound is inactive in the

CMS model of depression.

Example 21

Resident / Intruder Test (also known as Chronic Social Stress Test)

The resident / behavioral intruder assay is used by tracking compounds for antidepressant-like activity. Compound No. 8 was tested in this test, with the performance of the test according to the procedure as described in � rian�, R., Abumaria, N., Flugge, G., Fuchs, E., Ruther, E., Havemann-Reinecke, U., Behavioral Research rian Research, 162 (2005), pages 127-134.

Tables 5, 6 and 7 below, list the average and standard deviation values for measured parameters, for the following compounds, administered p.o. (orally): vehicle, imipramine control compounds at 10 mg / kg and venlafaxine at 10 mg / kg, Compound No. 8 to 60 mg / kg and Compound No. 8 to 120 mg / kg.

Table 5: Effect of Resident Intruder on Sacarosa Catchment

Dose

Sacarosa Catchment Media ± SD image5

Treatment

mg / kg Week 3 Week 4 Week 5 image5

Vehicle - not stressed

0 90.2 ± 2.5 * 89.0 ± 4.2 * 91.7 ± 2.1 * �

Vehicle - stressed

0 51.7 ± 26.7 69.3 ± 7.5 66.3 ± 6.1�

Imipramine - not stressed

10 87.9 ± 2.7 89.7 ± 5.3 91.0 ± 3.7�

Imipramine - stressed

10 70.5 ± 19.5 78.3 ± 15.1 73.6 ± 19.4�

Venlafaxine - not stressed

10 88.4 ± 9.1 91.5 ± 5.6 87.9 ± 15.0�

Venlafaxine - stressed

10 74.5 ± 16.7 76.1 ± 18.2 73.3 ± 17.6�

Compound No. 8 - not stressed

60 90.9 ± 3.5 92.3 ± 1.4 88.9 ± 7.4�

40 Table 6: Effect of Resident Intruder on Locomotive Activity

(CONT.)

Compound No. 8 - stressed

60 92.1 ± 3.2 * 89.5 ± 6.9 * 92.4 ± 4.5 * �

Compound No. 8 - not stressed

120 83.6 ± 22.1 91.3 ± 4.6 89.3 ± 5.1�

Compound No. 8 - stressed

120 76.1 ± 20.8 75.5 ± 20.6 87.4 ± 7.9 * �

* statistically significantly different from vehicle animals

stressed out of

Treatment

Dose in mg / kg Mean ± Locomotor SD Mean ± SD of Back Mean ± SD Sniffing Mean ± YES of Sniffing

Vehicle no

0 Week 1 Week 1 Week 1 week 1�

stressed out

8184.7 ± 1597.2

50.8 ± 10.2 * 47.8 ± 9.6 24.5 ± 4.9�

week 5

week 5

week 5

week 5�

8102.3 ± 1805.6 *

46.8 ± 7.6 * 43 ± 6.6 * 29.8 ± 5.3

Vehicle�

Week 1 Week 1 Week 1 Week 1

stressed out

5816.8 ± 1589.6 28 ± 11.2 s 27.5 ± 10.8 15.8 ± 5,

week 5

emanates 5

week 5

week 5

0

3920.8 ± 887.3 18 ± 9.1 14.5 ± 6.7 9 ± 2.6

Imipramine no

10 Week 1 Week 1 Week 1 Week 1

stressed

8162.8 ± 929.9

51.5 ± 12.6 48.1 ± 10.3 25.8 * 4.9

week

week 5 week 5 week 5

7278 ± 1030

42.1 ± 2.9 37.5 ± 2.1 26.4 ± 5.2

Imipramine

10 Week 1 Week 1 Week 1 Week 1

stressed

6037.8 ± 1382.8

30 ± 9.5  27.5 ± 7.9 14.4 ± 4.4

week 5

week 5

week 5

week 5

5642.8 ± 998.6

27.8 ± 7.4 24.3 ± 5.1 17.3 ± 3.4 * �

Venlafaxine no

10 Week 1 Week 1 Week 1 Week 1

stressed

9094.9 ± 1832.7

48.3 ± 11.2  43.3 ± 8.9 27.1 ± 5.2

week 5

week 5

week 5

week 5

8078.6 ± 1665.2

40.1 ± 8.9 38.6 ± 7.7 27 ± 4.7

Venlafaxine

10 Week 1 Week 1 Week 1 Week 1

stressed

6233.6 ± 1087.2

30.8 ± 6.6 28.6 ± 6.5 14.9 ± 3.5

week 5

week 5

week 5

week 5

6250.1 ± 789.2 *

35.1 ± 7.4 33.1 ± 7.5 * 18.3 ± 3.6

41

Compound No.

60 Week 1 Week 1 Week 1 Week 1

8 not stressed

8288.6 ± 2117.5

49.6 ± 8.7 44.1 ± 9.4 20.9 ± 3.3

week 5

week 5

week 5

week 5

7922.9 ± 1476

37.4 ± 11.5 33.4 ± 11.2 23.5 ± 6.4

Compound No.

60 Week 1 Week 1 Week 1 Week 1

8 stressed

5858.5 ± 708.2

26.5 ± 6.1 25 ± 7.3 13 ± 3.3

week 5

week 5

week 5

week 5

7080.9 ± 1238.7 *

32.8 ± 10.3 30.6 ± 11.1 24.8 ± 5.7

Compound No. 8 not stressed

120 Week 1 Week 1 Week 1 Week 1

8056.6 ± 867.2

42 ± 10.6 37.6 ± 8.4 22.8 ± 3.

week 5

week 5

week 5

week 5 25.5 ±

Four.

8648.3 ± 1060.9

36.5 ± 6.3 33.5 ± 5.9

Compound No.

120 Week 1 Week 1 Week 1 Week 1

8 stressed

6168.3 ± 1132.1

29.3 ± 7 27.5 ± 6.1 13 ± 3.6

week 5

week 5

week 5

week 5

6444 ± 1010.3 *

30.1 ± 6.4 30.4 ± 7.5 22.5 ± 4.�

* statistically significantly different from stressed animals from vehicle

Table 7: Effect of Resident Intruder on Forced Swimming Test

Treatment

Dose in mg / kg Immobility for 5 min: Mean ± SD of Week 5 image5

Vehicle - not stressed

0 165.5 ± 25 * �

Vehicle-stressed

0 227 ± 40.2�

Imipramine - not stressed

10 125.3 ± 50.1�

Imipramine - stressed

10 157.5 ± 71.6�

Venlafaxine - not stressed

10 181.8 ± 27.6�

Venlafaxine - stressed

10 190.4 ± 36.8

Compound No. 8 - not stressed

60 164.3 ± 25.3�

Compound No. 8 - stressed

60 175.1 ± 29.5�

Compound No. 8 - not stressed

120 136.7 ± 34.9�

Compound No. 8 - stressed

120 128.3 ± 37.4 * �

* statistically significantly different from stressed animals from vehicle

Compound No. 8 was active in the resident / intruder test indicating that Compound No. 8 would be expected

42

Be active as an antidepressant.

Example 22

As a specific embodiment of an oral composition, 100 mg of Compound No. 8 prepared as in Example 7 are formulated with sufficient finely divided lactose providing a total amount of 580 to 590 mg by filling a hard gel capsule of size O.

Claims (14)

1. A compound of formula (I) image 1 ���������� (I) or a pharmaceutically acceptable salt thereof for use in the treatment of mania, wherein R1 and R2 are independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; image 1 is selected from the group consisting of image2 in which b is an integer from 0 to 4; and in which c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; wherein "lower alkyl" refers to a carbon chain composition of 1-4 carbon atoms, provided that when image 1  is image 1 or image 1 then a is 1. 2. A compound of formula (I) image3 or a pharmaceutically acceptable salt thereof for use in the treatment of bipolar disorder, in which R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; image 1 is selected from the group consisting of image 1 Y image 1 in which b is an integer from 0 to 4; and in which c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; wherein "lower alkyl" refers to a carbon chain composition of 1-4 carbon atoms, provided that when image 1 is image 1 46 or image 1 then a is 1. 3. A compound of formula (I) 5 or a pharmaceutically acceptable salt thereof for use in the treatment of bipolar depression, in which R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; image3 image 1 is selected from the group consisting of image 1 47 image 1 Y image 1 in which b is an integer from 0 to 4; and in which c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; wherein "lower alkyl" refers to a carbon chain composition of 1-4 carbon atoms, provided that when image 1 is image 1 or image 1 48 then a is 1. 4. The compound or a pharmaceutically acceptable salt thereof as in any one of Claims 1, 2 and 3, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; image 1 is selected from the group consisting of image4 Y image 1 49 in which b is an integer from 0 to 2; and in which c is an integer from 0 to 1; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; wherein "lower alkyl" refers to a carbon chain composition of 1-4 carbon atoms, provided that when image 1 is or image 1 image 1 10 then a is 1. 5. The compound or a pharmaceutically acceptable salt thereof as in Claim 4, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl, a is an integer from 1 to 2; image 1 15 is selected from the group consisting of image 1 image 1 fifty Y image 1 in which b is an integer from 0 to 2; and in which c is 0; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; wherein "lower alkyl" refers to a carbon chain composition of 1-4 carbon atoms, provided that when image 1 is image 1 then a is 1. 6. The compound or a pharmaceutically acceptable salt thereof as in Claim 5, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and methyl; a is an integer from 1 to 2; image 1 fifteen is selected from the group consisting of 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (benzo [1,3] dioxolyl), 2- (3,4-dihydroH-benzo [1, 4] dioxepinyl), 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6- fluoro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (chromanyl), 2- (5-fluoro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7- chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-chloro-benzo [1,3] dioxolyl), 2- (7-nitro-2,3-dihydro-benzo [1, 4] dioxinyl), 2- (7-Methyl-2,3-dihydro-benzo [1,4] dioxinyl), 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6- Bromo-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (8-chloro-2, 3-dihydro-benzo [1,4] dioxinyl), 2- (2,3-dihydro-naphtho [2,3-b] [1,4] dioxinyl) and 2- (4-methyl-benzo [1,3 ] dioxolyl); wherein "lower alkyl" refers to a carbon chain composition of 1-4 carbon atoms, provided that when image 1 25 is 2- (3,4-dihydro-2H-benzo [1,4] dioxepinyl), then a is 1. The compound or a pharmaceutically acceptable salt thereof as in claim 6, wherein: R1 and R2 are each independently selected from the group consisting of hydrogen and methyl; R4 is selected 51 of the group consisting of hydrogen and methyl; a is an integer from 1 to 2; image 1 is selected from the group consisting of 2- (benzo [1,3] dioxolyl), 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (2,3-dihydro-benzo [1, 4] dioxinyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-methyl-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-bromo-2,3-dihydro-benzo [1,4] dioxinyl) and 2- (6,7 -dichloro-2,3-dihydrobenzo [1,4] dioxinyl). 8. The compound of any of claims 1, 2 and 3, wherein the compound of formula (I) is selected from the group consisting of (2S) - (-) - N- (6-chloro-2,3 -dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide; and pharmaceutically acceptable salts 10 of it.

9.

A compound selected from the group consisting of (2S) - (-) - N- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide; and pharmaceutically acceptable salts thereof for use in the treatment of mania.

10.

A compound selected from the group consisting of

15 (2S) - (-) - N- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide; and pharmaceutically acceptable salts thereof for use in the treatment of bipolar disorder. 11. A compound selected from the group consisting of (2S) - (-) - N- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide; and pharmaceutically acceptable salts thereof for use in the treatment of bipolar depression. 20 12. A compound of formula (II) image 1 or a pharmaceutically acceptable salt thereof for use in the treatment of mania. 13. A compound of formula (II) image5 or a pharmaceutically acceptable salt thereof for use in the treatment of bipolar disorder. 14. A compound of formula (II) 52 image 1 or a pharmaceutically acceptable salt thereof for use in the treatment of bipolar depression.

fifteen.

 The compound or a pharmaceutically acceptable salt thereof of any one of Claims 2 and 10, wherein the treatment of bipolar disorder comprises treating depression and mania of bipolar disorder.

16.

 The compound or a pharmaceutically acceptable salt thereof of any one of Claims 2 and 10, wherein the treatment of bipolar disorder comprises treating depression, mania and cyclization of bipolar disorder.