Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• the present invention is directed to the use of benzo-fused heterocycle sulfamide derivatives for the treatment of mania and bipolar disorder.
• Bipolar disorder is psychiatric disorder characterized by unpredictable swings in mood from mania (or hypomania) to depression. Some patients suffer only from recurrent attacks of mania, which in its pure form is associated with increased psychomotor activity; excessive social extroversion; decreased need for sleep; impulsivity and impairment in judgment; and expansive, grandiose, and sometimes irritable mood. In severe mania, patients may experience delusions and paranoid thinking indistinguishable from schizophrenia. Half of patients with bipolar disorder present with a mixture of psychomotor agitation and activation with dysphoria, anxiety, and irritability. It may be difficult to distinguish mixed mania from agitated depression.
• bipolar patients bipolar Il disorde ⁇
• the full criteria for mania are lacking, and the requisite recurrent depressions are separated by periods of mild activation and increased energy (hypomania).
• hypomania In cyclothymic disorder, there are numerous hypomanic periods, usually of relatively short duration, alternating with clusters of depressive symptoms that fail, either in severity or duration, to meet the criteria of major depression.
• the 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 onset within hours is possible, usually in the early morning hours.
• An untreated episode of either depression or mania can be as short as several weeks or last as long as 8 to 12 months, and rare patients have an unremitting chronic course.
• 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 cycling is linked to an underlying thyroid dysfunction and, in others, it is iatrogenically triggered by prolonged antidepressant treatment. Approximately half of patients have sustained difficulties in work performance and psychosocial functioning.
• Patients suffering from bipolar disorder typically complain of the following types of symptoms, depending on whether they are in a "manic" or "high” phase versus a "depressed” or “low” phase.
• manic phase symptoms include, but are not limited to (a) increased physical and mental activity and energy (b) heightened mood, exaggerated optimism and self- confidence; (c) excessive irritability, aggressive behavior; (d) decreased need for sleep without experiencing fatigue; (e) grandiose delusions, inflated sense of self-importance; (h) racing speech, racing thoughts, flight of ideas; (i) impulsiveness, poor judgment, distractibility; (j) reckless behavior and In the most severe cases, (k) delusions and hallucinations.
• manic phase symptoms include, but are not limited to (a) prolonged sadness or unexplained crying spells; (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, indecisiveness; (h) inability to take pleasure in former interests, social withdrawal; (i) unexplained aches and pains and (j) recurring thoughts of death or suicide.
• Bipolar disorder is common, affecting -1% of the population in the United States. 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 and men more manic episodes over a lifetime. Lithium carbonate is the mainstay of treatment in bipolar disorder, although sodium valproate and olanzapine are equally effective in acute mania, as is lamotrigine in the depressed 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 prevention of recurrent mania and, to a lesser extent, in the prevention of recurrent depression.
• Serious side effects from lithium administration are rare, but minor complaints such as gastrointestinal discomfort, nausea, diarrhea, polyuria, weight gain, skin eruptions, alopecia, and edema are common.
• lithium is initiated at 300 rng bid or tid, 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, adjunctive usage of lorazepam (1 to 2 mg every 4 h) or clozepam (0.5 to 1 mg every 4 h) may be beneficial to control agitation. Antipsychotics are indicated in patients with severe agitation who respond only partially to benzodiazepines.
• 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 cycling (i.e., more than four episodes a year) or who present with a mixed or dysphoric mania. Tremor and weight gain are the most common side effects; hepatotoxicity and pancreatitis are rare toxicities. Carbamazepine and oxcarbazepine, 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 possess some therapeutic benefit.
• FDA U.S. Food and Drug Administration
• bipolar mood disorder necessitates maintenance treatment. Compliance is frequently an issue and often requires enlistment and education of concerned family members. Efforts to identify and modify psychosocial factors that may trigger episodes are important, as is an emphasis on lifestyle regularity. Antidepressant medications are sometimes required for the treatment of severe breakthrough depressions, but their use should generally be avoided during maintenance treatment because of the risk of precipitating mania or accelerating the cycle frequency. Loss of efficacy over time may be observed with any of the mood-stabilizing agents. In such situations, an alternative agent or therapy is usually helpful.
• the treatment of bipolar disorder comprises treatment of the depression and the mania. More preferably, the treatment of bipolar disorder comprises treatment of the depression, the mania and the cycling that are characteristic of the disorder.
• the present invention is directed 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)
• R 1 and R 2 are each independently selected from the group consisting of hydrogen and lower alkyl
• R 4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2;
• each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
• the present invention is further directed 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 compound of formula (II)
• the present invention is further directed 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 is further directed 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 of formula (I) or formula (II) as described herein.
• the present invention is further directed 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 formula (II) as described herein.
• Exemplifying the invention is a method of treating mania comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described above.
• Exemplifying the invention is a method of treating bipolar disorder comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described above.
• the present invention is directed to the treatment of mania. In another embodiment, the present invention is directed to the treatment of bipolar mania. In another embodiment, the present invention is directed to the treatment of bipolar depression. In another embodiment, the present invention is directed to the treatment of bipolar disorder. In another ' embodiment, the present invention is directed to the treatment of the bipolar cycling. In another embodiment, the present invention is directed to the treatment of the depression and the mania associated with bipolar disorder. In yet another embodiment, the present invention is directed to the treatment of the depression, the mania and the cycling associated with bipolar disorder. In yet another embodiment, the present invention is directed to a method for treating bipolar disorder comprising stabilization of cycling. Thus, in an embodiment, the present invention is directed to a method of stabilizing bipolar cycling.
• the present invention is directed 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)
• the compounds of the present invention are useful for the treatment of the mania, regardless of cause. Further, the compounds of the present invention are useful for the treatment of depression, mania and / or the cycling that are characteristic of, symptomatic of or associated with bipolar disorder.
• the present invention is further directed to methods for the treatment of mania, bipolar depression, bipolar mania, bipolar cycling and / or bipolar disorder comprising administering to a subject in need thereof co-therapy with at least one antidepressant and / or at least one antipsychotic agent and / or at least one mood stabilizer and a compound of formula (I) or formula (II) as described herein.
• Bipolar disorder is psychiatric disorder characterized by unpredictable swings in mood from mania (or hypomania) to depression.
• the term "bipolar disorder” shall include bipolar disorder I (e.g. single manic episode, most recent episode hypomanic, most recent episode manic, most recent episode mixed, most recent episode depressed and most recent episode unspecified), bipolar disorder II, cyclothymic disorder and bipolar disorder not otherwise specified ( as these terms are defined by their diagnostic criteria, in the Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition, Text Revision, American Psychiatric Association, 2000 (DSM-IV-TR)).
• the bipolar disorder is characterized by depressive and manic (or hypomanic) phases, wherein the phases cycle.
• the bipolar disorder is bipolar disorder I or bipolar disorder II.
• mania shall include mania or a manic mood phase, regardless of underlying cause.
• bipolar mania is intended to mean the mania associated with, characteristic of or symptomatic of a bipolar disorder.
• methods of treating bipolar mania of the present invention are directed to methods which treat the mania and / or manic phase of bipolar disorders.
• cycling or "bipolar cycling” shall refer to the alternation of mood between depressive and manic phases characteristic of bipolar disorders.
• the present invention includes methods for the stabilization of said cycling, including, but not limited to, decreasing the frequency of the cycling and / or decreasing the magnitude of the manic and / or depressive phases.
• a mood stabilizer shall include any pharmaceutical agent which 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 which stabilizes the patients mood may act as an antidepressant, an antimanic or both and biases the patient mood toward euthymia.
• anti-antidepressant shall mean any pharmaceutical agent which treats depression. Suitable examples include, but are not limited to mono-amine oxidase inhibitors such as phenelzine, tranylcypromine, moclobemide, and the like; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, and the like; tetracyclics such as maprotiline, and the like; non-cyclics such as nomifensine, and the like; triazolopyridines such as trazodone, and the like; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, and the like; serotonin receptor antagonists such as nefazadone, and the like; serotonin
• the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertaline.
• antipsychotic includes, but are is not limited to (a) typical or traditional antipsychotics, such as phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (eg, thiothixene, flupentixol), butyrophenones (eg, haloperidol), dibenzoxazepines (eg, loxapine), dihydroindolones (eg, molindone), substituted benzamides (eg, sulpride, amisulpride), and the like; and (b) atypical antipsychotics, such as divalproate sodium, paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, ilope
• atypical antipsychotics include, but are not limited to: 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b]benzodia2epine, known as olanzapine and described in US Patent No 5,229,382 as useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild 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
• subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
• terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
• the present invention is directed to co-therapy or combination therapy, comprising administration of one or more compound(s) of formula (I) or formula (II) and one or more antipsychotic and / or antidepressant
• therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response.
• the therapeutically effective amount of co-therapy comprising administration of a compound of formula (I) or formula (II) and at least on antidepressant and / or at least one antipsychotic would be the amount of the compound of formula (I) or 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.
• 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), wherein the compound(s) of formula (I) or formula (II) and the antidepressant(s) and / or antipsychotic(s)are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation.
• the number of dosages administered per day for each compound may be the same or different.
• the present invention is directed to a method for the treatment of depression associated with or characteristic of or symptomatic of bipolar disorder. In another embodiment, the present invention is directed 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 is directed to a method for the treatment of cycling (between depression and mania or the depressive and manic phases) associated with or characteristic of or symptomatic of bipolar disorder.
• R 1 is selected from the group consisting of hydrogen and methyl.
• R 2 is selected from the group consisting of hydrogen and methyl.
• R 1 and R 2 are each hydrogen or R 1 and R 2 are each methyl.
• R 4 is selected from the group consisting of hydrogen and methyl, preferably, R 4 is hydrogen.
• a is 1.
• b is an integer from 0 to 2.
• c is an integer from 0 to 2.
• b is an integer from 0 to 1.
• c is an integer from 0 to 1.
• the sum of b and c is an integer form 0 to 2, preferably an integer form 0 to 1.
• presept invention b is an integer from 0 to 2 and c is 0.
• benzo[1 ,4]dioxinyl In another embodiment of the present invention, is selected from the group consisting of 2-(2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7- methyl-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(6-bromo-2,3-dihydro- benzo[1 ,4]dioxinyl).
• R 5 is selected from the group consisting of halogen and lower alkyl. In another embodiment of the present invention R 5 is selected from chloro, fluoro, bromo and methyl.
• the stereo-center on the compound of formula (I) is in the S-configu ration. In another embodiment of the present invention, the stereo-center on the compound of formula (I) is in the R-configuration.
• the compound of formula (I) is present as an enantiomerically enriched mixture, wherein the % enantiomeric enrichment (% ee) 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 wherein the substituents selected for one or more of the variables defined herein (i.e. R 1 , R 2 , R 3 , R 4 , X-Y and A) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
• halogen shall mean chlorine, bromine, fluorine and iodine.
• alkyl whether used alone or as part of a substituent group, includes straight and branched chains.
• alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
• lower when used with alkyl means a carbon chain composition of 1 -4 carbon atoms.
• alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
• substituents e.g., alkyl, aryl, etc.
• that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
• phenyl-alkyl- amino-carbonyl-alkyl refers to a group of the formula
• DIPEA or DlEA Diisopropylethylamine
• DMF N,N-Dimethylformam ⁇ de
• HPLC High Pressure Liquid Chromatography
• LAH Lithium Aluminum Hydride
• the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended 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 intended to be encompassed within the scope of this invention.
• suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
• alkali metal salts e.g., sodium or potassium salts
• alkaline earth metal salts e.g., calcium or magnesium salts
• suitable organic ligands e.g., quaternary ammonium salts.
• Scheme 1 Accordingly, a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, is reacted with sulfamide, a known compound, preferably wherein the sulfamide is present in an amount in the range of about 2 to about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, preferably at an elevated temperature in the range of about 50 0 C to about 100 0 C, more preferably at about reflux temperature, to yield the corresponding compound of formula (Ia).
• organic solvent such as THF, dioxane, and the like
• a suitably substituted compound of formula (X), a known compound or compound prepared by known methods is reacted with a suitably substituted compound of formula (Xl), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DMF, DMSO, and the like, to yield the corresponding compound of formula (I).
• a base such as TEA, DIPEA, pyridine, and the like
• organic solvent such as DMF, DMSO, and the like
• a suitably substituted compound of formula (XII) a known compound or compound prepared by known method (for example as described in Scheme 3 above) is reacted with NH 4 OH, a known compound, optionally in an organic solvent such as acetonitrile, and the like, to yield the corresponding compound of formula (XIII).
• the compound of formula (XIII) is reacted with a suitably selected reducing agent, such as LAH, and the like, and the like, in an organic solvent such as THF, diethyl ether, and the like, to yield the corresponding compound of formula (Xa).
• a suitably selected reducing agent such as LAH, and the like, and the like
• organic solvent such as THF, diethyl ether, and the like
• a suitably substituted compound of formula (XIV) a known compound or compound prepared by known methods, is reacted with NH 4 OH, in the presence of a coupling agent such as DCC, and the like, optionally in, an organic solvent such as acetonitrile, and the like, to yield the corresponding compound of formula (XV).
• a suitably substituted compound of formula (XVI) wherein J 1 is a suitable leaving group such as Br, Cl, I, tosyl, mesyl, triflyl, and the like a known compound or compound prepared by known methods (for example, by activating the corresponding compound wherein J 1 is OH), is reacted with a cyanide such as potassium cyanide, sodium cyanide, and the like, in an organic solvent such as DMSO, DMF, THF, and the like, to yield the corresponding compound of formula (XVII).
• a cyanide such as potassium cyanide, sodium cyanide, and the like
• a suitably substituted compound of formula (XVIII) a known compound or compound prepared by known methods is activated, according to known method, to yield the corresponding compound of formula (XIX), wherein J 2 is a suitable leaving group, such tosylate, Cl, Br, I, mesylate, triflate, and the like.
• the compound of formula (XIX) is reacted with a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like, in an organic solvent such as DMF, DMSO, acetonitrile, and the like, preferably, at an elevated temperature in the range of from 50 0 C to about 200°C, more preferably, at about reflux temperature, to yield the corresponding compound of formula (XX).
• a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like
• organic solvent such as DMF, DMSO, acetonitrile, and the like
• the compound of formula (XX) is reacted with N 2 H 4 , a known compound, in an organic solvent such as ethanol, methanol, and the like, preferably, at an elevated temperature in the range of from about 50 0 C to about 100 0 C, more preferably, at about reflux temperature, and the like, to yield the corresponding compound of formula (Xd).
• the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
• these isomers may be separated by conventional techniques such as preparative chromatography.
• the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
• the compounds may, for example, be resolved into their component enantiomers 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 followed by fractional crystallization and regeneration of the free base.
• the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
• 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 can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
• compositions of this invention one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
• a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
• any of the usual pharmaceutical media may be employed.
• suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
• the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
• injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
• the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
• compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.1 -1000 mg and may be given at a dosage of from about 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 range therein.
• the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post- periodic dosing may be employed.
• compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto ⁇ njector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
• the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
• a pharmaceutical carrier e.g.
• a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily 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.
• the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
• the method of treating depression described in the present invention may 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 into any form suitable for the mode of administration selected.
• Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
• compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions.
• forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
• compounds of the present 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.
• compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
• suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
• sterile suspensions and solutions are desired.
• Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
• Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of depression is required.
• compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 200 mg/kg of body weight per day.
• Racemic 2,3-dihydro-1 ,4-benzdioxin-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL) and cooled in an ice bath as dimethylsulfamoyl chloride (1.44 g, 10 mmol) was added. The reaction mixture was then stirred for 3 hr with continued cooling. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate solution was washed with brine, dried (MgSO 4 ) and evaporated in vacuo to yield an oil.
• the white powdery solid was combined with hydrazine (1.06 g, 33 mmol) in EtOH (80 mL) and heated at reflux for 2 h, then cooled to room temperature. 1 N HCI was added to adjust the reaction mixture's pH to pH 1.0 and the reaction mixture was then stirred for 15 min.
• White solid was filtered and washed with fresh EtOH (solid discarded) and the filtrate was evaporated in vacuo to a solid, which was partitioned between diethyl ether and dilute aqueous NaOH.
• (2S)-(-)-N-(2,3-Dihydro-7-nitro-benzo[1 ,4]dioxin-2-ylmethyl)-sulfamide (1.2 g, 4.15 mmol), was prepared from 4-nitrocatechol according to the process outlined in Example 4.
• the (2S)-(-)-N-(2,3-Dihydro-7-n ⁇ tro-benzo[1,4]di ⁇ xin-2- ylmethyl)-sulfamide was then combined with 10% Pd/C in methanol (120 ml_) and shaken under hydrogen atmosphere (39 psi) at room temperature for 3 h.
• the DSR assay is divided into two models: Reduction of Dominant Behavior Model (RDBM) of mania and Reduction of Submissive Behavior Model (RSBM) of depression.
• RDBM Dominant Behavior Model
• RSBM Submissive Behavior Model
• the RDBM wherein the dominant animals are treated with test compound, is predictive of the ability of the test compound to treat mania.
• the RSBM wherein the submissive animals are treated with test compound, is predictive of the ability of the test compound to treat depression.
• mice Male Sprague Dawley rats (140 to 16Og) from Charles River Laboratories Wilmington, MA were used in this assay. Shipments of rats were received at two-week intervals. Each shipment went through five-day quarantine, one-week acclimation period, and one-week selection process, followed by five-weeks of drug or vehicle treatment to those pairs selected.
• Rats were housed four per cage. Access to food was restricted to one hour per day after testing on Monday through Thursday. After testing on ⁇ riday, rats had free access to food until being fasted again on Sunday. At no time were the rats deprived of water. The food deprivation periods used had little effect on weight gain as the average weight of rats was about 30Og at the end of the study. At the conclusion of experiment rats were sacrificed by decapitation, the trunk blood and brains were collected for in vitro experiments and drug concentration measurements.
• the basic testing apparatus consisted of two chambers connected with a tunnel only large enough to allow one rat to pass through at a time. On the floor, at the mid-point 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 video tracked simultaneously. The camera can distinguish rats marked by different colors. Thus, the rats' heads were colored for the purpose of video tracking, red in one cage and yellow in the other cage. 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, time spent in the feeder zone by each rat was recorded by the video tracking software and saved into a text file. The test began with a random assignment of rats into pairs.
• Each member of a pair was placed in an opposite chamber of the testing apparatus. The time spent in the feeder zone by each animal was recorded.
• Dominance was assigned to the animal with the highest score during the second week of testing if three criteria were achieved.
• the normalized DL values were used for this calculation, where DL values for treatment weeks were normalized as a percent of the second week (pretreatment) value of that pair according the above formula.
• the minimum of the response determined drug positive activity, corresponding to efficacy, since DL values were always reduced if the response to a drug was positive.
• DL values were increased. If the drug did not have such activity the maximum of the response did not exceed 100%. Any maximal DL value significantly higher then control value (about 100%) indicated drug negative activity.
• Compound #8 was evaluated in the rat RDBM according to the procedure described in more detail below.
• the difference between dominant and submissive rats was lost after the first week of treatment; and after the second week of treatment when dosed at 2.5 mg/kg and 5.0 mg/kg.
• the difference between dominant and submissive rats was also lost after first week of treatment.
• the permissiveness of the dominant rats treated with Compound #8 or sodium valproate was observed to increase.
• the treated dominant rats permitted their submissive partners to increase their time on the feeder.
• sodium valproate treated animals (30 mg/kg) consistently showed a decreased dominance level 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 control only after the third week of treatment.
• AOT activity onset time
• AOT activity onset time
• the DSR assay is divided into two models: Reduction of Dominant Behavior Model (RDBM) of mania and Reduction of Submissive Behavior Model (RSBM) of depression.
• RDBM Dominant Behavior Model
• RSBM Submissive Behavior Model
• mice Male Sprague Dawley rats (140 to 16Og) from Charles River Laboratories Wilmington, MA were used in this assay. Shipments of rats were received at two-week intervals. Each shipment went through five-day quarantine, one-week acclimation period, and one-week selection process, followed by five-weeks of drug or vehicle treatment to those pairs selected.
• Rats were housed four per cage. Access to food was restricted to one hour per day after testing on Monday through Thursday. After testing on Friday, rats had free access to food until being fasted again on Sunday. At no time were the rats deprived of water. The food deprivation periods used had little effect on weight gain as the average weight of rats was about 30Og at the end of the study. At the conclusion of experiment rats were sacrificed by decapitation, the trunk blood and brains were collected for in vitro experiments and drug concentration measurements.
• the basic testing apparatus consisted of two chambers connected with a tunnel only large enough to allow one rat to pass through at a time. On the floor, at the mid-point 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 video tracked simultaneously. The camera can distinguish rats marked by different colors. Thus, the rats' heads were colored for the purpose of video tracking, red in one cage and yellow in the other cage. 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, time spent in the feeder zone by each rat was recorded by the video tracking software and saved into a text file.
• the test began with a random assignment of rats into pairs. Each member of a pair was placed in an opposite chamber of the testing apparatus. The time spent in the feeder zone by each animal was recorded. During the first week (five days) of testing the animals habituate to the new environment. Dominance was assigned to the animal with the highest score during the second week of testing if three criteria were achieved. First, there must have been a' significant difference (two-tailed t-test, P ⁇ 0.05) between the average daily drinking scores of both animals. Second, the dominant animal score must have been at least 25% greater than the submissive animal's score. Finally, there must have been no "reversals" during the pair selection week where the putative submissive rat out-scored its dominant partner on isolated occasions. Ideally there were minimal reversals during the acclimation week as well. About twenty-five to thirty-three percent of the initial animal pairs achieved these criteria and only these pairs were continued in the study.
• Terminal blood samples (0.5-1.0 ml_) were collected post experiment into heparinized tubes. Blood samples were centrifuged for cell removal, and 200 ⁇ L of plasma supernatant was then transferred to a clean vial, placed on dry ice, and subsequently stored in a -80 0 C freezer prior to analysis. Two hundred microliters of acetonitrile containing internal standard was added to 100 ⁇ L.of plasma or brain tissue to precipitate proteins and/or tissue residues. Samples were centrifuged and supernatant removed for analysis by liquid chromatography-triple quadruple 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 collected samples. Calibration standards were prepared in the range of 0.01 to 10 ⁇ M for quantitation. LC-ESI-MS/MS (negative mode) analysis was performed utilizing multiple reaction monitoring (MRM) for detection of characteristic ions for the test compound.
• MRM multiple reaction
• Dominance Level (week n in %) (Dominance Level (week n)) / (Dominance Level (week 2)
• the normalized DL values were used for this calculation, where DL values for treatment weeks were normalized as a percent of the second week (pretreatment) value of that pair according the above formula.
• the minimum of the response determined drug positive activity, corresponding to efficacy, since DL values were always reduced if the response to a drug was positive.
• DL values were increased. If the drug did not have such activity the maximum of the response did not exceed 100%. Any maximal DL value significantly higher then control value (about 100%) indicated drug negative activity.
• Compound #8 was evaluated in the Rat Reduction of Submissive Behavior 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, R.J., Neuroscience and Biobehavioral Review. 29 (2005) 715-737).
• RSBM Submissive Behavior Model
• Compound #8 was observed to reduce submissive behavior in a dose-dependent manner.
• Dominance Level (DL) values in the group of submissive rats treated with 2.5 mg/kg dose of Compound #8 did not significantly differ from control. However, the group treated with Compound #8 at 12.0 mg/kg showed DL values significantly different from vehicle treated controls after the second, fourth and fifth week of treatment. Similarly, the group treated with Compound #8 at 60 mg/kg showed a significant difference in DL values relative to vehicle starting at the first week and continuing through the treatment duration of 5 weeks. At the highest dose, (120 mg/kg) Compound #8 DL values were significantly different from the control group after first week, however, this significance dissipated after the second week of treatment. Fluoxetine treated animals (10 mg/kg) consistently showed increased submissiveness during first week of treatment.
• the activity onset time was estimated from the non-linear regression fit.
• the non-linear regression model was fit for each drug and dose normalized daily DL values.
• Activity Onset Time at the 50% effect (AOT50) and Emax for Compound #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 of the effect derived from this analysis was 52.4 ⁇ 32.7% (SEM), 87.9 + 42.6% (SEM) and 116.9 ⁇ 29.5% (SEM) for the 2.5 mg/kg, 12 mg/kg and 60 mg/kg dose respectively and was also not significantly different between these doses.
• Rats were considered fully kindled when they displayed five consecutive Stage 4 or 5 generalized seizures. Daily stimulations were continued for up to 13 consecutive days in all three groups until rats in the vehicle-treated group were fully kindled (i.e., five consecutive Stage 4 or 5 seizures). At this time, all rats were allowed a one- week stimulus and drug-free period; after which they were re-challenged in the absence of drug with the same stimulus employed during the acquisition phase (i.e., days 1-13). Rats treated with Compound #8 were subsequently stimulated once per day until they reached a fully kindled state.
• the after-discharge (AD) duration in both the vehicle and Compound #8 treated groups displayed a progressive increase over the course of the kindling acquisition phase. No statistical difference between treatment groups was observed.
• each rat was then stimulated every 30 min for 3 to 4 h. After each stimulation, individual seizure scores and after-discharge durations were recorded. The group mean ⁇ SEM were calculated for each parameter. Eight rats per dose and a minimum of four doses were used to establish an ED 50 value. Efficacy was measured as the ability of a compound to modify the seizure score (severity of spread) and after-discharge duration (ADD; excitability) of the generalized seizures.
• ADD after-discharge duration
• a decrease in seizure score and / or ADD may also be predictive of the ability of a test compound to treat the cycling associated with bipolar disorder.
• rats received 2-3 supra-threshold stimulations delivered every 30 min before treatment with Compound #8 (or vehicle) to ensure stability of the behavioral seizure stage and after-discharge duration. Fifteen minutes after the last stimulation, a single dose of vehicle or test compound was administered i.p. After 15 min, each rat was then stimulated every 30 min for 3 to 4 h. After each stimulation, individual seizure scores and after-discharge durations were recorded. The group mean ⁇ SEM was calculated for each parameter.
• mice are suspended by their tails to a metal or plastic rod using clip or scotch 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 which have antidepressant activity, decrease the duration of immobility of mice in this test.
• mice were ordered 5 weeks old and at the beginning of experiment their weight was 20 ⁇ 5g.
• Animals were housed in groups of four in plastic cages at an ambient temperature of 21 0 C to 23°C with an automated 12/12 hours light/dark cycle and access to water and a commercial rodent food ad libitum.
• DMI effects were statistically significant at 12, 30, 60 and 120 mg/kg.
• VLX effects were statistically significant at 6, 12, 30, 60 and 120 mg/kg.
• DLX effects were statistically significant at 60 and 120 mg/kg.
• ED 50 and E max values were calculated from these results by non-linear regression analysis. ED 50 and E max values are listed in Table 5 below. ED 50 values calculated for immobility and mobility were not significantly different across treatments. The ED5 0 value for Compound #8 was significantly lower than the ED 50 value for DLX but not different than the ED 50 values for DMI and VLX. The Emax values calculated for immobility and mobility were not significantly different for Compound #8 but were significantly different for all tested antidepressant. The E max immobility value for Compound #8 was also significantly lower then than antidepressant drug values.
• Animals were housed in groups of four in plastic cages at an ambient temperature of 21 0 C to 23°C with an automated 12 hour light/dark cycfe and access to water and commercial rodent food ad libitum. Animals were not handled more than for the routine bedding change prior to pre-test swim session.
• the basic apparatus consisted of a cylinder (46 cm tall x -20 cm diameter) filled with water to 30 cm deep, at a temperature of 25 ⁇ 1 0 C.
• the automated version of the FST was used to perform the experiments.
• Plumbing for automatic filling and emptying water connected the four cylinders. Cylinders were placed in the dividing chambers 25 cm wide to separate 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 immobility, swimming, climbing and escape times were recorded by the software. The four activities are defined as follow.
• Immobility the animal floats motionlessly or makes only those movements necessary to keep its head above water; Climb: the animal vigorously moves vertically while scratching the wall around the cylinder; Swim: the animal moves horizontally around in the cylinder more than necessary to keep its head above water; and Escape: sum of all vigorous active movements.
• a pre-test swim session for 15 minutes was performed. Following 48 hours later was a test session of 5-minute duration. Upon completion of a swim session, each animal was placed under a heat lamp in a cage with soft bedding for approximately 15 minutes to prevent hypothermia. Animals were pre-treated with a vehicle or test compound after completing the pre-test swim session, then 24 hours later and then shortly prior to the 5-minute test session; i.e., three injections were given to each animal between the two swim sessions that occurred on 3 consecutive days. The time prior to test session was 1 hour for desipramine, maprotyline, venlafaxine, lorazepam or 4 hours for Compound #8; the time of the maximal effect in the maximal electroshock seizures (MES) test.
• MES maximal electroshock seizures
• the ED 50 value for Compound #8 was significantly different from the ED 50 value for desipramine at p ⁇ 0.001 (two tail t-test). There was no statistically significant difference between E ma ⁇ values for desipramine and
• CMS chronic mild stress
• vehicle 0.5% methylcellulose, 1 ml/kg
• Compound #8 at 12 mg/kg, 30 mg/kg or 60 mg/kg
• imipramine 10 g/kg or venlafaxine at 10 mg/kg as reference treatments.
• the drugs were administered at approx. 10.00 and the weekly sucrose tests were carried out 24h following the last drug injections. After five weeks all treatments were terminated and 24h later the blood and/or brain samples were collected from all animals and submitted for further biochemical analysis. Stress was continued throughout the entire period of treatment.
• Resident / Intruder Assay also known as Chronic Social Stress Assay
• the behavioral resident / intruder assay is used to screen compounds for anti-depressant-like activity.
• Compound #8 was tested in this assay, with the assay run according to the procedure as described in Rygula, R-, Abumaria, N., Klige, G., Fuchs, E., Ruther, E., Havemann-Reinecke, U., Behavioral Brain Research, 162 (2005), pp127-134.
• Tables 5, 6 and 7 below list the mean and standard deviation values for measured parameters, for the following compounds, administered p.o. (orally): vehicle, control compounds imipramine at 10 mg/kg and venlafaxine at 10 mg/kg, Compound #8 at 60 mg/kg and Compound #8 at 120 mg/kg.
• Imipramine - stressed 10 70.5 ⁇ 19.5 78.3 ⁇ 15.1 73.6 ⁇ 19.4
• 100 mg of the Compound #8 prepared as in Example 7 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

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