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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/34—Tobacco-abuse
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism

Definitions

• the present invention provides pharmaceutical compositions and methods relating to 11 -piperazin- 1 -yldibenzo[ ⁇ /j [1 ,4]thiazepine. BACKGROUND OF THE INVENTION
• Quetiapine fumarate is described in U.S. Patent Number 4,879,288, which is incorporated herein by reference. Quetiapine fumarate is able to treat both the positive (hallucinations, delusions) and negative symptoms (emotional withdrawal, apathy) of psychosis and is associated with fewer neurological and endocrine related side effects compared to older agents. Quetiapine fumarate has also been associated with a reduction in hostility and aggression.
• Quetiapine fumarate is associated with fewer side effects such as EPS, acute dystonia, acute dyskinesia, as well as tardive dyskinesia. Quetiapine fumarate has also helped to enhance patient compliance with treatment, ability to function and overall quality of life, while reducing recidivism. P. Weiden et al., Atypical antipsychotic drugs and long-term outcome in schizophrenia, 11 J. Clin. Psychiatry, 53-60, 57 (1996). Because of quetiapine fumarate's enhanced tolerability profile its use is particularly advantageous in the treatment of patients that are hypersensitive to the adverse effects of antipsychotics (such as elderly patients).
• a method of treating comprising the administration of an effective amount of Formula I or its pharmaceutically acceptable salt to a mammal, at least one symptom or condition associated with, but not limited to: 1) Sleep Disorders including but not limited to a)Dyssomnia Disorders including but not limited to: i) Primary inomnia, ii) Primary Hypersomnia, and iii) narcolepsy; and b) Parasomnias Disorders including but not limited to i) Nightmare Disorder, Sleep Terror Disorder and Sleepwalking Disorder.
• Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence including but not limited to Mental Retardation, Learning Disorders, Motor Skills Disorder, Communication Disoorders, Pervasive Developmental Disorders, Attention-Deficit and Disruptive Behavior Disorders, Feeding and Eating Disorders of Infancy or Early Childhood, Tic Disorders, and Elimination Disorders; 2) Substance-Related Disorders including but not limited to Substance Dependence, Substance Abuse, Substance Intoxication, Substance Withdrawal, Alcohol- Related Disorders, Amphetamine (or Amphetamine-Like)-Related Disorders, Caffeine- Related Disorders, Cannabis-Related Disorders, Cocaine-Related Disorders, Hallucinogen- Related Disorders, Inhalant-Related Disorders, Nicotine-Related Disorders, Opioid-Related Disorders, Phencyclidine (or Phencyclidine-Like)-Related Disorders, and Sedative-, Hypnotic-
• a pharmaceutical composition comprising an effective amount of the compound of Formula I or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.
• a method of treating the symptoms or conditions provided herein comprising administering to a mammal a pharmaceutical composition as described above.
• the use of the compound of Formula I or its pharmaceutically acceptable salt and/or the above-mentioned pharmaceutical composition in the treatment of the symptoms or conditions provided herein in mammals.
• the use of the compound of Formula I or its pharmaceutically acceptable salt and/or the pharmaceutical composition in the manufacture of a medicament for use in the treatment of the symptoms or conditions provided herein in mammals.
• Figure 1 depicts an X-ray powder diffraction (XRPD) pattern consistent with crystalline 1 l-piperazin-l-yldibenzo[£/][l,4]thiazepine having Form A.
• XRPD X-ray powder diffraction
• the compound of Formula I is a dibenzothiazepine that has shown antidopaminergic activity. It has been shown to interact with a broad range of neurotransmitter receptors but has a higher affinity for serotonin (5-HT 2 ) receptors relative to dopamine (D 2 ) receptors in the brain.
• PET Preliminary positron emission topography
• the compound of Formula I was not shown to be efficacious in a mouse standard apomorphine swim test (p.o.) and in a rat D-Arnpehtamine locomotor activity test (s.c).
• the compound of Formula I has also been shown to have partial 5HT 1A agonist activity and has shown in-vivo efficacy in mouse and rat models for depression.
• the compound of Formula I may be used as an antipsychotic with a reduction in the potential to cause side effects such as acute dystonia, acute dyskinesia, as well as tardive dyskinesia typically seen with antipsychotics. Results generated from alpha receptor binding data further suggest that the compound of Formula I will have improved tolerability over that of quetiapine and suggest that one would observe a reduced incidence of hypotension. Further the compound of Formula I may be used to treat patients of all ages and is advantageous in the treatment of elderly patients.
• mammal means a warm-blooded animal, preferably a human.
• the compound of Formula I may be made by a variety of methods known in the chemical arts.
• the compound of Formula I may be prepared by starting from known compounds or readily prepared intermediates including taking the lactam of Formula II:
• the immino chloride of Formula III may also be generated with other agents such as thionyl chloride or phosphorous pentachloride.
• the imino chloride is then reacted with piperazine to give the compound of Formula I.
• the compound of Formula I provided herein is useful as a free base, but may also be provided in the form of a pharmaceutically acceptable salt, and/or in the form of a pharmaceutically acceptable solvate (including hydrates).
• pharmaceutically acceptable salts of Formula I include those derived from mineral acids such as for example: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydroiodic acid, nitrous acid, and phosphorous acid.
• Pharmaceutically acceptable salts may also be developed with organic acids including aliphatic mono dicarboxylates and aromatic acids.
• Other pharmaceutically acceptable salts of Formula I include but are not limited to hydrochloride, sulfate, pyrosulfate, bisulfate, bisulfite, nitrate, and phosphate.
• a clinician may determine the effective amount by using numerous methods already known in the art.
• the term "treating" within the context of the present invention encompasses to administer an effective amount of the compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring symptom or condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
• a particular amount of the compound of Formula I or its pharmaceutically acceptable salt can be administered in an amount up to about 750 mg per day; particularly from about 75 mg to about 750 mg per day.
• the amount of the compound of Formula I 5 or its pharmaceutically acceptable salt may be administered from about 1 mg to about 600 mg per day.
• the compound of Formula I or its pharmaceutically acceptable salt may be administered from about 100 mg to about 400 mg per day.
• the compound of Formula I or its pharmaceutically acceptable salt may be administered comprising a predetermined dosage of the compound of Formula I to a mammal between one and four times a day, wherein the predetermined dosage is from about 1 mg to about 600 mg.
• the present invention also provides a method of treating the symptoms or conditions provided herein comprising the step of administering an initial predetermined dosage of a compound of Formula I to a human patient twice a day, wherein the predetermined dosage is between 1 mg and 30 mg with increases in increments of 1-50 mg twice daily on the second and third day as tolerated. Thereafter, further dosage adjustments can be made at intervals of no less than 2 days.
• the pharmaceutical composition comprises up to about 750 mg of the compound of Formula I or its pharmaceutically acceptable salt, particularly from about 75 mg to about 750 mg.
• the pharmaceutical composition may comprise from about 1 mg to about 600 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof. In another embodiment of the invention, the pharmaceutical composition may comprise from about 100 mg to about 400 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.
• composition of the invention may accordingly be obtained by conventional procedures using conventional pharmaceutical excipients.
• pharmaceutical compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
• composition of the invention may be administered by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
• the amount of active ingredient that is combined with one or more excipients to produce a single dosage form, such as an oral dosage form, will necessarily vary depending upon the host treated and the particular route of administration.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the symptoms or conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
• Another aspect of the invention provides a compound of Formula I, or its pharmaceutically acceptable salt or solvate thereof, for use in treating the symptoms or conditions provided herein.
• the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in treating the symptoms or conditions provided herein.
• the present invention relates to methods of treating at least one of the above described symptoms or conditions comprising administering to a mammal an effective amount of the compound of Formula I or its pharmaceutically acceptable salt and one or more of other therapeutically active agents, benzodiazepines, 5-HTJ A ligands, 5-HT 1B ligands, 5-HT 1D ligands, mGluR2A agonists, mGluR5 antagonists, antipsychotics, NKl receptor antagonists, antidepressants, serotonin reuptake inhibitors, GABA II ligands, or mood stabilizers administered in combination as part of the same pharmaceutical composition, as well as to methods in which such active agents are administered separately as part of an appropriate dose regimen designed to obtain the benefits of combination therapy.
• other therapeutically active agents benzodiazepines, 5-HTJ A ligands, 5-HT 1B ligands, 5-HT 1D ligands, mGluR2A agonists, mGluR5 antagonists, antipsychotics, NK
• the appropriate dose regimen, the amount of each dose of an active agent administered, and the specific intervals between doses of each active agent will depend upon the subject being treated, the specific active agent being administered and the nature and severity of the specific disorder or condition being treated.
• the compounds of this invention when used as either a single active agent or when used in combination with another active agent, will be administered to a subject in an amount up to about 750 mg per day, in single or divided doses.
• Such compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times pe/ day. Variations may nevertheless occur depending upon the subject being treated and the individual response to the treatment, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
• dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases larger doses may be employed to achieve the desired effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
• Exemplary benzodiazepines may include but are not limited to adinazolam, alprazolam, bromazepam, clonazepam, chlorazepate, chlordiazepoxide, diazepam, estazolam, flurazepam, balezepam, lorazepam, midazolam, nitrazepam, oxazepam, quazepam, temazepam, triazolam and equivalents thereof.
• Exemplary 5-HT 1A and/or 5HT 1B ligands may include but are not limited to buspirone, amespirone, elzasonan, ipsapirone, gepirone, zopiclone and equivalents thereof.
• Exemplary mGluR 2 agonists may include (lS,3R)-l-aminocyclopentane-l,3- dicarboxylic acid, (2S,3S,4S)alpha-(carboxycyclopropyl)glycine, and 3,5- dihydroxyphenylglycine.
• Exemplary antidepressants may include but are not limited to maprotiline, amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortryptyline, protriptyline, trimipramine, SSRIs and SNRIs such as fluoxetine, paroxetine, citalopram, escitalopram, sertraline, venlafaxine, fluoxamine, and reboxetine.
• Exemplary antipsychotics may include but are not limited to clozapine, risperidone, quetiapine, olanzapine, amisulpride, sulpiride, zotepine, chlorpromazine, haloperidol, ziprasidone, and sertindole.
• Exemplary mood stabilizers may include but are not limited to Valproic acid (valproate) and its derivative (e.g. divalproex), lamotrigine, lithium, verapamil, carbamazepine and gabapentin.
• Crude imino chloride (27.35 g, 0.111 mole) was added to 1000 mL o-xylene in a 2000 mL round-bottom flask equipped with a magnetic stir bar and a reflux condenser with nitrogen inlet.
• To this solution was added commercially available piperazine (47.95g, 0.557 mole) in one portion as a dry solid at room temperature. The mixture was stirred until nearly all the piperazine dissolved. Then the reaction mixture was heated at reflux (142 degrees C) for 40 hours (out of convenience). The reaction was then allowed to cool to room temperature, and an aliquot was partitioned between IN NaOH / CH 2 Cl 2 .
• the reaction mixture was stripped down on the rotary evaporator under high vacuum to remove the xylene. The residue was partitioned between IN NaOH (400 mL) and CH 2 Cl 2 (200 mL). The layers were separated, and the aqueous phase further extracted with CH 2 Cl 2 (3 X 200 mL).
• the free base was converted to it's dihydrochloride salt by dissolving it in a mixture of methanol (125 mL) and diethyl ether (125 mL), then treating with 250 mL of 1.0 M HCl/ ether (Aldrich). An off -white gummy solid separated initially, and the mixture was farther diluted with 50Q mL ether. The gummy solid did not solidify on prolonged stirring. The solvents were decanted away from the gum. The gum was treated with absolute ethanol (200 mL), then stirred until crystallization occurred, giving a thick white suspension of crystals. This mixture was then slowly diluted with ether (800 mL) and allowed to stir overnight to complete the crystallization.
• Aqueous solution (584 mL; e.g., prepared by extraction of 11-piperazin-l- yldibenzo[b,fj[l,4]thiazepine into water/HCl from a toluene solution such as described below in Preparation B) containing 1 l-piperazin-l-yldibenzo[b,fj[l,4]thiazepine hydrochloride was charged to a jacketed 1 L flask. The flask was then charged with toluene (500 mL) and sodium hydroxide (48% w/w, 33.0 g). The mixture was stirred at 70 0 C for 30 minutes and became white and cloudy.
• the mixture was then allowed to settle for 30 min and the phases were separated.
• the final toluene volume was 560 mL containing about 74 g of 1 l-piperazin-l-yldibenzo[b,fj[l,4]thiazepine in good purity.
• a toluene solution of 1 l-piperazin-l-yldibenzo[b,fj[l,4]thiazepine (1500 mL, 0.686 mol) prepared by reaction of piperazine with 1 l-chloro-dibenzo[b,fj[l,4]-thiazepine in toluene (see, e.g., U. S. Pat. No. 4,879,288) was treated with 1500 mL deionized water and 90 mL of HCl (32% w/w). The resulting mixture was heated to 70 0 C and agitated for 45 min. Agitation was ceased and the mixture allowed to settle and phase separate for 30 min.
• the lower aqueous phase containing the HCl salt of 1 l-piperazin-l-yldibenzo[b,fj[l 5 4]thiazepine was isolated.
• the aqueous phase was then treated with 1000 mL of toluene and 99 g of aqueous NaOH (47% w/w).
• the resulting mixture was heated to 70 °C and agitated for 45 min. Agitation was ceased and the mixture allowed to settle and phase separate for 30 min.
• the lower aqueous phase was discarded and the upper organic phase retained to which 300 mL of deionized water was added.
• the resulting mixture was agitated for 15 min and then allowed to settle for 30 min.
• the aqueous phase was discarded and the organic phase retained.
• the organic phase was extracted once more with 300 mL of deionized water. About 750 mL of toluene from the organic phase was distilled out. The resulting concentrate was cooled to 60 °C, then 200 mL of methyl-t-butyl ether (MTBE) was added. The resulting mixture was cooled to ambient temperature then seeded with Form A seed crystals. The seeded mixture was then cooled to 10 °C and held at this temperature for 3 hours under slow agitation. The resulting solid was isolated under suction via a no. 3 sinter. The solid product was then washed with 120 mL of MTBE at ambient temperature and dried at 40 °C under vacuum resulting in 175 g (86.4%) of crystalline product. Assay 99.9% w/w by HPLC area %.
• Solid l l-piperazin-l-yldibenzo[b,fj[l,4]thiazepine (30 g, 0.1016 mol) prepared as described above was slurried in isopropanol (120 mL). The resulting mixture was warmed to about 63-64 °C to completely dissolve the solid. The resulting solution was filtered through a preheated (about 55 °C) split Buchner funnel fitted with filter paper with a pore size of 6 ⁇ m. ' The filtered solution was then adjusted to 55 °C and seeded with seed crystals of Form ' A (0.024 g).
• the seeded solution was maintained at 55 °C for about 2 h then linearly cooled to 40 0 C over the course of 6 h, linearly cooled to 20 0 C over the course of 2 h, and then linearly cooled to 0 °C over the course of 1 h.
• the resulting slurry was held at 0 °C for 12 h and the solid product cake (13 mm high x 68 mm diameter) was isolated by filtration.
• the product cake was displacement washed with 30 mL isopropanol prechilled to 0 °C and the cake allowed to deliquor.
• the product was then dried at 40 °C under vacuum yielding 24.9 g (83%) of Form A.
• X-ray powder diffraction (XRPD) peak data of crystalline Form A is provided below in Chart A. The following instrument setting were used.
• Scan range 2-40° 2 ⁇
• Receptor binding methods ⁇ -adrenergic subtype specific, are provided below.
• Receptor binding methods ⁇ -adrenergic nonselective, are provided below.
• CHO membranes (10 ⁇ g protein) expressing human 5-HT I A receptors were incubated in 100 ⁇ l of 2OmM HEPES, pH 7.4 assay buffer containing 1OmM MgCl 2, 10OmM NaCl, 0.1%BSA, 20 ⁇ M GDP, 200 ⁇ g WGA-PVT beads (Amersham RPNQOOOl), 200 pM GTPy 35 S (Perkin Elmer NEG-030H).
• [l,4]thiazepme was incubated with the above at 11 different concentrations varying from lO ⁇ M to 17OpM in Packard OptiPlates with shaking for 1.5 hrs at room temperature.
• 5-HT was used as a positive control, with an EC50 15.5 nM in the assay.
• One ⁇ M of 5-HT was used as maximum agonist activity (100%) for the compound efficacy determination.
• the plates were centrifuged to settle the beads and measured in a Parkard TopCount. Using this as " say, 11-piperazin-l- yldibenzo[&/j[l,4]thiazepine is shown to be a partial agonist of 5HT 1A receptor with an EC50 of 310 nM and a maximum efficacy of 66% relative to l ⁇ M of 5-HT.
• Oral Bioavailability l l-piperazm-l-yldibenzo[6/][l,4]thiazepme was administered to 3 Sprague-Dawley rats each either intravenously or orally at doses of 10 umol/kg or 30 umol/kg, respectively, in a sodium citrate (pH 3) formulation. Blood samples were removed from each animal at several timepoints after dosing. The blood samples were centrifuged to produce plasma. Aliquots of each plasma sample were analyzed by an HPLC method with mass spectrometric detection to measure 1 l-piperazin-l-yldibenzo[&,/][l,4]thiazepme. The area under the plasma concentration curves (AUC) constructed from the sample measurements following iv or po administration were used to calculate oral biovailability. The calculated oral bioavailability based on the results of this study was 11% for rat.
• AUC area under the plasma concentration curves
• Brain exposure was measured in rats. For concentrations of 11-piperazin-l- yldibenzo[ ⁇ /j[l,4]thiazepine in brain, rats were dosed either po or iv (n 3 per dose route). At one hour after compound administration, blood and brain samples were obtained and then processed for analysis using HPLC/MS to measure concentrations of 11-piperazin-l- yldibenzo[5,/][l,4]thiazepine. Average concentrations in rats one hour after oral dosing at 30 umol/kg po was 658 nmol/ml plasma and 2240 nmol/g brain tissue, giving a brain/plasma exposure ratio of 3.4. A similar analysis after iv dosing measured braur.plasma concentration ratios of 4.6 demonstrating penetration of the compound into the CNS.
• the Hl receptor binding method was carried out in accordance with the method set out in De Backer MD et al. Biochem. Biophys. Res Commun. 197(3); 1601, 1993.
• the compound/metabolite binds to the Hl receptor with a K; of 1.15 nM which suggests that it will have an effect on sleep.

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