US 20060204486A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0204486A1 Pyke et al. (43) Pub. Date: Sep. 14, 2006 (54) PHARMACEUTICAL COMPOSITIONS FOR Publication Classification THE TREATMENT AND/OR PREVENTION OF SCHIZOPHRENA AND RELATED (51) Int. Cl. DISEASES A6II 38/54 (2006.01) A6II 3/55 (2006.01) (75) Inventors: Robert Pyke, New Fairfield, CT (US); A61K 3.1/5415 (2006.01) Angelo Ceci, Mittlebiberach (DE) A 6LX 3/59 (2006.01) A6II 3L/496 (2006.01) Correspondence Address: A6II 3/445 (2006.01) MICHAEL P. MORRIS A6II 3/405 (2006.01) BOEHRINGERINGELHEM CORPORATION A6II 3L/98 (2006.01) 900 RIDGEBURY ROAD (52) U.S. Cl. ................... 424/94.2: 514/254.06; 514/220; P. O. BOX 368 514/259.41: 514/419; 514/317; RIDGEFIELD, CT 06877-0368 (US) 514/561; 514/225.8 (73) Assignee: Boehringer Ingelheim International GmbH, Ingelheim (DE) (57) ABSTRACT (21) Appl. No.: 11/364,306 The invention relates to new pharmaceutical compositions for the treatment and/or prevention of schizophrenia and (22) Filed: Feb. 28, 2006 methods for the preparation thereof. In a preferred embodi ment, the instant invention is directed to pharmaceutical Related U.S. Application Data combinations comprising flibanserin as one active ingredi ent in combination with at least one additional active ingre (60) Provisional application No. 60/658,566, filed on Mar. dient for the treatment and/or prevention of schizophrenia 4, 2005. and methods for the preparation thereof. US 2006/0204486 A1 Sep. 14, 2006 PHARMACEUTICAL COMPOSITIONS FOR THE antagonists, alpha 2 adrenoreceptor antagonists, AMPA TREATMENT AND/OR PREVENTION OF modulators and NK 3 antagonists. SCHIZOPHRENA AND RELATED DISEASES 0007 Especially preferred are pharmaceutical composi 0001. The invention relates to new pharmaceutical com tions comprising a therapeutically effective amount of fli positions for the treatment and/or prevention of Schizophre banserin 1 in combination with a therapeutically effective nia and related diseases and methods for the preparation amount of one or more, preferably one antipsychotic drug 2 thereof. In a preferred embodiment, the instant invention is selected from the group consisting of D2 antagonists. directed to pharmaceutical combinations comprising fli banserin as one active ingredient in combination with at 0008. The compositions according to the invention may least one additional active ingredient for the treatment contain flibanserin 1 and the one or more additional antip and/or prevention of Schizophrenia and related diseases and sychotic drugs 2 in a single formulation or in separate methods for the preparation thereof. formulations. If flibanserin and the one or more additional antipsychotic drugs are present in separate formulations BACKGROUND OF THE INVENTION these separate formulations may be administered simulta neously or sequentially. 0002 The invention relates to new pharmaceutical com positions for the treatment and/or prevention of Schizophre 0009. A preferred embodiment according to the invention nia and related diseases and methods for the preparation is directed to pharmaceutical compositions comprising a thereof. In one embodiment, the instant invention is directed therapeutically effective amount of flibanserin 1 and a to pharmaceutical combinations comprising a therapeuti therapeutically effective amount of one or more, preferably cally effective amount of flibanserin 1 as one active ingre one additional antipsychotic drug. 2, optionally in combina dient of combination with a therapeutically effective amount tion with a pharmaceutically acceptable excipient. of at one or more, preferably one additional antipsychotic 00.10 Examples of suitable additional antipsychotic drug 2 for the treatment and/or prevention of Schizophrenia drugs include Chlorpromazine. Thioridazine, Haloperidol, and related diseases and methods for the preparation thereof. Perphenazine. Thiothixene, Trifluoperazine, Fluphenazine, 0003. The compound 1—2–(4 (3 trifluoromethyl Clozapine, Risperidone, Olanzapine, Quetiapine, Pimozide, phenyl)ethyl-2,3-dihydro-1H-benzimidazol-2-one (fli Aripiprazole, Ziprasidone, Perospirone, Nemonapride, banserin) is disclosed in form of its hydrochloride in Euro Sertindole, Levosulpiride, Tandospirone, Bifeprunox, pean Patent Application EP-A-526434 and has the following Asenapine, Paliperidone, Mifepristone, Lamotrigine, Ilo chemical structure: peridone, Blonanserin, DU-125530, Lurasidone, ACP-103. Idazoxan, Org-24448, CX-516, Aplindore, SLV-313, SLV 310, Ocaperidone, PNU-170413, POL-255, ABT-089 Taln O etant, NE-100, LAX-101, LAX-111, RG-1068 (Secretin), Dexefraoxan, Dihydrexidine, SM-13496, D-Serine, Osanet is-( ant, EMR-62218, SB-399885, TC-1698, SR-147778, SLV 319, SSR-181507, AVE-5997, PNU-177864, Abaperidone, SSR-146977, Neboglamine, Lamictal XT, N-Desmethyl \-O-(S\ / clozapine, Topiramate and cycloserine, optionally in form of 1 x HC the pharmaceutically acceptable acid addition salts, in form of the hydrates and/or solvates and optionally in the form of the individual optical isomers, mixtures of the individual 0004 Flibanserin shows affinity for the 5-HT5-HT enantiomers or racemates thereof. and D-receptor. It is therefore a promising thereapeutic 0011 Flibansering 1 may be used inform of the free base, agent for the treatment of a variety of diseases, for instance optionally in form of its pharmaceutically acceptable acid depression, Schizophrenia, Parkinson, anxiety, sleep distur addition salts and/or optionally in form of the hydrates bances, sexual and mental disorders and age associated memory impairment. and/or solvates thereof. Suitable acid addition salts include for example those of the acids selected from, Succinic acid, 0005 One embodiment of the invention is directed to hydrobromic acid, acetic acid, fumaric acid, maleic acid, pharmaceutical compositions comparing a therapeutically methaneSulphonic acid, lactic acid, phosphoric acid, hydro effective amount of flibanserin 1 in combination with a chloric acid, Sulphuric acid, tartaric acid and citric acid. therapeutically effective amount of one or more additional Mixtures of the abovementioned acid addition salts may also antipsychotic drugs 2. be used. From the aforementioned acid addition salts the hydrochloride and the hydrobromide, particularly the hydro 0006 Another embodiment of the invention is directed to pharmaceutical compositions comprising a therapeutically chloride, are preferred. If flibanserin1 is used in form of the effective amount of flibanserin 1 in composition with a free base, it is preferably used in form of flibanserin poly therapeutically effective amount of one or more, preferably morph A as disclosed in WO 03/014079. one antipsychotic drug 2 selected from the group consisting 0012. The antipsychotic drugs 2 which are suitable to be of 5-HT1A agnostics, dopamine modulators, sodium channel combined with flibanserin within the teaching of the instant blockers, 5-HT uptake inhibitors, D3 antagonists, D2 invention and which are mentioned hereinbefore may also antagonists, D1 antagonists, D1 agonists, secretin agonist, be capable of forming acid addition salts with pharmaceu phospholipase A2 inhibitors, 5-HT2 antagonists, 5HT6 tically acceptable acids. Representative salts include the antagonists, COX 2 inhibitors, 5-HT2A antagonists, 5HT following: Acetate, Benzenesulfonate, Benzoate, Bicarbon modulators, NK3 antagonists, alpha 1 adrenoreceptor ate, Bisulfate, Bitartrate, Borate, Bromide, Camsylate, Car US 2006/0204486 A1 Sep. 14, 2006 bonate, Chloride, Clavulanate, Citrate, Dihydrochoride, together in one pharmaceutical composition. In addition, the Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, administration of one element of the combination of the Glyconate, Glutamate, Glycolylarsanilate, Hexylresorci present invention may be prior to, concurrent to, or Subse nate, Hydrabamine, Hydrobromide, Hydrochloride, quent to the administration of the other element of the Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lacto combination. bionate, Luarate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate. Mucate, 0022. The elements of the combination of 1 and 2 may be Napsylate, Nitrate, N-methylglucamine ammonium salt, administered by oral, parenteral (e.g., intramuscular, intra Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantoth peritoneal, intravenous or Subcutaneous injection or enate, Phosphate/diphosphate, Polygalacturonate, Salicy implant), buccal, nasal, vaginal, rectal, Sublingual, or topical (e..a... ocular eyedrop) routes of administration and may be late, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tar formulated, alone or together, in Suitable dosage unit for trate, Teoclate, Tosylate, Triethiodide and Valerate. mulations containing conventional non-toxic pharmaceuti 0013 Furthermore, where the compounds 2 carry an cally acceptable carriers, adjuvants and vehicles appropriate acidic moiety, Suitable pharmaceutically acceptable salts for each route of administration. thereof may include alkali metal salts, e.g., Sodium or potassium salts; alkaline earth metal salts, e.g., calcium or 0023 The pharmaceutical compositions for the adminis magnesium salts; and salts formed with Suitable organic tration of the components 1 and 2 of this invention may ligands, e.g., quaternary ammonium salts. conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of 0014. The compounds 2 may have chiral centers and pharmacy.