METHODS OF TREATMENT AND PHARMACEUTICAL COMPOSITIONS USING AN SGLT-2 INHIBITOR AND A NEUROLEPTIC AGENT

Abstract

The invention relates to methods for preventing, slowing the progression of, delaying or treating metabolic disorders induced in patients by the treatment with neuroleptic agents comprising administering to the patients an SGLT2 inhibitor.

Claims

1. A method for preventing, slowing the progression of, delaying or treating a metabolic disorder induced in a patient by the treatment of said patient with a neuroleptic agent, said method comprising administering to said patient an SGLT2 inhibitor and a neuroleptic agent, wherein said SGLT-2 inhibitor and said neuroleptic agent are administered in combination or alternation or sequentially to the patient, wherein said SGLT2 inhibitor is empagliflozin, dapagliflozin or canagliflozin and wherein said neuroleptic agent is olanzapine, haloperidol or clozapine.

2-6. (canceled)

7. The method according to claim 1, wherein said metabolic disorder induced in said patient by the treatment of said patient with a neuroleptic agent is weight gain.

8. The method according to claim 1, wherein said metabolic disorder induced in said patient by the treatment of said patient with a neuroleptic agent is hyperglycemia.

9. (canceled)

10. A method for treating a psychotic disorder in a diabetic patient, said method comprising administering to said patient a SGLT-2 inhibitor and a neuroleptic agent, wherein said SGLT-2 inhibitor and said neuroleptic agent are administered in combination or alternation or sequentially to the patient, wherein said SGLT2 inhibitor is empagliflozin, dapagliflozin or canagliflozin and wherein said neuroleptic agent is olanzapine, haloperidol or clozapine.

11. (canceled)

12. The method according to claim 10, wherein said patient: (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or (2) is an individual who shows one, two or more of the following conditions: (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 8.0%; or (3) is an individual wherein one, two, three or more of the following conditions are present: (a) obesity, visceral obesity and/or abdominal obesity, (b) triglyceride blood level ≥150 mg/dL, (c) HDL-cholesterol blood level <40 mg/dL in female patients and <50 mg/dL in male patients, (d) a systolic blood pressure ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, (e) a fasting blood glucose level ≥100 mg/dL.

13-17. (canceled)

18. A method for weight reduction, for reduction of body fat, for preventing an increase of body weight or for attenuating an increase of body weight in a patient treated for a psychotic disorder, said method comprising administering to said patient a SGLT2 inhibitor and a neuroleptic agent, wherein said SGLT-2 inhibitor and said neuroleptic agent are administered in combination or alternation or sequentially to the patient, wherein said SGLT2 inhibitor is empagliflozin, dapagliflozin or canagliflozin and wherein said neuroleptic agent is olanzapine, haloperidol or clozapine.

19-24. (canceled)

25. A method for treating, for reducing, for preventing or for attenuating an increase of hyperglycemia in a patient treated for a psychotic disorder, said method comprising administering to said patient an SGLT2 inhibitor and a neuroleptic agent, wherein said SGLT-2 inhibitor and said neuroleptic agent are administered in combination or alternation or sequentially to the patient, wherein said SGLT2 inhibitor is empagliflozin, dapagliflozin or canagliflozin and wherein said neuroleptic agent is olanzapine, haloperidol or clozapine.

26-30. (canceled)

31. A pharmaceutical composition comprising (a) a neuroleptic agent and (b) an SGLT2 inhibitor, wherein said SGLT2 inhibitor is empagliflozin, dapagliflozin or canagliflozin and wherein said neuroleptic agent is olanzapine, haloperidol or clozapine.

32-36. (canceled)

Description

BRIEF DESCRIPTION OF THE FIGURES

[0158] FIG. 1A: Oral glucose tolerance test for selected neuroleptic agents.

[0159] FIG. 1B: Glucose Area Under the Curve (AUC) for selected neuroleptic agents.

[0160] FIG. 2A: Oral glucose tolerance test for olanzapine in combination with selected SGLT-2 inhibitors.

[0161] FIG. 2B: Glucose AUC for olanzapine in combination with selected SGLT-2 inhibitors.

[0162] FIG. 3A: Oral glucose tolerance test for clozapine in combination with selected SGLT-2 inhibitors.

[0163] FIG. 3B: Glucose AUC for clozapine in combination with selected SGLT-2 inhibitors.

[0164] FIG. 4A: Oral glucose tolerance test for haloperidone in combination with selected SGLT-2 inhibitors.

[0165] FIG. 4B: Glucose AUC for haloperidone in combination with selected SGLT-2 inhibitors.

DETAILED DESCRIPTION

[0166] The aspects according to the present invention, in particular the methods and uses, refer to SGLT2 inhibitors and neuroleptic agents.

[0167] Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady state plasma glucose concentration and can therefore serve as an antidiabetic target.

[0168] Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodium-dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the tubuli along the sodium gradient. There are at least 3 SGLT isoforms that differ in their expression pattern as well as in their physico-chemical properties. SGLT2 is exclusively expressed in the kidney, whereas SGLT1 is expressed additionally in other tissues like intestine, colon, skeletal and cardiac muscle. Under normoglycemia, glucose is completely reabsorbed by SGLTs in the kidney, whereas the reuptake capacity of the kidney is saturated at glucose concentrations higher than 10 mM, resulting in glucosuria (hence the notion “diabetes mellitus”). This threshold concentration can be decreased by SGLT2-inhibition. It has been shown in experiments with the SGLT inhibitor phlorizin that SGLT-inhibition will partially inhibit the reuptake of glucose from the glomerular filtrate into the blood leading to glucosuria and subsequently to a decrease in blood glucose concentration.

[0169] In one aspect, the SGLT2 inhibitor is selected from the group G1 consisting of dapagliflozin, canagliflozin, atigliflozin, ipragliflozin, tofogliflozin, luseogliflozin, ertugliflozin, remogliflozin, sergliflozin and a compound of the formula

##STR00009##

[0170] and

[0171] glucopyranosyl-substituted benzene derivatives of the formula (I)

##STR00010##

[0172] wherein R.sup.1 denotes Cl, methyl or cyano; R.sup.2 denotes H, methyl, methoxy or hydroxy and R.sup.3 denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug of one of the beforementioned SGLT2 inhibitors.

[0173] Compounds of the formula (I) and methods of their synthesis are described for example in the following patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO 2008/055870, WO 2011/039107, and WO 2011/039108.

[0174] In the above glucopyranosyl-substituted benzene derivatives of the formula (I) the following definitions of the substituents are preferred.

[0175] Preferably R.sup.1 denotes chloro or cyano; in particular chloro.

[0176] Preferably R.sup.2 denotes H.

[0177] Preferably R.sup.3 denotes ethyl, cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Even more preferably R.sup.3 denotes cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Most preferably R.sup.3 denotes ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

[0178] Preferred glucopyranosyl-substituted benzene derivatives of the formula (I) are selected from the group of compounds (I.1) to (I.11):

##STR00011## ##STR00012## ##STR00013##

[0179] According to an embodiment of the present invention, the SGLT2 inhibitor is selected from the group G1a consisting of compounds of the beforementioned formula (I). Even more preferably, the group G1a consists of glucopyranosyl-substituted benzene derivatives of the formula (I) which are selected from the compounds (I.6), (I.7), (I.8), (I.9) and (I.11). A preferred example of a SGLT2 inhibitor according to the group G1a is the compound (I.9), also called empagliflozin.

[0180] According to another embodiment of the present invention, SGLT2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, atigliflozin, ipragliflozin, luseogliflozin, ertugliflozin, and tofogliflozin, in particular dapagliflozin or canagliflozin.

[0181] According to this invention, it is to be understood that the definitions of the above listed SGLT2 inhibitors, including the glucopyranosyl-substituted benzene derivatives of the formula (I), also comprise their hydrates, solvates and polymorphic forms thereof, and prodrugs thereof. With regard to the preferred compound (1.7), an advantageous crystalline form is described in the international patent application WO 2007/028814 which hereby is incorporated herein in its entirety. With regard to the preferred compound (I.8), an advantageous crystalline form is described in the international patent application WO 2006/117360 which hereby is incorporated herein in its entirety. With regard to the preferred compound (I.9) an advantageous crystalline form is described in the international patent application WO 2006/117359 and WO 2011/039107 which hereby are incorporated herein in its entirety. With regard to the preferred compound (I.11) an advantageous crystalline form is described in the international patent application WO 2008/049923 which hereby is incorporated herein in its entirety. These crystalline forms possess good solubility properties which enable a good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline forms are physico-chemically stable and thus provide a good shelf-life stability of the pharmaceutical composition.

[0182] A preferred crystalline form (I.9X) of the compound (I.9) can be characterized by an X-ray powder diffraction pattern that comprises peaks at 18.84, 20.36 and 25.21 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern (XRPD) is made using CuK.sub.α1 radiation.

[0183] In particular said X-ray powder diffraction pattern comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern is made using CuK.sub.α1 radiation.

[0184] In particular said X-ray powder diffraction pattern comprises peaks at 14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81, 25.21 and 25.65 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern is made using CuK.sub.α1 radiation.

[0185] More specifically, the crystalline form (I.9X) is characterized by an X-ray powder diffraction pattern, made using CuK.sub.α1 radiation, which comprises peaks at degrees 2Θ (±0.1 degrees 2Θ) as contained in Table 1. Particularly characteristic are peaks with a relative intensity I/I.sub.0 above 20.

TABLE-US-00001 TABLE 1 X-ray powder diffraction pattern of the crystalline form (I.9X) (only peaks up to 30° in 2 Θ are listed): 2 Θ [°] d-value [Å] Intensity I/I.sub.0 [%] 4.46 19.80 8 9.83 8.99 4 11.68 7.57 4 13.35 6.63 14 14.69 6.03 42 15.73 5.63 16 16.20 5.47 8 17.95 4.94 30 18.31 4.84 22 18.43 4.81 23 18.84 4.71 100 19.16 4.63 42 19.50 4.55 31 20.36 4.36 74 20.55 4.32 13 21.18 4.19 11 21.46 4.14 13 22.09 4.02 19 22.22 4.00 4 22.71 3.91 28 23.44 3.79 27 23.72 3.75 3 24.09 3.69 3 24.33 3.66 7 24.81 3.59 24 25.21 3.53 46 25.65 3.47 23 26.40 3.37 2 26.85 3.32 8 27.26 3.27 17 27.89 3.20 2 28.24 3.16 3 29.01 3.08 4 29.41 3.03 18

[0186] Even more specifically, the crystalline form (I.9X) is characterized by an X-ray powder diffraction pattern, made using CuK.sub.α1 radiation, which comprises peaks at degrees 2Θ (±0.1 degrees 2Θ) as shown in FIG. 1 of WO 2006/117359.

[0187] Furthermore, the crystalline form (I.9X) is characterized by a melting point of about 149° C.±5° C. (determined via DSC; evaluated as onset-temperature; heating rate 10 K/min). The obtained DSC curve is shown in FIG. 2 of WO 2006/117359.

[0188] The X-ray powder diffraction patterns are recorded, within the scope of the present invention, using a STOE-STADI P-diffractometer in transmission mode fitted with a location-sensitive detector □(OED) and a Cu-anode as X-ray source (CuKα1 radiation, □λ=1,54056 Å, 40 kV, 40 mA). In the Table 1 above the values “2Θ [°]” denote the angle of diffraction in degrees and the values “d [Å]” denote the specified distances in Å between the lattice planes. The intensity shown in the FIG. 1 of WO 2006/117359 is given in units of cps (counts per second).

[0189] In order to allow for experimental error, the above described 2Θ values should be considered accurate to ±0.1 degrees 2Θ, in particular ±0.05 degrees 2Θ. That is to say, when assessing whether a given sample of crystals of the compound (I.9) is the crystalline form in accordance with the invention, a 2Θ value which is experimentally observed for the sample should be considered identical with a characteristic value described above if it falls within ±0.1 degrees 2Θ of the characteristic value, in particular if it falls within ±0.05 degrees 2Θ of the characteristic value.

[0190] The melting point is determined by DSC (Differential Scanning Calorimetry) using a DSC 821 (Mettler Toledo).

[0191] In one embodiment, a pharmaceutical composition or dosage form according to the present invention comprises the compound (I.9), wherein at least 50% by weight of the compound (I.9) is in the form of its crystalline form (I.9X) as defined hereinbefore. Preferably in said composition or dosage form at least 80% by weight, more preferably at least 90% by weight of the compound (I.9) is in the form of its crystalline form (I.9X) as defined hereinbefore.

[0192] The term “dapagliflozin” as employed herein refers to dapagliflozin, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 03/099836 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/116179 and WO 2008/002824 for example.

[0193] The term “canagliflozin” as employed herein refers to canagliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00014##

[0194] The compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example.

[0195] The term “atigliflozin” as employed herein refers to atigliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00015##

[0196] The compound and methods of its synthesis are described in WO 2004/007517 for example.

[0197] The term “ipragliflozin” as employed herein refers to ipragliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00016##

[0198] The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.

[0199] The term “tofogliflozin” as employed herein refers to tofogliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00017##

[0200] The compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280 for example.

[0201] The term “luseogliflozin” as employed herein refers to luseogliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00018##

[0202] The term “ertugliflozin” as employed herein refers to ertugliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00019##

[0203] and is described for example in WO 2010/023594.

[0204] The compound of the formula

##STR00020##

[0205] is described for example in WO 2008/042688 or WO 2009/014970.

[0206] The term “remogliflozin” as employed herein refers to remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888 for example.

[0207] The term “sergliflozin” as employed herein refers to sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.

[0208] For avoidance of any doubt, the disclosure of each of the foregoing documents cited above in connection with the specified SGLT2 inhibitors is specifically incorporated herein by reference in its entirety.

[0209] Neuroleptic agents that are useful in the present invention in combination with a SGLT-2 inhibitor include, but are not limited to typical and atypical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., droperidol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenylbutylpiperidines (e.g., pimozide), and typical antipsychotic drugs, including benzisoxazoles (e.g., risperidone), olanzapine, quetiapine, osanetant and ziprasidone.

[0210] Accordingly, suitable neuroleptic agents for use in combination with a SGLT-2 inhibitor according to the present invention include butyrophenones, such as haloperidol, pimozide, and droperidol. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, thioridazine and acetophenazine. Suitable examples of thioxanthenes include thiothixene and chlorprothixene.

[0211] Suitable neuroleptic agents for use in combination with a SGLT-2 inhibitor according to the present invention also include thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benzisothiazolyl-piperazines.

[0212] Suitable neuroleptic agents for use in combination with a SGLT-2 inhibitor according to the present invention also include triazines such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole.

[0213] Suitable neuroleptic agents for use in combination with a SGLT-2 inhibitor according to the present invention also include dibenzazepines such as clozapine.

[0214] Other neuroleptic agents for use in combination with a SGLT-2 inhibitor according to the present invention also include sulpiride.

[0215] Particularly suitable neuroleptic agents for use in the invention are neuroleptic agents selected from the group G2a selected from olanzapine, risperidone, quetiapine, amisulpiride, aripiprazole, haloperidol, clozapine, ziprasidone, zotepine, paliperidone and osanetant.

[0216] Particularly suitable neuroleptic agents for use in the invention are olanzapine, clozapine, risperidone and quetiapine.

[0217] Haloperidol has the following structure:

##STR00021##

[0218] Clozapine has the following structure:

##STR00022##

[0219] Olanzapine has the following structure:

##STR00023##

[0220] Risperidone has the following structure:

##STR00024##

[0221] Quetiapine has the following structure:

##STR00025##

[0222] Amisulpiride has the following structure:

##STR00026##

[0223] Sulpiride has the following structure:

##STR00027##

[0224] Additional suitable neuroleptic agents for use in combination with a SGLT-2 inhibitor according to the present invention also include neuroleptic agents selected form the group G2b consisting of asenapine, blonanserin, iloperidone, lurasidone, mosapramine, paliperidone, pericyazine, perospirone, promazine and zuclopenthixol.

[0225] Additional suitable neuroleptic agents for use in combination with a SGLT-2 inhibitor according to the present invention also include combinations of two or more of the above neuroleptic agents or combinations including one or more of the above neuroleptic agents with one or more additional compounds, for example olanzapine and fluoxetine or perphenazine and amitriyptyline.

[0226] The chemical names of selected compounds for use in the context of the present invention are shown below (group G2):

TABLE-US-00002 INN IUPAC Amisulpiride 4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5- ethylsulfonyl-2-methoxy-benzamide Aripiprazole 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4- dihydroquinolin-2(1H)-one-2,6-diazabicyclo[4.4.0]deca- 1,3-dien-5-one Asenapine (3aS,12bS)-5-Chloro-2,3,3a,12b-tetrahydro-2-methyl- 1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole Blonanserin 2-(4-ethylpiperazin-1-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10- hexahydrocycloocta[b]pyridine Chlorpromazine 3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl- propan-1-amine Clozapine 8-chloro-11-(4-methylpiperazin-1-yl)-5H- dibenzo[b,e][1,4]diazepine Doperidol 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,5,6- tetrahydropyridin-4-yl]-1,3-dihydro-2H-benzimidazol-2- one Fluphenazine 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10- yl]propyl]piperazin-1-yl]ethanol Haloperidol 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4- fluorophenyl)-butan-1-one Iloperidone 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone Lurasidone (3aR,4S,7R,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol- 3-yl)-piperazin-1-yl]methyl}cyclohexyl)methyl]hexahydro- 1H-4,7-methanisoindol-1,3-dione Mosapramine 1′-[3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5- yl)propyl]hexahydro-2H-spiro[imidazo[1,2-a]pyridine- 3,4′-piperidin]-2-one Olanzapine 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3- b][1,5]benzodiazepine Osanetant N-(1-{3-[(3R)-1-benzoyl-3-(3,4-dichlorophenyl)piperidin- 3-yl]propyl}-4-phenylpiperidin-4-yl]-N-methylacetamide Paliperidone (RS)-3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1- piperidyl]ethyl]-7-hydroxy-4-methyl-1,5- diazabicyclo[4.4.0]deca-3,5-dien-2-one Pericyazine 10-[3-(4-hydroxypiperidin-1-yl)propyl]-10H- phenothiazine-2-carbonitrile Perospirone (3aR,7aS)-2-{4-[4-(1,2-benzisothiazol-3-yl)piperazin-1- yl]butyl}hexahydro-1H-isoindole-1,3(2H)-dione Perphenazine 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-1-yl]ethanol Pimozide 1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3- dihydro-2H-benzimidazole-2-one Prochlorperazine 2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H- phenothiazine Promazine N,N-dimethyl-3-(10H-phenothiazin-10-yl)-propan-1- amine Quetiapine 2-(2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-1- piperazinyl)ethoxy)ethanol Risperidone 4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]- 3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one Sulpiride (±)-5-(aminosulfonyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2- methoxybenzamide Thioridazine 10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}-2- methylsulfanylphenothiazine Thiothixene (9Z)-N,N-dimethyl-9-[3-(4-methylpiperazin-1- yl)propylidene]-9H-thioxanthene-2-sulfonamide Trifluoperazine 10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)- 10H-phenothiazine Ziprasidone 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6- chloro-1,3-dihydro-2H-indol-2-one Zotepine 2-[(8-chlorodibenzo(b,f)thiepin-10-yl)oxy]-N,N- dimethylethanamine Zuclopenthixol cis-(Z)-2-(4-(3-(2-chloro-9H-thioxanthen-9- ylidene)propyl)piperazin-1-yl)ethanol

[0227] It will be appreciated that the neuroleptic agents when used in combination with an SGLT-2 inhibitor may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.

[0228] Unless otherwise noted, according to this invention it is to be understood that the definitions of the active agents (including the SGLT2 inhibitors and neuroleptic agents) mentioned hereinbefore and hereinafter may also contemplate their pharmaceutically acceptable salts, and prodrugs, hydrates, solvates and polymorphic forms thereof. Particularly the terms of the therapeutic agents given herein refer to the respective active drugs. With respect to salts, hydrates and polymorphic forms thereof, particular reference is made to those which are referred to herein.

[0229] In a further embodiment, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is selected from the group G1 and the neuroleptic agent is selected from the group G2.

[0230] In a further embodiment, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is selected from the group G1 and the neuroleptic agent is selected from the group G2a.

[0231] In a further embodiment, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is selected from the group G1 and the neuroleptic agent is selected from the group G2b.

[0232] In a further embodiment, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is selected from the group G1a and the neuroleptic agent is selected from the group G2.

[0233] In a further embodiment, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is selected from the group G1a and the neuroleptic agent is selected from the group G2a.

[0234] In a further embodiment, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is selected from the group G1a and the neuroleptic agent is selected from the group G2b.

[0235] In a particular embodiment, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is the compound of the formula (I.9), also called empagliflozin.

[0236] In a further aspect, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor and the neuroleptic agent are as follows:

TABLE-US-00003 SGLT-2 inhibitor Neuroleptic agent Empagliflozin Olanzapine Empagliflozin Clozapine Empagliflozin Risperidone Empagliflozin Quetiapine Empagliflozin Paliperidone Empagliflozin Aripiprazole

[0237] In a further aspect, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor and the neuroleptic agent are as follows:

TABLE-US-00004 SGLT-2 inhibitor Neuroleptic agent Dapagliflozin Olanzapine Dapagliflozin Clozapine Dapagliflozin Risperidone Dapagliflozin Quetiapine Dapagliflozin Paliperidone Dapagliflozin Aripiprazole

[0238] In a further aspect, the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor and the neuroleptic agent are as follows:

TABLE-US-00005 SGLT-2 inhibitor Neuroleptic agent Canagliflozin Olanzapine Canagliflozin Clozapine Canagliflozin Risperidone Canagliflozin Quetiapine Canagliflozin Paliperidone Canagliflozin Aripiprazole

[0239] Accordingly, in the context of the present invention, an SGLT-2 inhibitor according to the present invention can be useful to compensate the side effects resulting from the administration of a neuroleptic agent in a patient, in particular metabolic side effects. In one aspect, an SGLT-2 inhibitor according to the present invention can be useful to compensate the weight gain in a patient resulting from the administration of a neuroleptic agent to the patient. In another aspect, an SGLT-2 inhibitor according to the present invention can be useful to compensate hyperglycemia in a patient resulting from the administration of a neuroleptic agent to the patient. As described hereinbefore by the use of a method according to this invention or the administration of a pharmaceutical composition according to this invention and in particular in view of the effect of the SGLT2 inhibitors therein, a reduction of weight gain due to the administration of neuroleptic agent may result, or no gain in weight or even a reduction in body weight may result. In some instances, a metabolic side effect of the treatment with certain neuroleptic agents may be an increase in blood pressure associated with an increase in body weight, for example an increase in systolic or diastolic blood pressure, or both. In these instances, an SGLT-2 inhibitor according to the present invention may be useful to compensate such increase in blood pressure (systolic or diastolic blood pressure, or both) in a patient resulting from the administration of a neuroleptic agent to the patient. Accordingly, in one aspect, the present invention provides a method for treating, for reducing, for preventing or for attenuating hypertension associated with weight gain in a patient treated for a psychotic disorder, said method comprising administering to said patient a SGLT2 inhibitor and a neuroleptic agent. In a further aspect, the present invention provides the use of a SGLT2 inhibitor for treating, for reducing, for preventing or for attenuating hypertension associated with weight gain in a patient treated with a neuroleptic agent.

[0240] In a further aspect, an SGLT-2 inhibitor according to the present invention can be useful to reduce or prevent discontinuation of treatment with a neuroleptic agent in a patient treated with such neuroleptic agent.

[0241] In the context of the present invention, a metabolic disorder includes type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes and diabetes related to cystic fibrosis. A metabolic disorder in the context of the present invention also includes weight gain. A metabolic disorder in the context of the present invention also includes pre-diabetes. A metabolic disorder in the context of the present invention may be also hypertension associated with weight gain.

[0242] In a further aspect, a treatment or prophylaxis according to this invention is advantageously suitable in those patients in need of such treatment or prophylaxis, for example patients treated with a neuroleptic agent, who are diagnosed of one or more of the conditions selected from the group consisting of overweight and obesity, in particular class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity. In addition, a treatment or prophylaxis according to this invention is advantageously suitable in those patients in which a weight increase is contraindicated.

[0243] When this invention refers to patients requiring treatment or prevention, it relates primarily to treatment and prevention in humans, but the methods and pharmaceutical compositions of the present invention may also be used accordingly in veterinary medicine in mammals. In the scope of this invention the term “patient” covers adult humans (age of 18 years or older), adolescent humans (age 10 to 17 years) and children (age 6-9 years).

[0244] In one aspect of the invention, a psychotic disorder is schizophrenia. In one aspect of the invention, a patient is a subject treated for a psychotic disorder, for example schizophrenia.

[0245] In one aspect of the invention, symptom or psychosis severity in subjects with schizophrenia is measured using a PANSS score (Positive and Negative Syndrome Scale). The PANSS score is well known in the art.

[0246] In one aspect of the invention, a patient in a combination, composition, method or use according to the present invention is a subject is treated for one of the following disorders: [0247] psychosis, [0248] acute and chronic psychosis, [0249] acute psychotic state, [0250] psychosis in major depression, [0251] agitation in schizophrenia or bipolar disorders, [0252] treatment-resistant schizophrenia, [0253] acute agitation in schizophrenia, [0254] delirium, [0255] delirium in AIDS.

[0256] In another aspect of the invention, a patient in a combination, composition, method or use according to the present invention is a subject is treated for depression. In a further aspect, a patient is a subject is treated for one of the following disorders: [0257] agitated depression, [0258] adjunct in major depression, [0259] dysthymia, [0260] bipolar disorders, [0261] manic phase of bipolar disorder, [0262] bipolar mania.

[0263] In another aspect of the invention, a patient in a combination, composition, method or use according to the present invention is a subject is treated for manic episodes associated with bipolar I disorder. In another aspect, a patient is a subject is treated for mixed episodes associated with bipolar I disorder. In one other aspect, a patient is a subject is treated for manic or mixed episodes associated with bipolar I disorder. In another aspect, a patient is a subject is treated for acute agitation associated with schizophrenia and bipolar I mania. In another aspect, a patient is a subject is treated for depressive episodes associated with bipolar I disorder.

[0264] In a further aspect of the invention, a patient in a combination, composition, method or use according to the present invention is a subject is treated for one of the following other mental states leading to mental disturbances or mental dysfunction: [0265] insomnia, [0266] pruritus, [0267] preanesthesia, [0268] suicidal behavior, [0269] anxiety, [0270] post-traumatic stress disorder (PTSD), [0271] autism, [0272] tension and anxiety linked to alcohol withdrawal, [0273] dysphoria of epileptic, [0274] severe anxiety.

[0275] According to an embodiment of the present invention, there is provided a method for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin (HbA1c) in a patient treated with a neuroleptic agent who is diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG) with insulin resistance, with metabolic syndrome and/or with type 1 diabetes mellitus or type 2 diabetes mellitus characterized in that a neuroleptic agent and an SGLT2 inhibitor as defined hereinbefore and hereinafter are administered, for example in combination or alternation or sequentially, to the patient.

[0276] Furthermore, the methods, uses and the pharmaceutical composition, according to this invention are particularly suitable in the treatment of patients treated with a neuroleptic agent who are diagnosed having one or more of the following conditions [0277] (a) obesity (including class I, II and/or III obesity), visceral obesity and/or abdominal obesity, [0278] (b) triglyceride blood level ≥150 mg/dL, [0279] (c) HDL-cholesterol blood level <40 mg/dL in female patients and <50 mg/dL in male patients, [0280] (d) a systolic blood pressure ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, [0281] (e) a fasting blood glucose level ≥100 mg/dL.

[0282] It is assumed that patients treated with a neuroleptic agent and diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), with insulin resistance and/or with metabolic syndrome suffer from an increased risk of developing a cardiovascular disease, such as for example myocardial infarction, coronary heart disease, heart insufficiency, thromboembolic events. A glycemic control according to this invention may result in a reduction of the neuroleptic-induced side effects including cardiovascular risks.

[0283] A method or pharmaceutical composition according to this invention can be particularly suitable in the long term treatment or prophylaxis of the diseases and/or conditions as described hereinbefore and hereinafter, in particular in the long term glycemic control in patients with type 2 diabetes mellitus being treated with a neuroleptic agent, such as a typical or atypical neuroleptic agent.

[0284] The term “long term” as used hereinbefore and hereinafter indicates a treatment of or administration in a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.

[0285] Therefore, a particularly preferred embodiment of the present invention provides a method for therapy, preferably oral therapy, for improvement, especially long term improvement, of glycemic control in patients with type 2 diabetes mellitus, especially in patients with late stage type 2 diabetes mellitus, in particular in patients additionally diagnosed of overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity being treated with a neuroleptic agent, such as a typical or atypical neuroleptic agent.

[0286] In the following preferred ranges of the amount of the SGLT2 inhibitor and the neuroleptic to be employed in the pharmaceutical composition and the methods and uses according to this invention are described. These ranges refer to the amounts to be administered per day with respect to an adult patient, in particular to a human being, for example of approximately 70 kg body weight, and can be adapted accordingly with regard to an administration 1 or 2 times daily and with regard to other routes of administration and with regard to the age of the patient. The ranges of the dosage and amounts are calculated for the individual active moiety.

[0287] The preferred dosage range of the SGLT2 inhibitor is in the range from 0.5 mg to 500 mg, for example from 0.5 mg to 200 mg, for example from 1 to 100 mg, for example from 1 to 50 mg per day. The oral administration is preferred. Therefore, a dosage form for the SGLT-2 inhibitor may comprise the hereinbefore mentioned amounts, in particular from 1 to 50 mg or 1 to 25 mg. Particular dosage strengths (e.g. per tablet or capsule) are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25 or 50 mg of the compound of the formula (I), in particular of the compound (I.9). The application of the active ingredient may occur one, two or three times a day, preferably once a day.

[0288] Typical dosages for empagliflozin are 10 mg and 25 mg once daily. Typical dosages for dapagliflozin are 1 mg, 2.5 mg, 5 mg and 10 mg once daily, and 2.5 mg and 5 mg twice daily.

[0289] Typical dosages for canagliflozin are 100 mg and 300 mg once daily, or 50 mg or 150 mg twice daily.

[0290] A minimum dosage level for the neuroleptic agent will vary depending upon the choice of agent, but is typically about 0.5 mg per day for the most potent compounds or about 20 mg per day for less potent compounds. A maximum dosage level for the neuroleptic agent is typically 30 mg per day for the most potent compounds or 200 mg per day for less potent compounds. The compounds are administered one to three times daily, preferably once or twice a day, and especially once a day.

[0291] Examples of routes of administration, form and dosage ranges for exemplary neuropeltic agents are disclosed below.

[0292] Clozapine is typically administered orally in the form of tablets and in a dosage range of 12.5-900 mg/day or 300-900 mg/day, in particular 350-420 mg/day.

[0293] Olanzapine is typically administered orally in the form of tablets and in a dosage range of 5-25 mg/day, 10-25 mg/day or 5-20 mg/day. Typical dosages for olanzapine are 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg once daily.

[0294] Ziprasidone is typically administered orally in the form of capsules and in a dosage range of 20-80 mg/twice a day or 80-160 mg/day.

[0295] Risperidone is typically administered orally in the form of solution or tablets and in a dosage range of 2-16 mg/day, in particular 2-4 mg/day or 4-12 mg/day or intra-venously in long-acting injectable form. Quetiapine fumarate is typically administered orally in the form of tablets and in a dosage range of oral tablets 50-900 mg/day or 300-900 mg/day.

[0296] Sertindole is typically administered in a dosage range of 4-24 mg/day.

[0297] Haloperidol is typically administered orally in the form of tablets and in a dosage range of 1-100 mg/day or 1-15 mg/day, in particular 5-15 mg/day.

[0298] Haloperidol Decanoate is typically administered orally by parenteral injection.

[0299] Chlorpromazine is typically administered by rectal suppositories or orally by capsules, solution or tablets, or by parenteral injection in the range of 30-800 mg/day or 200-500 mg/day.

[0300] Fluphenazine is typically administered in a dosage range of 0.5-40 mg/day or 1-5 mg/day.

[0301] Fluphenazine Decanoate is typically administered by parenteral injection.

[0302] Thiothixene is typically administered orally in the form of capsules and in a dosage range of 6-60 mg/day or 8-30 mg/day.

[0303] Thiothixene hydrochloride is typically administered orally or parentally in the form of a solution or injection, respectively.

[0304] Trifluoperazine is typically administered in a dosage range of 2-40 mg/day.

[0305] Perphenazine is typically administered orally in the form of solution or tablets and in a dosage range of 12-64 mg/day or 16-64 mg/day.

[0306] Thioridazine is typically administered orally in the form of suspension, solution or tablets and in a dosage range of 150-800 mg/day or 100-300 mg/day.

[0307] Mesoridazine is typically administered in a dosage range of 30-400 mg/day.

[0308] Molindone is typically administered in a dosage range of 50-225 mg/day or 15-150 mg/day.

[0309] Molindone hydrochloride is typically administered orally in the form of solution

[0310] Loxapine is typically administered in a dosage range of 20-250 mg/day or 60-100 mg/day.

[0311] Loxapine hydrochloride is typically administered orally or parentally in the form of solution or injection.

[0312] Loxapine succinate is typically administered orally in the form of capsules.

[0313] Pimozide is typically administered in a dosage range of 1-10 mg/day.

[0314] In the methods and uses according to the present invention the neuroleptic agent and the SGLT2 inhibitor are administered in combination or alternation or sequentially. The term “administration in combination” means that the active ingredients are administered at the same time, i.e. simultaneously, or essentially at the same time. The term “administration in alternation” means that at first one of the two active ingredients, i.e. the SGLT2 inhibitor or the neuroleptic agent, is administered and after a period of time the other active ingredient, i.e. the neuroleptic agent or the SGLT2 inhibitor, is administered whereby this administration scheme may be repeated one or more times. The period of time between the administration of the first and of the second active ingredient may be in the range from 1 min to 12 hours.

[0315] The administration which is in combination or in alternation may be once, twice, three times or four times daily, preferably once or twice daily. The term “sequentially” means that to a patient the first active ingredient, in particular the neuroleptic agent, is administered to the patient one or more times in a first period of time followed by an administration of the second active ingredient, in particular the SGLT2 inhibitor which is administered to the patient one or more times in a second period of time. In other words, the term “sequentially” includes a first therapy, in particular with the neuroleptic agent, in a first period of time followed by a second therapy, in particular with the SGLT2 inhibitor, in a second period of time.

[0316] A pharmaceutical composition which is present as a separate or multiple dosage form, preferably as a kit of parts, is useful in combination therapy to flexibly suit the individual therapeutic needs of the patient.

[0317] A pharmaceutical composition may be formulated for oral, parenteral (including subcutaneous) or other routes of administration in liquid or solid form. Oral administration of the SGLT2 inhibitor is preferred. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with one or more pharmaceutically acceptable carriers, like liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. Examples of pharmaceutical compositions comprising the SGLT2 inhibitor compound (I.9) are described in WO 2010/092126 which is incorporated herein in its entirety.

[0318] The pharmaceutical composition may be formulated in the form of solutions, suspensions, emulsions, tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, fast dissolving tablets, oral fast-dispersing tablets. Preferably the pharmaceutical composition of the SGLT2 inhibitor is in the form of tablets.

[0319] A pharmaceutical composition and dosage forms preferably comprises one or more pharmaceutical acceptable carriers. Preferred carriers must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of pharmaceutically acceptable carriers are known to the one skilled in the art.

[0320] A pharmaceutical composition may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0321] Injectable formulations may be prepared according to known formulation techniques, e.g. using suitable liquid carriers, which usually comprise sterile water, and, optionally, further additives such as e.g. preservatives, pH adjusting agents, buffering agents, isotoning agents, solubility aids and/or tensides or the like, to obtain injectable solutions or suspensions. In addition, injectable formulations may comprise further additives, for example salts, solubility modifying agents or precipitating agents which retard release of the drug(s).

[0322] For further details on dosage forms, formulations and administration of SGLT2 inhibitors of this invention and/or neuroleptic agent of this invention, reference is made to scientific literature and/or published patent documents, particularly to those cited herein.

[0323] Pharmaceutical compositions (or formulations) may be packaged in a variety of ways.

[0324] Generally, an article for distribution includes one or more containers that contain the one or more pharmaceutical compositions in an appropriate form. Tablets are typically packed in an appropriate primary package for easy handling, distribution and storage and for assurance of proper stability of the composition at prolonged contact with the environment during storage.

[0325] Primary containers for tablets may be bottles or blister packs.

[0326] Solutions for injection may be available in typical suitable presentation forms such as vials, cartridges or prefilled (disposable) pens, which may be further packaged.

[0327] The article may further comprise a label or package insert, which refers to instructions customarily included in commercial packages of therapeutic products, that may contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. In one embodiment, the label or package inserts indicates that the composition can be used for any of the purposes described hereinbefore or hereinafter.

[0328] Methods for the manufacture of SGLT2 inhibitors according to this invention and of prodrugs thereof are known to the one skilled in the art. Advantageously, the compounds according to this invention can be prepared using synthetic methods as described in the literature, including patent applications as cited hereinbefore. Methods of manufacture are described in the WO 2006/120208 and WO 2007/031548. With regard to the preferred compound (I.9) an advantageous crystalline form is described in the international patent application WO 2006/117359 and WO 2011/039108 which hereby are incorporated herein in its entirety.

[0329] The active ingredients may be present in the form of a pharmaceutically acceptable salt. The active ingredients or a pharmaceutically acceptable salt thereof may be present in the form of a solvate such as a hydrate or alcohol adduct.

[0330] Any of the above mentioned combinations and methods within the scope of the invention may be tested using animal models known in the art.

[0331] For example, methods according to this invention can be tested in genetically hyperinsulinemic or diabetic animals like db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rats or Zucker Diabetic Fatty (ZDF) rats. In addition, they can be tested in animals with experimentally induced diabetes like HanWistar or Sprague Dawley rats pretreated with streptozotocin.

[0332] The effect on glycemic control of the methods and compositions according to this invention can be tested after single dosing of the SGLT2 inhibitor and the neuroleptic agent alone and in combination in an oral glucose tolerance test in the animal models described hereinbefore.

[0333] The time course of blood glucose can be followed after an oral glucose challenge in overnight fasted animals. In addition, after multiple dosing of the SGLT2 inhibitor and the neuroleptic agent alone and in combination in the animal models described hereinbefore, the effect on glycemic control can be determined by measuring the HbA1c value in blood. In such experiments body weight, blood pressure and various metabolic markers can also be determined. Accordingly, the effects of chronic administration of an SGLT-2 inhibitor and a neuroleptic agent, alone and in combination, on body weight, food and water intake, blood pressure and various metabolic markers could be evaluated in animal models.

[0334] The invention is further described in the following examples, which are not intended to limit the scope of the invention.

PHARMACOLOGICAL EXAMPLES

Example 1

Oral Glucose Tolerance Test in ZDF Rats

[0335] An oral glucose tolerance test is performed in overnight fasted 9-weeks old male Zucker Diabetic Fatty (ZDF) rats (ZDF/Crl-Lepr.sup.fa). A pre-dose blood sample is obtained by tail bleed.

[0336] Blood glucose is measured with a glucometer, and the animals are randomized for blood glucose (n=5/group). Subsequently, the groups receive a single oral administration of either vehicle or a neuroleptic agent in the presence or absence of a SGLT-2 inhibitor. The animals receive an oral glucose load (2 g/kg) 30 min after compound administration. Blood glucose is measured in tail blood 30 min, 60 min, 90 min, 120 min, and 180 min after the glucose challenge. Glucose excursion is quantified by calculating the reactive glucose AUC.

[0337] The data are presented as mean±SEM. The two-sided unpaired Student t-test is used for statistical comparison of the control group and the active groups.

[0338] In one glucose tolerance test experiment, the SGLT-2 inhibitor is the compound (I.9) and the neuroleptic agent is olanzapine, risperidone, quetiapine, amisulpiride, aripiprazole, haloperidol, clozapine, ziprasidone, zotepine or osanetant.

Example 2

Acute Effects of Antipsychotic Drugs on Glucose Levels During a Glucose Tolerance Test

[0339] Female rats (n=8 per group) are treated with vehicle (controls) or low- and high doses of an atypical neuroleptic agent in the presence or absence of a SGLT-2 inhibitor after overnight fasting. Before treatment with the neuroleptic agent, fasting plasma glucose is measured in each animal (time 0). Glucose levels are then tested at 60, 180 and 360 minutes after dosing. Immediately after the last glucose testing, animals are subjected to a Glucose Tolerance Test, for instance by receiving an intraperitoneal challenge injection of 1 g/ml/kg of glucose. Thereafter, glucose levels are measured every 15 minutes for 2 hours.

[0340] In one glucose tolerance test experiment, the SGLT-2 inhibitor is the compound (I.9) and the neuroleptic agent is olanzapine, risperidone, quetiapine, amisulpiride, aripiprazole, haloperidol, clozapine, ziprasidone, zotepine or osanetant.

Example 3

Treatment of Hyperglycemia or Type 2 Diabetes

[0341] Patients receiving treatment with a neuroleptic agent and having elevated blood glucose levels or even overt type 2 diabetes are treated by a method according to the invention.

[0342] Blood glucose levels of the patients are determined, and the effect of an SGLT2 inhibitor in comparison to placebo or a different therapy is assessed. This can be observed in patients treated for long periods, e.g. 3 months to 1 year or even 1 to 6 years, according to the invention. For example, the fasting glucose and/or HbA1c value is observed.

Example 4

Oral Glucose Tolerance Test

[0343] The aim of this study is to evaluate the acute effects of selected neuroleptic agents (clozapine, olanzapine, haloperidol) in an oral glucose tolerance test (OGTT) alone or in combination with selected SGLT-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin).

[0344] Animals

[0345] Female Wistar rats (weight range 250-300 g upon arrival) are obtained from Janvier (Le Genest Saint Isle-France, France) and housed in pairs or three together at a temperature of 21±4° C. and 55±20% humidity. The animals are maintained on a reverse phase light-dark cycle (lights off for 8 h from 09.30-17.30 h) during which time the room is illuminated by red light.

[0346] The animals are housed and have free access to a fat diet and tap water until the night before the oral glucose tolerance test (OGTT) experiment.

[0347] An oral glucose tolerance test is performed in overnight fasted animals. A pre-dose blood sample (t0-90 min) is obtained by tail bleed. Blood glucose is measured with a glucometer, and the animals are randomized for blood glucose (n=8/group). Subsequently, the groups receive a single oral administration of either vehicle or a neuroleptic agent in the presence or absence of an SGLT-2 inhibitor. The animals receive an oral glucose load (2 g/kg) 60 min after compound administration. Blood glucose is measured in tail blood 15 min, 30 min, 60 min, 120 min, and 180 min after the glucose challenge. Glucose excursion is quantified by calculating the reactive glucose AUC. The data are presented as mean±SEM. The two-sided unpaired Student t-test is used for statistical comparison of the control group and the active groups.

[0348] In these experiments, the SGLT-2 inhibitors dapagliflozin, canagliflozin and empagliflozin are tested at the dose of 10 mg/kg po (per oral route, 5 ml/kg in Natrosol 0.5%) alone or in combination with three different neuroleptic agents injected subcutaneously (in a 5% acetic acid+7.5% 10M NaOH solution) for olanzapine (8 mg/kg sc) and clozapine (8 mg/kg sc), or administered intraperitonally in a 0.9% NaCl solution for haloperidol (4 mg/kg).

[0349] Clozapine, olanzapine and haloperidol impaired glucose tolerance as illustrated in FIG. 1A.

[0350] Glucose AUCs are significantly (p<0.001) increased versus control with the neuroleptic agents (FIG. 1B). The numbers above each bar graph in FIG. 1B represent the percentage of increase in AUC over control.

[0351] In another set of experiments, SGLT-2 inhibitors are combined with the neuroleptic agents.

[0352] FIG. 2A illustrates the OGTT of olanzapine in combination with the SGLT-2 inhibitors. All SGLT-2 inhibitors tested reduced significantly the AUC glucose in comparison to olanzapine alone (FIG. 2B). The numbers above each bar graph in FIG. 2B represent the percentage of increase in AUC over control.

[0353] OGTT with SGLT-2 inhibitors in combination with clozapine are represented in FIG. 3A.

[0354] The SGLT-2 inhibitors improve the AUC glucose when combined with clozapine in comparison to clozapine alone (FIG. 3B). The numbers above each bar graph represent the percentage increase AUC over control.

[0355] Similar effects have been observed with haloperidol (FIG. 4A). But because the worsening of the OGTT was less pronounced with haloperidol compared to olanzapine and clozapine, the improvements in glucose tolerance when combined with SGLT-2 inhibitors were less pronounced (FIG. 4B).

EXAMPLES OF FORMULATIONS

[0356] The following examples of formulations, which may be obtained analogously to methods known in the art, serve to illustrate the present invention more fully without restricting it to the contents of these examples. The term “active substance” denotes an SGLT-2 inhibitor according to this invention, especially a compound of the formula (I), for example a compound of the formula (I.9) or its crystalline form (I.9X).

[0357] The active pharmaceutical ingredient or active substance, i.e. the compound (I.9), preferably in the crystalline form (I9.X), is milled with a suitable mill like pin- or jet-mill in order to obtain the desired particle size distribution before manufacturing of the pharmaceutical composition or dosage form.

[0358] Examples of typical particle size distribution values X90, X50 and X10 for the preferred active pharmaceutical ingredient according to the invention are shown in the table below.

[0359] Typical Particle Size Distribution Results

TABLE-US-00006 Active substance Active substance Batch 1 Batch 2 X10  1.8 μm  1.7 μm X50 18.9 μm 12.1 μm X90 45.3 μm 25.9 μm

Example 1

Dry Ampoule Containing 50 mg of Active Substance per 10 ml

[0360] Composition:

TABLE-US-00007 Active substance 50.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml

[0361] Preparation:

[0362] Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections.

Example 2

Dry Ampoule Containing 25 mg of Active Substance per 2 ml

[0363] Composition:

TABLE-US-00008 Active substance  25.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml

[0364] Preparation:

[0365] Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections.

Example 3

Tablet Containing 50 mg of Active Substance

[0366] Composition:

TABLE-US-00009 (1) Active substance 50.0 mg (2) Mannitol 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg

[0367] Preparation:

[0368] (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.

[0369] Diameter of the tablets: 9 mm.

Example 4

Capsules Containing 50 mg of Active Substance

[0370] Composition:

TABLE-US-00010 (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Mannitol 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg

[0371] Preparation:

[0372] (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.

Example 5

Tablets containing 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg of active substance

[0373]

TABLE-US-00011 2.5 mg 5 mg 10 mg 25 mg 50 mg Mg/per Mg/per Mg/per Mg/per Mg/per Active substance tablet tablet tablet tablet tablet Wet granulation active substance 2.5000 5.000 10.00 25.00 50.00 Lactose 40.6250 81.250 162.50 113.00 226.00 Monohydrate Microcrystalline 12.5000 25.000 50.00 40.00 80.00 Cellulose Hydroxypropyl 1.8750 3.750 7.50 6.00 12.00 Cellulose Croscarmellose 1.2500 2.500 5.00 4.00 8.00 Sodium Purified Water q.s. q.s. q.s. q.s. q.s. Dry Adds Microcrystalline 3.1250 6.250 12.50 10.00 20.00 Cellulose Colloidal silicon 0.3125 0.625 1.25 1.00 2.00 dioxide Magnesium stearate 0.3125 0.625 1.25 1.00 2.00 Total core 62.5000 125.000 250.00 200.00 400.00 Film Coating Film coating system 2.5000 4.000 7.00 6.00 9.00 Purified Water q.s. q.s. q.s. q.s. q.s. Total 65.000 129.000 257.00 206.00 409.00

Example 6

[0374] Manufacturing Process for Tablets

Example 7

Pharmaceutical Composition Containing Other Fillers

[0375] Copovidone is dissolved in purified water at ambient temperature to produce a granulation liquid. A glucopyranosyl-substituted benzene derivative according to the present invention, mannitol, pregelatinized starch and corn starch are blended in a suitable mixer, to produce a pre-mix. The pre-mix is moistened with the granulation liquid and subsequently granulated.

[0376] The moist granulate is sieved through a suitable sieve. The granulate is dried at about 60° C. inlet air temperature in a fluid bed dryer until a loss on drying value of 1-4% is obtained. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm.

[0377] Magnesium stearate is passed through a sieve for delumping and added to the granulate.

[0378] Subsequently the final blend is produced by final blending in a suitable blender for three minutes and compressed into tablet cores.

[0379] Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water in a suitable mixer at ambient temperature to produce a coating suspension. The tablet cores are coated with the coating suspension to a weight gain of about 3% to produce film-coated tablets. The following formulation variants can be obtained:

TABLE-US-00012 mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet tablet tablet Active substance 2.5 5.0 10.0 25.0 50.0 Mannitol 133.4 130.9 125.9 110.9 221.8 Pregelatinised starch 18.0 18.0 18.0 18.0 36.0 Maize starch 18.0 18.0 18.0 18.0 36.0 Copovidone 5.4 5.4 5.4 5.4 10.8 Magnesium stearate 2.7 2.7 2.7 2.7 5.4 Film coat 5.0 5.0 5.0 5.0 10.0 Total 185.0 185.0 185.0 185.0 370.0

Example 8

Pharmaceutical Composition Containing Other Disintegrant

[0380] Copovidone is dissolved in purified water at ambient temperature to produce a granulation liquid. An glucopyranosyl-substituted benzene derivative according to the present invention, mannitol, pregelatinized starch and corn starch are blended in a suitable mixer, to produce a pre-mix. The pre-mix is moistened with the granulation liquid and subsequently granulated.

[0381] The moist granulate is sieved through a suitable sieve. The granulate is dried at about 60° C. inlet air temperature in a fluid bed dryer until a loss on drying value of 1-4% is obtained. The dried granulate is sieved through a sieve with a mesh size of 1.0 mm.

[0382] Crospovidone is added to the dried granulate and mixed for 5 minutes to produce the main blend. Magnesium stearate is passed through a sieve for delumping and added to main blend. Subsequently the final blend is produced by final blending in a suitable blender for three minutes and compressed into 8 mm round tablet cores with a compression force of 16 kN.

[0383] Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water in a suitable mixer at ambient temperature to produce a coating suspension. The tablet cores are coated with the coating suspension to a weight gain of about 3% to produce film-coated tablets. The following formulation variants can be obtained:

TABLE-US-00013 mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet tablet tablet Active substance 2.5 5.0 10.0 25.0 50.0 Mannitol 127.5 125.0 120.0 105.0 210.0 Microcrystalline Cellulose 39.0 39.0 39.0 39.0 78.0 Crospovidone 2.0 2.0 2.0 2.0 4.0 Copovidone 5.4 5.4 5.4 5.4 10.8 Magnesium stearate 3.6 3.6 3.6 3.6 7.2 Film coat 5.0 5.0 5.0 5.0 10.0 Total 185.0 185.0 185.0 185.0 370.0

[0384] The tablet hardness, the friability, the content uniformity, the disintegration time and the dissolution properties are determined as described hereinbefore.

Example 9

Direct Compression Formulation

[0385] 1. Screen the active ingredient, microcrystalline cellulose, croscarmellose.sodium and either hydroxypropyl cellulose or polyethylene glycol powder through a 20 mesh hand screen.

[0386] 2. Add the above items into the high shear mixer and mix for two minutes.

[0387] 3. Make a premix (˜1/1) of the lactose and colloidal silicon dioxide.

[0388] 4. Screen the premix through a 20 mesh hand screen and add to the mixer.

[0389] 5. Screen the remaining lactose through a 20 mesh hand screen and add to the mixer.

[0390] 6. Mix in components in the mixer for 2 minutes.

[0391] 7. Screen the magnesium stearate through a 30 mesh hand screen and add to the mixer.

[0392] 8. Mix for 1 minute 30 seconds to obtain the final blend.

[0393] 9 Tabletting of the final blend on a suitable tabletting press.

[0394] 10. Optionally film coating of the tablet cores.

TABLE-US-00014 mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet tablet tablet Active substance 2.5000 5.000 10.00 25.0 50.0 Lactose 43.7500  87.500  175.00 74.0 148.0 Monohydrate Microcrystalline 12.5000  25.000  50.00 80.0 160.0 Cellulose Polyethylene glycol — — — 10.0 20.0 Croscarmellose 1.2500 2.500 5.00 8.0 16.0 sodium Hydroxypropyl 1.8750 3.750 7.50 — — cellulose Colloidal Silicon 0.3125 0.625 1.25 1.0 2.0 dioxide Magnesium stearate 0.3125 0.625 1.25 2.0 4.0 Film coat 2.5000 4.000 7.00 6.00 9.00 Purified water q.s. q.s. q.s. q.s. q.s. Total 65.000  129.000  257.00 206.00 409.00

Example 10

Tablets Containing 0.5 mg, 5 mg, 25 mg, 100 mg of Active Substance

[0395]

TABLE-US-00015 0.5 mg 5 mg 25 mg 100 mg mg/per mg/per mg/per mg/per Active substance tablet tablet tablet tablet Wet granulation active substance 2.5000 5.000 25.00 100.00 Lactose 60.00 55.00 42.00 168.00 Monohydrate Microcrystalline 20.00 20.00 38.00 152.00 Cellulose Hydroxypropyl 5.00 5.00 7.50 30.00 Cellulose Croscarmellose 4.00 4.00 6.00 24.00 Sodium Purified Water q.s. q.s. q.s. q.s. Dry Adds Microcrystalline 10.00 10.00 30.00 120.00 Cellulose Colloidal silicon — 0.50 0.75 3.00 dioxide Magnesium 0.50 0.50 0.75 3.00 stearate Total 100.00 100.00 150.00 600.00

[0396] The active substance, e.g. the compound (I.9), preferably in the crystalline form (I.9X), hydroxypropyl cellulose, and croscarmellose sodium are mixed in a blender. This premix is mixed with lactose monohydrate and a portion of microcrystalline cellulose. The resulting blend is granulated with purified water. Multiple granulation subparts may be produced for an individual tablet batch, as needed, depending on the batch size and equipment used.

[0397] The granulation is discharged onto dryer trays and dried. The granulation is then milled. The remainder of the microcrystalline cellulose is added (as a premix with the colloidal silicon dioxide for all strengths other than the 0.5 mg) to the milled granulation, and mixed. The magnesium stearate is premixed with a portion of the blend, screened into the remainder of the granulation, and mixed.

[0398] The final tablet blend is compressed into tablets using a tablet press. The finished tablets are packaged using a suitable container closure system.

Example 11

Tablets Containing 1 mg, 5 mg, 25 mg of Active Substance

[0399]

TABLE-US-00016 1 mg 5 mg 25 mg Active substance mg/per tablet mg/per tablet mg/per tablet Wet granulation active substance 1.00 5.00 25.00 Lactose 63.00 59.00 39.00 Monohydrate Microcrystalline 20.00 20.00 20.00 Cellulose Hydroxypropyl 3.00 3.00 3.00 Cellulose Croscarmellose 2.00 2.00 2.00 Sodium Purified Water q.s. q.s. q.s. Dry Adds Microcrystalline 10.00 10.00 10.00 Cellulose Colloidal silicon 0.50 0.50 0.50 dioxide Magnesium stearate 0.50 0.50 0.50 Total 100.00 100.00 100.00

[0400] The active substance, e.g. the compound (I.9), preferably in the crystalline form (I.9X), is passed through a screen and added to a blender or a high shear granulator. The hydroxypropyl cellulose and croscarmellose sodium are passed through a screen, added to the drug substance, and mixed. The intra-granular portion of microcrystalline cellulose is passed through a screen into a high shear granulator and mixed with the drug substance premix. Lactose is then added by passing the material through a screen into the granulator and mixing. The resulting blend is granulated with purified water. For larger batches, multiple granulation subparts may be produced for an individual tablet batch, as needed, depending on the batch size and equipment used.

[0401] The granulation is discharged onto dryer trays and dried. The granulation is then passed through a mill into a blender. The colloidal silicon dioxide is pre-mixed with a portion of the extra-granular microcrystalline cellulose. This premix is passed through a mill into the blender, followed by the remaining extra-granular microcrystalline cellulose, and mixed with the milled granulation. The magnesium stearate is premixed with a portion of the blend, passed through a mill into the remainder of the granulation, and mixed.

[0402] The final tablet blend is compressed into tablets using a tablet press. The finished tablets are packaged using a suitable container closure system.