MXPA03001086A - Tartrate salts of thiazolidinedione derivative. - Google Patents

Abstract

A novel pharmaceutical compound 5- [4-2 -(N-methyl-N -(2-pyridyl)amino) ethoxy] benzyl] thiazolidine- 2, 4-dione Meso- Tartrate or a solvate thereof, a process for preparing such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.

Description

COMPOSITE PHARMACEUTICAL NOVEDOSO DESCRIPTIVE MEMORY This invention relates to a novel pharmaceutical composition, to a process for the preparation of the pharmaceutical compound, and to the use of the pharmaceutical compound in medicine. The European patent application, publication number 0,306,228, refers to certain thiazolidinedione derivatives described as having hypoglycemic and hypolipidemic activity. The compound of Example 30 of EP 0,306,228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino-2,4-dione (also referred to below as "compound (I)"). The international patent application, publication number WO94 / 05659, describes certain salts of the compounds of EP 0,306,228, one of which is the tartrate salt. The preferred salt of WO94 / 05659 is the maleic acid salt. It has now been discovered that the compound (I) forms a novel tartrate salt (hereinafter also referred to as the "Meso-Tartrate"). The novel Meso-Tartrate is a stable crystalline material of high melting point; therefore, it is suitable for global preparation and management. Meso-Tartrate is subject to large-scale pharmaceutical processing, especially in manufacturing procedures that require or require generate heat, for example, milling, fluid bed drying, spray drying, thermal fusion processing and sterilization by autoclaving. Meso-Tartrate can also be prepared by an efficient, economical and reproducible process, particularly suitable for large-scale preparation. The novel Meso-Tartrate also has useful pharmaceutical properties and, in particular, it is indicated that it will be useful for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof. Accordingly, the present invention provides the meso-tartrate salt of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino-2,4-dione, or a Solvate of it. Suitably, Meso-Tartrate is a mono-tartrate salt. The mono-tartrate salts optionally also comprise another monovalent salt ion, such as an ammonium or alkali metal cation. In a favored aspect, the Meso-Tartrate provides an infrared spectrum substantially in accordance with Fig. 1. In a favored aspect, the Meso-Tartrate provides a Raman spectrum substantially in accordance with Fig. 2. In a favored aspect, the Meso -Tartrate provides an X-ray powder diffraction pattern (XRPD) substantially in accordance with In Table 1 or Figure 3. In a favored aspect, the Meso-Tartrate provides a spectrum of 13 C NMR in the solid state substantially in accordance with Figure 4. In a favored aspect, the Meso-Tartrate provides a melting point in the scale from 147 to 157 ° C, such as 148 to 155 ° C, for example, 148 ° C, 153 ° C and 155 ° C. In a preferred aspect, the invention provides the meso-tartrate salt of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino-2,4-dione, characterized in that provides: (i) an infrared spectrum substantially in accordance with Figure 1; and (i) a Raman spectrum substantially in accordance with Figure 2; and (iii) an X-ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3; and (iv) a 13 C NMR spectrum in the solid state substantially in accordance with Figure 4. The present invention encompasses the meso-tartrate or solvate thereof isolated in pure form, or when mixed with other materials. In this way, in one aspect, the Meso-Tartrate or solvate thereof is provided in isolation. In another aspect, the Meso-Tartrate, or solvate thereof, is provided in purified form.

In another aspect, the Meso-Tartrate, or solvate thereof, is provided in crystalline form. Also, the invention provides the Meso-Tartrate or solvate thereof in a pharmaceutically acceptable solid form, such as a solid dosage form, especially when adapted for oral administration. In addition, the invention also provides the Meso-Tartrate or solvate thereof in a pharmaceutically acceptable form, especially in a global form, said form being particularly capable of pharmaceutical processing, especially in manufacturing processes that require or generate heat, for example, milling.; for example, heat drying, especially fluid bed drying or spray drying; for example, thermal fusion processing; for example, heat sterilization, such as boiling in an autoclave. In addition, the invention provides the Meso-Tartrate or solvate thereof in a pharmaceutically acceptable form, especially in a global form, and especially in a form that has been processed in a manufacturing process that requires or generates heat, for example, in a form milled for example, in a heat-dried form, especially a dried form of fluidized bed or a spray-dried form; for example, in a form that has been processed by thermal fusion; for example, in a form that has been sterilized with heat, such as by boiling in an autoclave.

A suitable solvate is a hydrate. The invention also provides a process for the preparation of the Meso-Tartrate or a solvate thereof, characterized in that 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino-214 -dione (compound (I)) or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a meso-tartrate ion source and then, if required, a Meso-Tartrate solvate is prepared resulting; and the Meso-Tartrate or a solvate thereof, is recovered. A suitable reaction solvent is a ketone, for example, acetone, or an ether, for example, tetrahydrofuran, an alkanol such as propan-2-ol, a hydrocarbon such as toluene, an ester such as ethyl acetate, a nitrile as acetonitrile, or a halogenated hydrocarbon such as dichloromethane or water, or an organic acid such as acetic acid; or a mixture of them. Conveniently, the source of the meso-tartrate ion is meso-tartaric acid. The meso-tartaric acid is preferably added as a solid or in solution, for example, in water or a lower alcohol such as methanol, ethanol or propan-2-ol, or a mixture of solvents. An alternative source of meso-tartrate ion is provided by a suitably soluble base salt of meso-tartaric acid, for example, ammonium meso-tartrate, or the meso-tartaric acid salt of an amine, eg, ethylamine or diethylamine . The concentration of the compound (I) is preferably in the scale of 2 to 25% by weight / volume, or more preferably on the scale of 5 to 20%. The concentration of the tartaric acid solutions is preferably in the range of 5 to 125% w / v. The reaction is usually carried out at room temperature, or at an elevated temperature, for example, at the reflux temperature of the solvent, although any convenient temperature that provides the required product can be used. Solvates, such as hydrates, of the Meso-Tartrate, are prepared in accordance with conventional procedures. Recovery of the required compound generally comprises crystallization from a suitable solvent or mixture of solvents, conveniently the reaction solvent, usually assisted by cooling. For example, Meso-Tartrate can be crystallized from a ketone such as acetone, or an ether such as tetrahydrofuran or water, or a mixture thereof. An improved yield of the salt can be obtained by evaporating all or part of the solvent, or by crystallization at elevated temperature, followed by controlled cooling, optionally in stages. Careful control of the precipitation temperature can be used to improve the reproducibility of the product form. Crystallization can also be initiated by seeding with Meso-Tartrate crystals, or a solvate thereof, but this is not essential. When the mono-tartrate salt comprises another monovalent salt ion, such as an alkali metal or ammonium cation, said ion is conveniently by reacting the mopo-tartrate salt with a solution of the selected monovalent salting ion, for example, a metal or ammonium ion. Alternatively, the compound (I) can be treated with a mono-tartrate salt of said monovalent salting ion. The compound (I) is prepared according to known procedures, such as those described in EP 0,306,228 WO94 / 05659. The descriptions of EP 0,306,228 and WO94 / 05659 are incorporated herein by reference. Meso-tartaric acid is a commercially available compound. When used herein, the term "Tdß onset" is generally determined by differential scanning calorimetry, and has a meaning generally understood in the art, as expressed, for example, in "Pharmaceutical Thermal Analysis, Techniques and Applications. ", Ford and Timmins, 1989, as" the temperature corresponding to the intersection of the pre-transition base line with the extrapolated salient edge of the transition ". When used herein with respect to certain compounds, the term "good flow properties" is suitably characterized by said compound having a Hausner ratio less than or equal to 1.5, especially less than or equal to 1.25. The term "Hausner's relationship" is a term accepted in the art.

When used herein, the term "prophylaxis of conditions associated with diabetes mellitus" includes the treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinemia, and gestational diabetes. Diabetes mellitus means diabetes mellitus type preference II. Conditions associated with diabetes include hyperglycemia and insulin resistance and obesity. Other conditions associated with diabetes include hypertension, cardiovascular disease, especially atherosclerosis, certain eating disorders, in particular the regulation of appetite and the ingestion of food in subjects suffering from disorders associated with under-feeding, such as anorexia nervosa, and disorders associated with overeating, such as obesity and bulimic anorexia. Other conditions associated with diabetes include polycystic ovary syndrome and steroid-induced insulin resistance. Complications of conditions associated with diabetes mellitus encompassed herein include kidney disease, especially kidney disease associated with the development of type II diabetes, including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and renal phase disease. terminal. As mentioned above, the compound of the invention has useful therapeutic properties: therefore, the present invention provides the Meso-Tartrate or a solvate thereof, for use as an active therapeutic substance. More particularly, the present invention provides Meso-Tartrate, or a solvate thereof, for use in the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof. The Meso-Tartrate or a solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the Meso-Tartrate, or a solvate thereof, are in general those described for the compound (I), in the publications mentioned above. Accordingly, the present invention also provides a pharmaceutical composition comprising the Meso-Tartrate, or a solvate thereof, and a pharmaceutically acceptable carrier therefor. The Meso-Tartrate or a solvate thereof is usually administered in unit dosage form. The active compound can be administered by any suitable route, but usually by the oral or parenteral routes. For such use, the compound will normally be used in the form of a pharmaceutical composition in association with a carrier, diluent and / or pharmaceutical excipient, although the exact form of the composition will naturally depend on the mode of administration.

The compositions are prepared by mixing, and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions. , suppositories and transdermal devices. Orally administrating compositions are preferred, in particular the oral compositions configured, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tableting agents, lubricants, disintegrators, colorants, flavors and wetting agents. The tablets can be coated according to methods well known in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrators include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable humectant agents include sodium lauryl sulfate. Solid oral compositions can be prepared by conventional methods of mixing, filling, tableting, or the like. Repeated mixing operations can be used to distribute the agent active in compositions that use large amounts of fillers. Said operations are, in fact, conventional in the art. Oral liquid prations may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Said liquid prations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavoring or coloring agents. For parenteral administration, unit dosage forms of fluid containing a compound of the present invention and a sterile vehicle are pred. The compound, depending on the vehicle and concentration, can be suspended or dissolved. Parenteral solutions are usually pred by dissolving the active compound in a vehicle, and sterilizing by filtration before filling in an ampoule or suitable container, and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and pH regulating agents, also dissolve in the vehicle. To improve stability, the composition can be frozen after filling in the bottle, and the water removed under vacuum. Parenteral suspensions are pred in substantially the same manner, except that the active compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound. As is common practice, the compositions will usually be accompanied by written or printed instructions for use in the medical treatment involved. As used herein, the term "pharmaceutically acceptable" encompasses compounds, compositions and ingredients for human and veterinary use; for example, the term "pharmaceutically acceptable salt" encompasses a veterinarily acceptable salt. The present invention further provides a method for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof, in a human or non-human mammal, which comprises administering an effective and non-toxic amount of Meso-Tartrate, or a solvate thereof, to a human or non-human mammal that needs it. Conveniently, the active ingredient can be administered as a pharmaceutical composition defined hereinbefore, and this forms a particular aspect of the present invention. In another aspect, the present invention provides the use of the Meso-Tartrate or a solvate thereof, in the manufacture of a medicament for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof. In the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, the Meso-Tartrate or a solvate thereof can be taken in amounts that provide the compound (I) in suitable doses, as described in EP 0,306,228, WO94 / 05659 or WO98 / 55122. No adverse toxicological effects are indicated in the treatments mentioned above for the compounds of the invention. The following examples illustrate the invention, but in no way limit it.

EXAMPLE 1 Meso-tartrate of 5-.4-r2- (N-Methyl-N- (2-pyridyl) amino) -β-β-phenyl-2,4-diol-2,4-dione A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) -toxy] benzyl] thiazolidino-2,4-dione (8.0 g) was stirred and heated to 50 ° C. and tetra h id rofu rano (160 ml). A solution of meso-tartaric acid (3.84 g) in water (20 ml) was added, and the mixture was stirred at 50 ° C for 15 minutes, filtered, and the clear filtrate was cooled to 21 ° C. The solvent was evaporated under reduced pressure at 40 ° C, acetone (40 ml) was added, and the mixture was stirred at 21 ° C to give a white suspension. The product was collected by filtration, washed with acetone and dried under vacuum, to give 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino meso-tartrate. -2,4-dione (10.6 g) as a white crystalline solid.

EXAMPLE 2 Meso-tartrate of 5-r4-r2-fN-methyl-N- (2-plrldipamno) ethoxybenzenediazolid-2,4-dlone A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] -bepcyl] thiazolidino-2,4-dione (3.0 g, 8.4 mmol), acetone (40 ml) and tetrahydrofuran (5 ml), was heated to reflux for 2.5 hours with stirring. To this was added a solution of meso-tartaric acid monohydrate (1.41 g, 8.4 mmol) in water (2 ml). The reaction mixture was heated to reflux with stirring for 2.5 hours, then cooled to 21 ° C, and stirred for 16 hours at 21 ° C. The white solid was collected by filtration, washed with acetone (40 ml), and then dried under reduced pressure for 2.5 hours at 21 ° C, to give meso-tartrate of 5- [4- [2- (N -methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino-2,4-dione (3.25 g) as a white crystalline solid.

EXAMPLE 3 Meso-tartrate of 5-.4-.2- (N-metll-N- (2-pyridyl) amyl) ethoxy-1-benzyl-3-alanzol-2,4-diopa A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) -ethoxy] benzyl] thiazolidino-2,4-dione (10.0 g, 28 mmol), acetone (120 ml) and tetrahydrofuran (15 ml), was heated to reflux for 50 minutes with stirring. To this was added a solution of meso-tartaric acid monohydrate (4.7 g, 28 mmol) in water (60 ml). The reaction mixture was heated to reflux with stirring for 1 hour, then cooled to 21 ° C, and stirred for 16 hours at 21 ° C. The white solid was collected by filtration, washed with acetone (50 ml), and then dried under reduced pressure for 3 hours at 21 ° C, to give meso-tartrate of 5- [4- [2- (N -methyl-N- (2-pyridyl) amino) -toxy] benzyl] thiazolidino-2,4-dione (11.7 g) as a white crystalline solid.

Characteristic data recorded for the product of Example 1 The infrared absorption spectrum of a mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at a resolution of 2 cm "1 (Figure 1). at intervals of 1 cm "1. Bands were observed at 3405, 1738, 1694, 1629, 1556, 1537, 1505, 1459, 1436, 1418, 1330, 1268, 1249, 1223, 1182, 1167, 1143, 1104, 1074, 1057, 1033, 1000, 949, 916, 887, 853, 818, 771, 717, 668, 619, 568, 528, 515 cm "1. The infrared spectrum of the solid product was recorded using a Perkin-Elmer Spectrum One FT-IR spectrometer with a universal ATR accessory, bands were observed at 3407, 2937, 2750, 1739, 1693, 1628, 1555, 1535, 1504, 1476, 1459, 1412, 1388, 1358, 1330, 1261, 1248, 1222, 1182, 1167, 1143, 1101, 1074, 1056, 1033, 999, 948, 916, 887, 853, 818, 771, 744, 717, 667 cm "1. The Raman spectrum of the product (Figure 2) was recorded with the sample in an NMR tube using a Nicolet 960 E.S.P. spectrometer. FT-Raman, at a resolution of 4 cm * 1 with excitation from a laser beam Nd: V04 (1064 nm) with an energy output of 400 mW. Bands were observed at 3101, 3059, 2952, 2922, 2877, 1739, 1604, 1544, 1458, 1438, 1394, 1331, 1270, 1222, 1203, 979, 887, 827, 739, 668, 638, 605, 472, 344 cm "1. The X-ray powder diffractogram pattern of the product was recorded (figure 3) using the following acquisition conditions: tube anode: Cu, generator voltage: 40 kV, generator current: 40 mA, angle Start: 2.0 ° 2T, final angle: 35.0 ° 2T, step size: 0.02 ° 2T, time per step: 2.5 seconds The XRPD angles and characteristic relative intensities are recorded in Table 1.

TABLE 1 10 15 20 The solid state NMR spectrum of the product was recorded (figure 4) on a Bruker AMX360 instrument operating at 90.55 MHz. The solid was packed in a 4 mm zirconia MAS rotor, adapted with a Kel-F cap, and spinning rotor at approximately 1.0 kHz. The 13C MAS spectrum was acquired by cross-polarization from coupled Hartmann-Hahn protons (CP 3ms contact time, 15 s repetition time), and the protons were decoupled during acquisition using a mixed phase modulated sequence of two pulses (TPPM). The chemical changes were referenced externally to the glycine carboxylate signal at 176.4 ppm relative to TMS, and were observed at 183.0, 177.2, 175.4, 173.0, 160.0, 159.0, 151.8, 144.2, 138.9, 134.3, 130.8, 128.2, 123.6, 113.7, 112.8, 77.4, 76.7, 74.5, 55.5, 53.5, 50.0, 42.4, 36.6, 33.8 ppm.

Properties of Meso-Tartrate Stability of the Meso-Tartrate in the solid state, recorded for the product of Example 1 The stability of the drug substance in the solid state was determined, storing approximately 1.0 g of the material in a glass flask ai) 40 ° C / 75% humidity relative (RH), open exposure for 1 month, and b) at 50 ° C, closed, for 1 month. In both cases, the material was tested by CLAR for degradation products and final content. a) 40 ° C / 75% RH: no significant degradation was observed (HPLC test, 97% initial). b) 50 ° C: no significant degradation was observed (HPLC test, initial 98%).

Meso-Tartrate Melting Point The melting point of Meso-Tartrate was determined according to the method described in the United States Pharmacopoeia, USP 23, 1995, < 741 > "Melting range or temperature, Procedure for Class", using a Buchi 545 melting point instrument. Product of Example 1, melting point: 149 ° C. Product of example 2, melting point: 153 ° C. Product of example 3, melting point: 155 ° C.

Tjß ¡n¡? O of the Meso-Tartrate The Tdβ onset of the drug substance was determined by differential scanning calorimetry, using a Perkin-Elmer DSC apparatus. Product of Example 1, Tdß onset (10 ° C / minute, closed crucible): 146 ° C, product of Example 2, Tdß onset (10 ° C / minute, open crucible): 153 ° C, product of Example 3, Tdβ start (10 ° C / minute, open crucible): 154 ° C.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound, 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) -ethoxy] benzyl] thiazolidino-2,4-dione, Meso-Tartrate salt, or a solvate thereof.

2. The compound according to claim 1, further characterized in that it provides: (i) an infrared spectrum substantially in accordance with Figure 1; (ii) a Raman spectrum substantially in accordance with Figure 2; (iii) an X-ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3; or (iv) a solid state 13C NMR spectrum substantially in accordance with Figure 4. The compound according to claim 1, further characterized by providing two or more of: (i) an infrared spectrum substantially in accordance with figure 1; and (ii) a Raman spectrum substantially in accordance with Figure 2; and (iii) an X-ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3; and (iv) a 13C NMR spectrum in the solid state substantially in accordance with Figure 4. 4. The compound according to any of claims 1 to 3, further characterized in that it is in purified form. 5.- The compound in accordance with any of the claims 1 to 3, further characterized in that it is in a solid dosage form. 6. The compound according to any of claims 1 to 3, further characterized in that it is in a form that is capable of pharmaceutical processing in a manufacturing process that requires or generates heat, for example, milling; for example, heat drying, especially fluid bed drying or spray drying; for example, thermal fusion processing; for example, heat sterilization, such as boiling in an autoclave. 7. The compound according to any of claims 1 to 3, further characterized in that it is in a form that has been processed in a manufacturing process that requires or generates heat, for example, in a milled form; for example, in a heat-dried form, especially a dried form of fluidized bed or a spray-dried form; for example, in a form that has been processed by thermal fusion; for example, in a form that has been sterilized with heat, such as by boiling in an autoclave. 8. The compound according to any of claims 1 to 3, further characterized in that it is in a pharmaceutically acceptable form having good flow properties. 9. A process for preparing the Meso-Tartrate, or a solvate thereof, characterized in that 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) -toxy] benzyl] thiazolidino-2 , 4-dione (compound (I)), or a salt of the it is reacted with a meso-tartrate ion source and then, if required, a resultant Meso-Tartrate solvate is prepared; and the Meso-Tartrate or a solvate thereof, is recovered. 10. A pharmaceutical composition, characterized in that it comprises meso-tartrate of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] -benzyl] thiazolidino-2,4-dione, or a solvate thereof, and a pharmaceutically acceptable vehicle therefor. 11. A compound, 5- [4- [2- (N-methyl-N- (2-pyridyl) amylo) ethoxy] -benzyl] thiazolidino-2,4-dione, Meso-Tartrate or a solvate thereof, for use as an active therapeutic substance. 12. The use of Meso-Tartrate of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione or a solvate thereof , in the manufacture of a medicament for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus, and certain complications thereof.